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Peras M, Bilić E, Mareković I. Recent Insights into the Pathogenesis, Diagnostics, and Treatment of BK Virus Infections in Children After Hematopoietic Stem Cell Transplantation. Pathogens 2025; 14:236. [PMID: 40137721 PMCID: PMC11944647 DOI: 10.3390/pathogens14030236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/29/2025] Open
Abstract
BK polyomavirus (BKPyV) is a pathogen responsible for infectious complications in hematopoietic stem cell transplant (HSCT) recipients. This review aims to give an insight into recent data about the structure and genomic organization, epidemiology, clinical manifestations, diagnosis, and current treatment options of BKPyV infections in children after HSCT. News regarding viral replication and pathogenesis include the generation of miRNA, new mechanisms of viral shedding by releasing infectious particles via extracellular vesicles, and human bladder microvascular endothelial cells probably acting as viral reservoirs enabling low-level viral replication and persistence. In studies conducted over the past five years, BKPyV hemorrhagic cystitis (BKPyV-HC) has a prevalence rate of 4 to 27% in children undergoing HSCT. Diagnostics still has unsolved dilemmas like whole blood or plasma samples as well as the standardization of molecular methods to allow for reporting in international units. In terms of treatment, new approaches have been used in the past five years, including the use of mesenchymal stem cells (MSCs), virus-specific T cells (VSTs), and recombinant human keratinocyte growth factor (rH-KGF), although the efficacy of some of these treatments has only been documented in isolated studies. This complication continues to pose a substantial clinical challenge, characterized by an absence of effective preventive and therapeutic measures.
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Affiliation(s)
- Mislav Peras
- Department of Microbiology, Institute of Public Health Zagreb County, 10 000 Zagreb, Croatia
| | - Ernest Bilić
- Department of Pediatrics, University Hospital Centre Zagreb, 10 000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
| | - Ivana Mareković
- School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
- Department of Clinical Microbiology, Infection and Prevention Control, 10 000 Zagreb, Croatia
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2
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Lorentzen EM, Henriksen S, Rinaldo CH. Massive entry of BK Polyomavirus induces transient cytoplasmic vacuolization of human renal proximal tubule epithelial cells. PLoS Pathog 2024; 20:e1012681. [PMID: 39570904 PMCID: PMC11581322 DOI: 10.1371/journal.ppat.1012681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/20/2024] [Indexed: 11/24/2024] Open
Abstract
BK polyomavirus (BKPyV) is a ubiquitous human virus that establishes a persistent infection in renal tubular epithelial cells and mainly causes disease in kidney transplant recipients. The closely related simian polyomavirus SV40 is known to cause cytoplasmic vacuolization in simian kidney cells, possibly increasing progeny release and cell death. This study aimed to determine whether BKPyV causes cytoplasmic vacuolization in primary human renal proximal tubule epithelial cells (RPTECs) and to investigate its potential role in the replication cycle. Using a large infectious dose (MOI 100-1000), a fraction of RPTECs (10-72%) showed early-wave vacuolization from 3 hours post-infection (hpi), which was mainly reversed by 36 hpi. Independent of the infectious dose, late-wave vacuolization occurred around the timepoint of progeny release. BKPyV receptor binding and internalization were required, as neuraminidase pretreatment and preincubation or treatment with a BKPyV-specific neutralizing antibody prevented early or late-occurring vacuolization. Microscopy revealed that the vacuoles were enlarged acidic endo-/lysosomal structures (dextran, EEA1, Rab5, Rab7, LAMP1, and/or Lysoview positive) that contained membrane-bound BKPyV. Time-lapse microscopy and quantitative PCR revealed that cell death and progeny release preceded late-wave vacuolization, mainly affecting cells directly neighboring the lysed cells. Thus, vacuolization had little impact on cell death or progeny release. Addition of the V-ATPase inhibitor Bafilomycin A1 at 0 hpi blocked vacuolization and BKPyV replication, but addition at 2 hpi only blocked vacuolization, suggesting that continuous endosomal acidification and maturation is needed for vacuole formation, but not for BKPyV replication. Our study shows that a massive uptake of BKPyV in RPTECs induces transient enlargement of endo-/lysosomes and is an early event in the viral replication cycle. Vacuolization gives no clear benefit for BKPyV and is possibly the result of a transiently overloaded endocytic pathway. Focal vacuolization around lysed cells suggests that the spread of BKPyV is preferably local.
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Affiliation(s)
- Elias Myrvoll Lorentzen
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
- Metabolic and Renal Research Group, Department of Clinical Medicine, UiT—The Arctic University of Norway, Tromsø, Norway
| | - Stian Henriksen
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
- Metabolic and Renal Research Group, Department of Clinical Medicine, UiT—The Arctic University of Norway, Tromsø, Norway
| | - Christine Hanssen Rinaldo
- Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway
- Metabolic and Renal Research Group, Department of Clinical Medicine, UiT—The Arctic University of Norway, Tromsø, Norway
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Fan J, Zheng S, Wang M, Yuan X. The critical roles of caveolin-1 in lung diseases. Front Pharmacol 2024; 15:1417834. [PMID: 39380904 PMCID: PMC11458383 DOI: 10.3389/fphar.2024.1417834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 09/09/2024] [Indexed: 10/10/2024] Open
Abstract
Caveolin-1 (Cav-1), a structural and functional component in the caveolae, plays a critical role in transcytosis, endocytosis, and signal transduction. Cav-1 has been implicated in the mediation of cellular processes by interacting with a variety of signaling molecules. Cav-1 is widely expressed in the endothelial cells, smooth muscle cells, and fibroblasts in the various organs, including the lungs. The Cav-1-mediated internalization and regulation of signaling molecules participate in the physiological and pathological processes. Particularly, the MAPK, NF-κB, TGFβ/Smad, and eNOS/NO signaling pathways have been involved in the regulatory effects of Cav-1 in lung diseases. The important effects of Cav-1 on the lungs indicate that Cav-1 can be a potential target for the treatment of lung diseases. A Cav-1 scaffolding domain peptide CSP7 targeting Cav-1 has been developed. In this article, we mainly discuss the structure of Cav-1 and its critical roles in lung diseases, such as pneumonia, acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, pulmonary fibrosis, and lung cancer.
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Affiliation(s)
| | | | | | - Xiaoliang Yuan
- Department of Respiratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
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Sato N, Shiraki A, Mori KP, Sakai K, Takemura Y, Yanagita M, Imoto S, Tanabe K, Shiraki K. Preemptive intravenous human immunoglobulin G suppresses BK polyomavirus replication and spread of infection in vitro. Am J Transplant 2024; 24:765-773. [PMID: 37977231 DOI: 10.1016/j.ajt.2023.11.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 11/19/2023]
Abstract
BK polyomavirus (BKPyV) infection causes various diseases in immunocompromised patients. Cells from human lung and kidney were infected with BKPyV and treated with commercially available intravenous immunoglobulin G (IVIG). Its effects on BKPyV replication and spread of infection were investigated, focusing on administration timing. IVIG treatment 3 hours after infection suppressed BKPyV replication assessed by real-time PCR and expression of the viral capsid protein 1 and large T-antigen. IVIG effectively reduced the number of BKPyV-infected cells 2 weeks after infection in an antibody titer-dependent manner. Virus release in the culture supernatants was not influenced by IVIG treatment 6-80 hours and 3-9 days after infection. Collectively, IVIG did not affect viral release from infected cells but inhibited the spread of infection by neutralizing the released virus and blocking the new infected cell formation, indicating greater efficacy in early localized infection. BKPyV replication resumed in IVIG-treated cultures at 7 days after IVIG removal. Early prophylactic administration of IVIG is expected to reduce the growth and spread of BKPyV infection, resulting in the reduction of infected cell lesions and prevention of BKPyV-associated diseases.
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Affiliation(s)
- Noriaki Sato
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsuko Shiraki
- Department of Anesthesiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keita P Mori
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Nephrology and Dialysis, Medical Research Institute Kitano Hospital, PIIF Tazuke-Kofukai, Osaka, Japan
| | - Kaoru Sakai
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kazunari Tanabe
- Organ Transplant Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Kimiyasu Shiraki
- Faculty of Nursing, Senri Kinran University, Suita, Osaka, Japan.
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Wang Y, Fang Y, Yan Z, Xia R, Zeng W, Deng W, Xu J, Feng X, Peng J, Miao Y. Fatal BK polyomavirus-associated pneumonia: report of two cases with literature review. BMC Infect Dis 2023; 23:592. [PMID: 37697264 PMCID: PMC10494412 DOI: 10.1186/s12879-023-08577-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 08/31/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND In immunocompromised populations, such as patients with AIDS and recipients of solid organ and hematopoietic stem cell transplants, BK polyomavirus (BKPyV) can reactivate and cause several diseases, which can lead to death in their severe forms. Unlike hemorrhagic cystitis and BKPyV-associated nephropathy, BKPyV-associated pneumonia is rare, with only seven known cases worldwide. However, the disease can rapidly progress with extremely high mortality. CASE PRESENTATION Herein, we report two cases of BKPyV-associated pneumonia following hematopoietic stem cell transplantation. Both patients had consistent infectious pneumonia and graft-versus-host disease after stem cell transplantation. The diagnosis of BKPyV-associated pneumonia was confirmed by metagenomic next-generation sequencing and polymerase chain reaction after the sudden worsening of the pulmonary infection signs and symptoms concomitant with renal dysfunction and systemic immune weakening. Both patients eventually died of systemic multi-organ failure caused by severe pneumonia. CONCLUSIONS Currently, BKPyV reactivation cannot be effectively prevented. Immunocompromised patients must actively manage their primary lung infections, pay close attention to pulmonary signs and imaging changes. Especially during and after steroid pulse therapy or immunosuppressive therapy for graft versus host diseases, BKPyV load in blood/urine needs to be regularly measured, and the immunosuppressive intensity should be adjusted properly after the BKPyV reactivation diagnosis. Clinical trials of new antiviral drugs and therapies for BKPyV are urgently needed.
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Affiliation(s)
- Yuchen Wang
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Yiling Fang
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Ziyan Yan
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Renfei Xia
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Wenli Zeng
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Wenfeng Deng
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Jian Xu
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China
| | - Xiaoqin Feng
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Jie Peng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
| | - Yun Miao
- Department of Transplantation, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China.
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Juin SK, Ouseph R, Gondim DD, Jala VR, Sen U. Diabetic Nephropathy and Gaseous Modulators. Antioxidants (Basel) 2023; 12:antiox12051088. [PMID: 37237955 DOI: 10.3390/antiox12051088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/05/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.
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Affiliation(s)
- Subir Kumar Juin
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Rosemary Ouseph
- Division of Nephrology & Hypertension, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Dibson Dibe Gondim
- Department of Pathology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Venkatakrishna Rao Jala
- Department of Microbiology & Immunology, Brown Cancer Center, Center for Microbiomics, Inflammation and Pathogenicity, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Yang F, Chen X, Zhang H, Zhao GD, Yang H, Qiu J, Meng S, Wu P, Tao L, Wang Q, Huang G. Single-Cell Transcriptome Identifies the Renal Cell Type Tropism of Human BK Polyomavirus. Int J Mol Sci 2023; 24:ijms24021330. [PMID: 36674845 PMCID: PMC9861348 DOI: 10.3390/ijms24021330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/05/2023] [Accepted: 01/09/2023] [Indexed: 01/12/2023] Open
Abstract
BK polyomavirus (BKPyV) infection is the main factor affecting the prognosis of kidney transplant recipients, as no antiviral agent is yet available. A better understanding of the renal-cell-type tropism of BKPyV can serve to develop new treatment strategies. In this study, the single-cell transcriptomic analysis demonstrated that the ranking of BKPyV tropism for the kidney was proximal tubule cells (PT), collecting duct cells (CD), and glomerular endothelial cells (GEC) according to the signature of renal cell type and immune microenvironment. In normal kidneys, we found that BKPyV infection-related transcription factors P65 and CEBPB were PT-specific transcription factors, and PT showed higher glycolysis/gluconeogenesis activities than CD and GEC. Furthermore, in the BKPyV-infected kidneys, the percentage of late viral transcripts in PT was significantly higher than in CD and GEC. In addition, PT had the smallest cell-cell interactions with immune cells compared to CD and GEC in both normal and BKPyV-infected kidneys. Subsequently, we indirectly demonstrated the ranking of BKPyV tropism via the clinical observation of sequential biopsies. Together, our results provided in-depth insights into the renal cell-type tropism of BKPyV in vivo at single-cell resolution and proposed a novel antiviral target.
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Affiliation(s)
- Feng Yang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-Sen University, Guangzhou 510080, China
- Guangdong Provincial International Cooperation Based of Science and Technology (Organ Transplantation), Sun Yat-Sen University, Guangzhou 510080, China
| | - Xutao Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Hui Zhang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Guo-Dong Zhao
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Huifei Yang
- Department of Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510080, China
| | - Jiang Qiu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
| | - Siyan Meng
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Penghan Wu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Liang Tao
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qin Wang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
- Correspondence: (Q.W.); (G.H.)
| | - Gang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Sun Yat-Sen University, Guangzhou 510080, China
- Guangdong Provincial International Cooperation Based of Science and Technology (Organ Transplantation), Sun Yat-Sen University, Guangzhou 510080, China
- Correspondence: (Q.W.); (G.H.)
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8
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Virus-Associated Nephropathies: A Narrative Review. Int J Mol Sci 2022; 23:ijms231912014. [PMID: 36233315 PMCID: PMC9569621 DOI: 10.3390/ijms231912014] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/23/2022] [Accepted: 10/06/2022] [Indexed: 12/13/2022] Open
Abstract
While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient's underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies.
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9
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BK Virus Infection and BK-Virus-Associated Nephropathy in Renal Transplant Recipients. Genes (Basel) 2022; 13:genes13071290. [PMID: 35886073 PMCID: PMC9323957 DOI: 10.3390/genes13071290] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/18/2022] [Accepted: 07/20/2022] [Indexed: 01/27/2023] Open
Abstract
Poliomavirus BK virus (BKV) is highly infective, causing asymptomatic infections during childhood. After the initial infection, a stable state of latent infection is recognized in kidney tubular cells and the uroepithelium with negligible clinical consequences. BKV is an important risk factor for BKV-associated diseases, and, in particular, for BKV-associated nephropathy (BKVN) in renal transplanted recipients (RTRs). BKVN affects up to 10% of renal transplanted recipients, and results in graft loss in up to 50% of those affected. Unfortunately, treatments for BK virus infection are restricted, and there is no efficient prophylaxis. In addition, consequent immunosuppressive therapy reduction contributes to immune rejection. Increasing surveillance and early diagnosis based upon easy and rapid analyses are resulting in more beneficial outcomes. In this report, the current status and perspectives in the diagnosis and treatment of BKV in RTRs are reviewed.
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Luo S, Yang M, Zhao H, Han Y, Jiang N, Yang J, Chen W, Li C, Liu Y, Zhao C, Sun L. Caveolin-1 Regulates Cellular Metabolism: A Potential Therapeutic Target in Kidney Disease. Front Pharmacol 2021; 12:768100. [PMID: 34955837 PMCID: PMC8703113 DOI: 10.3389/fphar.2021.768100] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/08/2021] [Indexed: 01/09/2023] Open
Abstract
The kidney is an energy-consuming organ, and cellular metabolism plays an indispensable role in kidney-related diseases. Caveolin-1 (Cav-1), a multifunctional membrane protein, is the main component of caveolae on the plasma membrane. Caveolae are represented by tiny invaginations that are abundant on the plasma membrane and that serve as a platform to regulate cellular endocytosis, stress responses, and signal transduction. However, caveolae have received increasing attention as a metabolic platform that mediates the endocytosis of albumin, cholesterol, and glucose, participates in cellular metabolic reprogramming and is involved in the progression of kidney disease. It is worth noting that caveolae mainly depend on Cav-1 to perform the abovementioned cellular functions. Furthermore, the mechanism by which Cav-1 regulates cellular metabolism and participates in the pathophysiology of kidney diseases has not been completely elucidated. In this review, we introduce the structure and function of Cav-1 and its functions in regulating cellular metabolism, autophagy, and oxidative stress, focusing on the relationship between Cav-1 in cellular metabolism and kidney disease; in addition, Cav-1 that serves as a potential therapeutic target for treatment of kidney disease is also described.
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Affiliation(s)
- Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Ming Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Hao Zhao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Yachun Han
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Na Jiang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Chenrui Li
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Yan Liu
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Chanyue Zhao
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
| | - Lin Sun
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China
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11
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Orlowski S, Mourad JJ, Gallo A, Bruckert E. Coronaviruses, cholesterol and statins: Involvement and application for Covid-19. Biochimie 2021; 189:51-64. [PMID: 34153377 PMCID: PMC8213520 DOI: 10.1016/j.biochi.2021.06.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/01/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022]
Abstract
The infectious power of coronaviruses is dependent on cholesterol present in the membranes of their target cells. Indeed, the virus enters the infected cell either by fusion or by endocytosis, in both cases involving cholesterol-enriched membrane microdomains. These membrane domains can be disorganized in-vitro by various cholesterol-altering agents, including statins that inhibit cell cholesterol biosynthesis. As a consequence, numerous cell physiology processes, such as signaling cascades, can be compromised. Also, some examples of anti-bacterial and anti-viral effects of statins have been observed for infectious agents known to be cholesterol dependent. In-vivo, besides their widely-reported hypocholesterolemic effect, statins display various pleiotropic effects mediated, at least partially, by perturbation of membrane microdomains as a consequence of the alteration of endogenous cholesterol synthesis. It should thus be worth considering a high, but clinically well-tolerated, dose of statin to treat Covid-19 patients, in the early phase of infection, to inhibit virus entry into the target cells, in order to control the viral charge and hence avoid severe clinical complications. Based on its efficacy and favorable biodisposition, an option would be considering Atorvastatin, but randomized controlled clinical trials are required to test this hypothesis. This new therapeutic proposal takes benefit from being a drug repurposing, applied to a widely-used drug presenting a high efficiency-to-toxicity ratio. Additionally, this therapeutic strategy avoids any risk of drug resistance by viral mutation since it is host-targeted. Noteworthy, the same pharmacological approach could also be proposed to address different animal coronavirus endemic infections that are responsible for heavy economic losses.
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Affiliation(s)
- Stéphane Orlowski
- Institute for Integrative Biology of the Cell (I2BC), CNRS UMR 9198, and CEA / DRF / Institut des Sciences du Vivant Frédéric-Joliot / SB2SM, and Université Paris-Saclay, 91191, Gif-sur-Yvette, Cedex, France.
| | - Jean-Jacques Mourad
- Department of Internal Medicine and ESH Excellence Centre, Groupe Hospitalier Paris Saint-Joseph, Paris, France.
| | - Antonio Gallo
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
| | - Eric Bruckert
- Department of Endocrinology and Prevention of Cardiovascular Diseases, Institute of Cardiometabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
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12
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Arpali E, Sunnetcioglu E, Demir E, Saglam A, Ozluk Y, Velioglu A, Yelken B, Baydar DE, Turkmen A, Oguz FS. Significance of caveolin-1 immunohistochemical staining differences in biopsy samples from kidney recipients with BK virus viremia. Transpl Infect Dis 2021; 23:e13605. [PMID: 33749103 DOI: 10.1111/tid.13605] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/08/2021] [Accepted: 03/14/2021] [Indexed: 12/12/2022]
Abstract
BK virus infections which usually remains asymptomatic in healthy adults may have different clinical manifestations in immunocompromised patient population. BK virus reactivation can cause BK virus nephropathy in 8% of kidney transplant patients and graft loss may be seen if not treated. Clathrin or Caveolar system is known to be required for the transport of many viruses from Polyomaviruses family including BK viruses. In this study, kidney transplant patients with BK virus viremia were divided into two groups according to the BK virus nephropathy found in kidney biopsy (Group I: Viremia+, Nephropathy+ / Group II: Viremia+, Nephropathy-). Kidney biopsies were examined with immunohistochemical staining to determine the distribution and density of the Caveolin-1 and Clathrin molecules. Immunohistochemical staining of the 31 pathologic specimens with anti-caveolin-1 immunoglobulin revealed statistically significant difference between group-I and group-II. The number of the specimens stained with anti-caveolin-1 was less in group I. On the other hand, we did not find any difference between the groups regarding the anti-clathrin immunochemical analysis. According to these findings, caveolin-1 expression differences in kidney transplant patients may be important in disease progression.
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Affiliation(s)
- Emre Arpali
- Department of Medical Biology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Ecem Sunnetcioglu
- Department of Pathology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Erol Demir
- Division of Nephrology, Department of Internal Medicine, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Arzu Saglam
- Department of Pathology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Arzu Velioglu
- Division of Nephrology, Department of Internal Medicine, School of Medicine, Marmara University, Istanbul, Turkey
| | - Berna Yelken
- Department of Organ Transplantation, Koç University Hospital, İstanbul, Turkey
| | - Dilek E Baydar
- Department of Pathology, School of Medicine, Koç University, İstanbul, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Department of Internal Medicine, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
| | - Fatma S Oguz
- Department of Medical Biology, Istanbul School of Medicine, Istanbul University, Istanbul, Turkey
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13
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Mayberry CL, Bond AC, Wilczek MP, Mehmood K, Maginnis MS. Sending mixed signals: polyomavirus entry and trafficking. Curr Opin Virol 2021; 47:95-105. [PMID: 33690104 DOI: 10.1016/j.coviro.2021.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/14/2021] [Accepted: 02/15/2021] [Indexed: 12/31/2022]
Abstract
Polyomaviruses are mostly non-pathogenic, yet some can cause human disease especially under conditions of immunosuppression, including JC, BK, and Merkel cell polyomaviruses. Direct interactions between viruses and the host early during infection dictate the outcome of disease, many of which remain enigmatic. However, significant work in recent years has contributed to our understanding of how this virus family establishes an infection, largely due to advances made for animal polyomaviruses murine and SV40. Here we summarize the major findings that have contributed to our understanding of polyomavirus entry, trafficking, disassembly, signaling, and immune evasion during the infectious process and highlight major unknowns in these processes that are open areas of study.
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Affiliation(s)
- Colleen L Mayberry
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA
| | - Avery Cs Bond
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA
| | - Michael P Wilczek
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA
| | - Kashif Mehmood
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA
| | - Melissa S Maginnis
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME, USA; Graduate School in Biomedical Sciences and Engineering, The University of Maine, Orono, ME, USA.
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14
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Non-permissive human conventional CD1c+ dendritic cells enable trans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization. PLoS Pathog 2021; 17:e1009042. [PMID: 33592065 PMCID: PMC7886149 DOI: 10.1371/journal.ppat.1009042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 01/04/2021] [Indexed: 12/31/2022] Open
Abstract
The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney transplant recipients (KTRs) and hematopoietic stem cell transplant recipients. In KTRs, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDCs) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived dendritic cells (MDDCs), an in vitro model for mDCs, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDCs. Endocytosed virions were efficiently transmitted to permissive cells and protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDCs from the blood and kidney parenchyma behaved similarly to MDDCs thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading. Dr Sylvia Gardner first discovered the BK polyomavirus (BKPyV) in the urine of a kidney-transplant recipient in 1970. In the 1990’s, the widespread use of potent immunosuppressive drugs such as tacrolimus, sirolimus or mycophenolate mofetil led to the emergence of BKPyV nephropathy. Recently, various studies reported a specific influx of myeloid dendritic cells (mDCs) in the renal tissue of kidney-transplant patients who were diagnosed with a BKPyV nephropathy. MDCs are immune cells both residing in tissues and migrating to other organs or compartments like the blood when changes in their environment occur. Their main functions are the detection of danger signals such as pathogens or tumors and the processing of antigens to prime naïve specific effectors of the adaptive immune response. Although anti-BKPyV cellular immune responses have been investigated in post-transplant recipients as well as healthy individuals, supporting an active role of mDCs little is known about how mDCs and BKPyV interact with each other. Our study provides the basis to understand the role played by mDCs in virus capture through an unprecedented endocytic mechanism and possibly in viral protection from neutralization by specific antibodies. Moreover, we showed that mDCs are unable to sense BKPyV particles or BKPyV-infected dying cells as a danger signal, supporting the view that other DC subsets might act as the true antigen presenting cells that promote the adaptive immune response against BKPyV infection.
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15
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Ripa I, Andreu S, López-Guerrero JA, Bello-Morales R. Membrane Rafts: Portals for Viral Entry. Front Microbiol 2021; 12:631274. [PMID: 33613502 PMCID: PMC7890030 DOI: 10.3389/fmicb.2021.631274] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/14/2021] [Indexed: 02/02/2023] Open
Abstract
Membrane rafts are dynamic, small (10-200 nm) domains enriched with cholesterol and sphingolipids that compartmentalize cellular processes. Rafts participate in roles essential to the lifecycle of different viral families including virus entry, assembly and/or budding events. Rafts seem to participate in virus attachment and recruitment to the cell surface, as well as the endocytic and non-endocytic mechanisms some viruses use to enter host cells. In this review, we will introduce the specific role of rafts in viral entry and define cellular factors implied in the choice of one entry pathway over the others. Finally, we will summarize the most relevant information about raft participation in the entry process of enveloped and non-enveloped viruses.
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Affiliation(s)
- Inés Ripa
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
| | - Sabina Andreu
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
| | - José Antonio López-Guerrero
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
| | - Raquel Bello-Morales
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
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16
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Mayberry CL, Maginnis MS. Taking the Scenic Route: Polyomaviruses Utilize Multiple Pathways to Reach the Same Destination. Viruses 2020; 12:v12101168. [PMID: 33076363 PMCID: PMC7602598 DOI: 10.3390/v12101168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/08/2020] [Accepted: 10/09/2020] [Indexed: 01/02/2023] Open
Abstract
Members of the Polyomaviridae family differ in their host range, pathogenesis, and disease severity. To date, some of the most studied polyomaviruses include human JC, BK, and Merkel cell polyomavirus and non-human subspecies murine and simian virus 40 (SV40) polyomavirus. Although dichotomies in host range and pathogenesis exist, overlapping features of the infectious cycle illuminate the similarities within this virus family. Of particular interest to human health, JC, BK, and Merkel cell polyomavirus have all been linked to critical, often fatal, illnesses, emphasizing the importance of understanding the underlying viral infections that result in the onset of these diseases. As there are significant overlaps in the capacity of polyomaviruses to cause disease in their respective hosts, recent advancements in characterizing the infectious life cycle of non-human murine and SV40 polyomaviruses are key to understanding diseases caused by their human counterparts. This review focuses on the molecular mechanisms by which different polyomaviruses hijack cellular processes to attach to host cells, internalize, traffic within the cytoplasm, and disassemble within the endoplasmic reticulum (ER), prior to delivery to the nucleus for viral replication. Unraveling the fundamental processes that facilitate polyomavirus infection provides deeper insight into the conserved mechanisms of the infectious process shared within this virus family, while also highlighting critical unique viral features.
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Affiliation(s)
- Colleen L. Mayberry
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA;
| | - Melissa S. Maginnis
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA;
- Graduate School in Biomedical Sciences and Engineering, The University of Maine, Orono, ME 04469, USA
- Correspondence:
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17
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Dobson SJ, Mankouri J, Whitehouse A. Identification of potassium and calcium channel inhibitors as modulators of polyomavirus endosomal trafficking. Antiviral Res 2020; 179:104819. [PMID: 32389733 PMCID: PMC7205714 DOI: 10.1016/j.antiviral.2020.104819] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/02/2020] [Accepted: 05/04/2020] [Indexed: 12/12/2022]
Abstract
During virus entry, members of the Polyomaviridae transit the endolysosomal network en route to the endoplasmic reticulum (ER), from which degraded capsids escape into the cytoplasm and enter the nucleus. Emerging evidence suggests that viruses require both endosomal acidification and the correct ionic balance of K+ and Ca2+ ions in endosomes for correct virus trafficking and genome release. Here, using two polyomaviruses with different capsid architectures, namely Simian virus 40 (SV40) and Merkel cell polyomavirus (MCPyV), we describe methods to rapidly quantify virus infection using IncuCyte ZOOM imaging analysis, and use this system to investigate the role of both K+ and Ca2+ channels during the early stages of virus entry. Using broad spectrum blockers of both K+ and Ca2+ channels to specifically target host cell ion channel functionality, we show that MCPyV, but not SV40 can be inhibited by K+ channel modulators, whilst both viruses are restricted by the broad spectrum Ca2+ channel inhibitor verapamil. Using a panel of more specific Ca2+ blockers, we show that both MCPyV and SV40 are dependent on the activity of two-pore Ca2+ channels (TPCs), as the TPC-specific blocker tetrandrine prevented capsid disassembly and nuclear transport required for virus entry. We therefore reveal a novel target to restrict the entry of polyomaviruses, which given the known role of TPCs during endolysosomal-ER fusion, is likely to be applicable to other viruses that transit this pathway.
We describe novel high-throughput assays to study SV40 and MCPyV infection. MCPyV, but not SV40, is sensitive to K+ channel inhibition. Verapamil inhibits MCPyV and SV40 infection. Tetrandrine is a potent inhibitor of MCPyV and SV40 infection. Two-pore channel 1/2 activity is essential for polyomavirus entry.
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Affiliation(s)
- Samuel J Dobson
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, United Kingdom
| | - Jamel Mankouri
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
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18
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Multifaceted Functions of Host Cell Caveolae/Caveolin-1 in Virus Infections. Viruses 2020; 12:v12050487. [PMID: 32357558 PMCID: PMC7291293 DOI: 10.3390/v12050487] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 02/07/2023] Open
Abstract
Virus infection has drawn extensive attention since it causes serious or even deadly diseases, consequently inducing a series of social and public health problems. Caveolin-1 is the most important structural protein of caveolae, a membrane invagination widely known for its role in endocytosis and subsequent cytoplasmic transportation. Caveolae/caveolin-1 is tightly associated with a wide range of biological processes, including cholesterol homeostasis, cell mechano-sensing, tumorigenesis, and signal transduction. Intriguingly, the versatile roles of caveolae/caveolin-1 in virus infections have increasingly been appreciated. Over the past few decades, more and more viruses have been identified to invade host cells via caveolae-mediated endocytosis, although other known pathways have been explored. The subsequent post-entry events, including trafficking, replication, assembly, and egress of a large number of viruses, are caveolae/caveolin-1-dependent. Deprivation of caveolae/caveolin-1 by drug application or gene editing leads to abnormalities in viral uptake, viral protein expression, or virion release, whereas the underlying mechanisms remain elusive and must be explored holistically to provide potential novel antiviral targets and strategies. This review recapitulates our current knowledge on how caveolae/caveolin-1 functions in every step of the viral infection cycle and various relevant signaling pathways, hoping to provide a new perspective for future viral cell biology research.
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19
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Chan BD, Wong G, Jiang Q, Lee MML, Wong WY, Chen F, Wong WT, Zhu L, Wong FKM, Tai WCS. Longitudinal study of BK Polyomavirus outcomes, risk factors, and kinetics in renal transplantation patients. Microb Pathog 2020; 142:104036. [PMID: 32017958 DOI: 10.1016/j.micpath.2020.104036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 01/31/2020] [Accepted: 01/31/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND In the immunocompromised conditions following renal transplantation, BK virus can reactivate and cause BK virus associated nephropathy (BKVN). Increased BK viral loads and extended duration of infection have been linked to development of BKVN. The aim of this study was to observe the incidence of BKV infection and BKVN, and kinetics of infection and disease in renal transplantation recipients. METHODS From 2014 to 2018, we conducted a longitudinal cohort observational study of 139 renal transplantation patients treated at a single clinic. Quantitative PCR assay was conducted to assess longitudinal BK viral loads. Analysis of patient clinical characteristics was performed to determine risk factors for BKV infection and associated disease. RESULTS Of our cohort, 29 (20.9%) patients developed high BK viremia, and 7 (5.0%) developed biopsy-confirmed BKVN. Clinical parameters associated with diabetes (FBS, HbA1c) and hyperlipidemia (TG, TC, LDL-C) were found to be correlated with development of high BK viremia or BKVN. In 3 of 4 patients receiving intravenous immunoglobulin (IVIG) treatment, BK viral loads were reduced by at least 1 log within 2-3 months of administration. Significant differences were measured in BK viral loads and kidney function between BK viremic patients and BKVN patients by 3-9 months post-transplantation. CONCLUSIONS We identified diabetes and hyperlipidemia as potential risk factors for development of high BK viremia and/or BKVN. IVIG was seen to be effective in reducing viral titers. The period 3-9 months post-transplantation was identified as important for development of BKVN from high BK viremia.
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Affiliation(s)
- Brandon Dow Chan
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Gabriella Wong
- Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Qing Jiang
- School of Statistics, Beijing Normal University, Beijing, China
| | - Magnolia Muk-Lan Lee
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Wing-Yan Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China
| | - Feifei Chen
- School of Statistics, Renmin University of China, Beijing, China
| | - Wing-Tak Wong
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Lixing Zhu
- Department of Mathematics, The Hong Kong Baptist University, Kowloon Tong, Hong Kong S.A.R, China
| | | | - William Chi-Shing Tai
- Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology (Incubation), The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China.
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20
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Horníková L, Bruštíková K, Forstová J. Microtubules in Polyomavirus Infection. Viruses 2020; 12:E121. [PMID: 31963741 PMCID: PMC7019765 DOI: 10.3390/v12010121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
Microtubules, part of the cytoskeleton, are indispensable for intracellular movement, cell division, and maintaining cell shape and polarity. In addition, microtubules play an important role in viral infection. In this review, we summarize the role of the microtubules' network during polyomavirus infection. Polyomaviruses usurp microtubules and their motors to travel via early and late acidic endosomes to the endoplasmic reticulum. As shown for SV40, kinesin-1 and microtubules are engaged in the release of partially disassembled virus from the endoplasmic reticulum to the cytosol, and dynein apparently assists in the further disassembly of virions prior to their translocation to the cell nucleus-the place of their replication. Polyomavirus gene products affect the regulation of microtubule dynamics. Early T antigens destabilize microtubules and cause aberrant mitosis. The role of these activities in tumorigenesis has been documented. However, its importance for productive infection remains elusive. On the other hand, in the late phase of infection, the major capsid protein, VP1, of the mouse polyomavirus, counteracts T-antigen-induced destabilization. It physically binds microtubules and stabilizes them. The interaction results in the G2/M block of the cell cycle and prolonged S phase, which is apparently required for successful completion of the viral replication cycle.
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Affiliation(s)
| | | | - Jitka Forstová
- Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25250 Vestec, Czech Republic; (L.H.); (K.B.)
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21
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Caveolin-1 rs4730751 single-nucleotide polymorphism may not influence kidney transplant allograft survival. Sci Rep 2019; 9:15541. [PMID: 31664124 PMCID: PMC6820546 DOI: 10.1038/s41598-019-52079-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 10/11/2019] [Indexed: 11/27/2022] Open
Abstract
Caveolin-1 is a protein (encoded by the CAV1 gene) supposedly harboring a protective effect against fibrosis. CAV1 rs4730751 single nucleotide polymorphism (SNP) AA genotype was initially associated with lower graft survival compared to non-AA. However, subsequent studies could not find the same effect. CAV1 rs4730751 SNP was investigated on 918 kidney donors. Multivariate Cox-model analyses were performed to evaluate risk factors for graft loss. Longitudinal changes on long-term estimated glomerular filtration rate (eGFRs) were evaluated with a linear mixed model. Histopathological findings from protocolled biopsies after 3 months post transplantation were also analyzed. Donor CAV1 rs4730751 genotyping proportions were 7.1% for AA, 41.6% for AC and 51.3% for CC. The AA genotype, compared to non-AA, was not associated with lower graft survival censored or not for death (multivariate analysis: HR = 1.23 [0.74–2.05] and HR = 1.27 [0.84–1.92]). Linear mixed model on long-term eGFRs revealed also no significant difference according to the genotype, yet we observed a trend. AA genotype was also not associated with a higher degree of fibrosis index on protocolled kidney biopsies at 3 months. To conclude, donor CAV1 rs4730751 SNP may impact on kidney transplantation outcomes, but this study could not confirm this hypothesis.
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22
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Alcendor DJ. BK Polyomavirus Virus Glomerular Tropism: Implications for Virus Reactivation from Latency and Amplification during Immunosuppression. J Clin Med 2019; 8:jcm8091477. [PMID: 31533282 PMCID: PMC6780320 DOI: 10.3390/jcm8091477] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/16/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022] Open
Abstract
BK polyomavirus (BKPyV), or BKV infection, is ubiquitous and usually non-pathogenic, with subclinical infections in 80–90% of adults worldwide. BKV infection is often associated with pathology in immunocompromised individuals. BKV infection often is associated with renal impairment, including ureteral stenosis, hemorrhagic cystitis, and nephropathy. BKV infection is less commonly associated with pneumonitis, retinitis, liver disease, and meningoencephalitis. BKV is known to replicate, establish latency, undergo reactivation, and induce clinical pathology in renal tubular epithelial cells. However, recent in vitro studies support the notion that BKV has expanded tropism-targeting glomerular parenchymal cells of the human kidney, which could impact glomerular function, enhance inflammation, and serve as viral reservoirs for reactivation from latency during immunosuppression. The implications of BKV expanded tropism in the glomerulus, and how specific host and viral factors that would contribute to glomerular inflammation, cytolysis, and renal fibrosis are related to BKV associated nephropathy (BKVAN), have not been explored. The pathogenesis of BKV in human glomerular parenchymal cells is poorly understood. In this review, I examine target cell populations for BKV infectivity in the human glomerulus. Specifically, I explore the implications of BKV expanded tropism in the glomerulus with regard viral entry, replication, and dissemination via cell types exposed to BKV trafficking in glomerulus. I also describe cellular targets shown to be permissive in vitro and in vivo for BKV infection and lytic replication, the potential role that glomerular parenchymal cells play in BKV latency and/or reactivation after immunosuppression, and the rare occurrence of BKV pathology in glomerular parenchymal cells in patients with BKVAN.
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Affiliation(s)
- Donald J Alcendor
- Center for AIDS Health Disparities Research, Meharry Medical College, 1005 Dr. D.B. Todd Jr. Blvd., Hubbard Hospital, 5th Floor, Rm. 5025, Nashville, TN 37208, USA.
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23
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Chong S, Antoni M, Macdonald A, Reeves M, Harber M, Magee CN. BK virus: Current understanding of pathogenicity and clinical disease in transplantation. Rev Med Virol 2019; 29:e2044. [PMID: 30958614 DOI: 10.1002/rmv.2044] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/19/2022]
Abstract
BK polyomavirus (BKV) is an important cause of graft loss in renal transplant recipients that continues to pose a significant challenge to clinicians due to its frequently unpredictable onset, persistence, and the lack of effective antiviral agents or prevention strategies. This review covers our current understanding of epidemiology, viral transmission and disease progression, and treatment and prevention strategies that have been used to manage this disease.
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Affiliation(s)
- Stephanie Chong
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Michelle Antoni
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, London, UK
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, London, UK
| | - Matthew Reeves
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | - Mark Harber
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Ciara N Magee
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
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JC Polyomavirus Entry by Clathrin-Mediated Endocytosis Is Driven by β-Arrestin. J Virol 2019; 93:JVI.01948-18. [PMID: 30700597 DOI: 10.1128/jvi.01948-18] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 01/22/2019] [Indexed: 01/09/2023] Open
Abstract
JC polyomavirus (JCPyV) establishes a persistent, lifelong, asymptomatic infection within the kidney of the majority of the human population. Under conditions of severe immunosuppression or immune modulation, JCPyV can reactivate in the central nervous system (CNS) and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease. Initiation of infection is mediated through viral attachment to α2,6-sialic acid-containing lactoseries tetrasaccharide c (LSTc) on the surface of host cells. JCPyV internalization is dependent on serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HT2Rs), and entry is thought to occur by clathrin-mediated endocytosis (CME). However, the JCPyV entry process and the cellular factors involved in viral internalization remain poorly understood. Treatment of cells with small-molecule chemical inhibitors and RNA interference of 5-HT2R endocytic machinery, including β-arrestin, clathrin, AP2, and dynamin, significantly reduced JCPyV infection. However, infectivity of the polyomavirus simian virus 40 (SV40) was not affected by CME-specific treatments. Inhibition of clathrin or β-arrestin specifically reduced JCPyV internalization but did not affect viral attachment. Furthermore, mutagenesis of a β-arrestin binding domain (Ala-Ser-Lys) within the intracellular C terminus of 5-HT2AR severely diminished internalization and infection, suggesting that β-arrestin interactions with 5-HT2AR are critical for JCPyV infection and entry. These conclusions illuminate key host factors that regulate clathrin-mediated endocytosis of JCPyV, which is necessary for viral internalization and productive infection.IMPORTANCE Viruses usurp cellular factors to invade host cells. Activation and utilization of these proteins upon initiation of viral infection are therefore required for productive infection and resultant viral disease. The majority of healthy individuals are asymptomatically infected by JC polyomavirus (JCPyV), but if the host immune system is compromised, JCPyV can cause progressive multifocal leukoencephalopathy (PML), a rare, fatal, demyelinating disease. Individuals infected with HIV or taking prolonged immunomodulatory therapies have a heightened risk for developing PML. The cellular proteins and pathways utilized by JCPyV to mediate viral entry are poorly understood. Our findings further characterize how JCPyV utilizes the clathrin-mediated endocytosis pathway to invade host cells. We have identified specific components of this pathway that are necessary for the viral entry process and infection. Collectively, the conclusions increase our understanding of JCPyV infection and pathogenesis and may contribute to the future development of novel therapeutic strategies for PML.
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Guo Y, Duan M, Wang X, Gao J, Guan Z, Zhang M. Early events in rabies virus infection—Attachment, entry, and intracellular trafficking. Virus Res 2019; 263:217-225. [DOI: 10.1016/j.virusres.2019.02.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 01/28/2019] [Accepted: 02/13/2019] [Indexed: 12/20/2022]
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Prado JCM, Monezi TA, Amorim AT, Lino V, Paladino A, Boccardo E. Human polyomaviruses and cancer: an overview. Clinics (Sao Paulo) 2018; 73:e558s. [PMID: 30328951 PMCID: PMC6157077 DOI: 10.6061/clinics/2018/e558s] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 05/15/2018] [Indexed: 12/27/2022] Open
Abstract
The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers.
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Affiliation(s)
- José Carlos Mann Prado
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Telma Alves Monezi
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Aline Teixeira Amorim
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Vanesca Lino
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Andressa Paladino
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Enrique Boccardo
- Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
- *Corresponding author. E-mail:
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Scadden JRW, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant 2017; 7:329-338. [PMID: 29312862 PMCID: PMC5743870 DOI: 10.5500/wjt.v7.i6.329] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 11/17/2017] [Accepted: 12/01/2017] [Indexed: 02/05/2023] Open
Abstract
BK virus (BKV) is a polyomavirus that is able to cause renal dysfunction in transplanted grafts via BK virus-associated nephritis (BKVAN). This condition was mis-diagnosed in the past due to clinical and histopthological similarities with acute rejection. Due to the prevalence of the virus in the population, it is an important pathogen in this context, and so it is important to understand how this virus functions and its' relationship with the pathogenesis of BKVN. Screening for BKV often reveals viruria and/or viremia, which then manifests as BKVN, which can be asymptomatic or result in clinical features namely renal dysfunction. The pathogenesis of BKV infection is still unclear and needs to be further investigated; nevertheless there are a variety of hypotheses that indicate that there are a host of factors that play important roles. Treatments for BKVAN include a reduction in immunosuppression, the use of antiviral therapy or the combination of both treatment options.
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Affiliation(s)
- Jacob RW Scadden
- University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom
| | - Adnan Sharif
- Department of Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | - Kassi Skordilis
- Department of Renal Histopathology, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | - Richard Borrows
- Department of Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
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Udayantha HMV, Bathige SDNK, Priyathilaka TT, Lee S, Kim MJ, Lee J. Identification and characterization of molluscan caveolin-1 ortholog from Haliotis discus discus: Possible involvement in embryogenesis and host defense mechanism against pathogenic stress. Gene Expr Patterns 2017; 27:85-92. [PMID: 29128397 DOI: 10.1016/j.gep.2017.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 06/13/2017] [Accepted: 11/06/2017] [Indexed: 02/05/2023]
Abstract
Caveolins are principal membrane proteins of caveolae that play a central role in signal transduction, substrate transport, and membrane trafficking in various cell types. Numerous studies have reported the crucial role of caveolin-1 (CAV1) in response to invading microbes; yet, very little is known about molluscan CAV1. In this study, we identified and characterized CAV1 ortholog from the disk abalone, Haliotis discus discus (HdCAV1). The cDNA sequence of HdCAV1 is 826 bp long and encodes a 127-amino acid polypeptide. Characteristic caveolin superfamily domain (Glu3 - Lys126) and two possible transmembrane domains (Cys48 - Tyr67 and Ile103 - Phe120) were identified in the HdCAV1 protein. Homology analysis revealed that HdCAV1 shared higher identity (>47%) with molluscans, but lower identity with other species. Phylogenetic tree constructed by the neighbor-joining (NJ) method revealed a distinct evolutionary pathway for molluscans. Transcriptional analysis by SYBR Green qPCR showed the highest expression of HdCAV1 mRNA in late veliger stage, as compared to that in other embryonic developmental stages of disk abalone. In adult animals, gill tissue showed highest HdCAV1 transcript levels under normal physiological condition. Stimulations with two bacteria (Vibrio parahaemolyticus and Listeria monocytogenes), viral hemorrhagic septicemia virus, and two pathogen-associated molecular patterns (LPS and poly I:C) significantly modulated the expression of HdCAV1 transcripts. Collectively, these data suggest that CAV1 plays an important role in embryogenesis and host immune defense in disk abalone.
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Affiliation(s)
- H M V Udayantha
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Department of Fisheries and Aquaculture, Faculty of Fisheries and Marine Sciences and Technology, University of Ruhuna, Matara, Sri Lanka
| | - S D N K Bathige
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Sri Lanka Institute of Nanotechnology (SLINTEC), Nanotechnology and Science Park, Mahenwatta, Pitipana, Homagama, Sri Lanka
| | - Thanthrige Thiunuwan Priyathilaka
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Sukkyoung Lee
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea
| | - Myoung-Jin Kim
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea.
| | - Jehee Lee
- Department of Marine Life Sciences, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea; Fish Vaccine Research Center, Jeju National University, Jeju Self-Governing Province 63243, Republic of Korea.
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Helle F, Brochot E, Handala L, Martin E, Castelain S, Francois C, Duverlie G. Biology of the BKPyV: An Update. Viruses 2017; 9:v9110327. [PMID: 29099746 PMCID: PMC5707534 DOI: 10.3390/v9110327] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Revised: 10/30/2017] [Accepted: 10/30/2017] [Indexed: 12/29/2022] Open
Abstract
The BK virus (BKPyV) is a member of the Polyomaviridae family first isolated in 1971. BKPyV causes frequent infections during childhood and establishes persistent infections with minimal clinical implications within renal tubular cells and the urothelium. However, reactivation of BKPyV in immunocompromised individuals may cause serious complications. In particular, with the implementation of more potent immunosuppressive drugs in the last decade, BKPyV has become an emerging pathogen in kidney and bone marrow transplant recipients where it often causes associated nephropathy and haemorrhagic cystitis, respectively. Unfortunately, no specific antiviral against BKPyV has been approved yet and the only therapeutic option is a modulation of the immunosuppressive drug regimen to improve immune control though it may increase the risk of rejection. A better understanding of the BKPyV life cycle is thus needed to develop efficient treatment against this virus. In this review, we provide an update on recent advances in understanding the biology of BKPyV.
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Affiliation(s)
- Francois Helle
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Etienne Brochot
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Lynda Handala
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Elodie Martin
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Sandrine Castelain
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Catherine Francois
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
| | - Gilles Duverlie
- EA4294, Unité de Virologie Clinique et Fondamentale, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, 80054 Amiens, France.
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Krawczyk KM, Hansson J, Nilsson H, Krawczyk KK, Swärd K, Johansson ME. Injury induced expression of caveolar proteins in human kidney tubules - role of megakaryoblastic leukemia 1. BMC Nephrol 2017; 18:320. [PMID: 29065889 PMCID: PMC5655893 DOI: 10.1186/s12882-017-0738-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 09/25/2017] [Indexed: 11/17/2022] Open
Abstract
Background Caveolae are membrane invaginations measuring 50–100 nm. These organelles, composed of caveolin and cavin proteins, are important for cellular signaling and survival. Caveolae play incompletely defined roles in human kidneys. Induction of caveolin-1/CAV1 in diseased tubules has been described previously, but the responsible mechanism remains to be defined. Methods Healthy and atrophying human kidneys were stained for caveolar proteins, (caveolin 1–3 and cavin 1–4) and examined by electron microscopy. Induction of caveolar proteins was studied in isolated proximal tubules and primary renal epithelial cells. These cells were challenged with hypoxia or H2O2. Primary tubular cells were also subjected to viral overexpression of megakaryoblastic leukemia 1 (MKL1) and MKL1 inhibition by the MKL1 inhibitor CCG-1423. Putative coregulators of MKL1 activity were investigated by Western blotting for suppressor of cancer cell invasion (SCAI) and filamin A (FLNA). Finally, correlative bioinformatic studies of mRNA expression of caveolar proteins and MKL1 were performed. Results In healthy kidneys, caveolar proteins were expressed by the parietal epithelial cells (PECs) of Bowman’s capsule, endothelial cells and vascular smooth muscle. Electron microscopy confirmed caveolae in the PECs. No expression was seen in proximal tubules. In contrast, caveolar proteins were expressed in proximal tubules undergoing atrophy. Caveolar proteins were also induced in cultures of primary epithelial tubular cells. Expression was not enhanced by hypoxia or free radical stress (H2O2), but proved sensitive to inhibition of MKL1. Viral overexpression of MKL1 induced caveolin-1/CAV1, caveolin-2/CAV2 and SDPR/CAVIN2. In kidney tissue, the mRNA level of MKL1 correlated with the mRNA levels for caveolin-1/CAV1, caveolin-2/CAV2 and the archetypal MKL1 target tenascin C (TNC), as did the MKL1 coactivator FLNA. Costaining for TNC as readout for MKL1 activity demonstrated overlap with caveolin-1/CAV1 expression in PECs as well as in atrophic segments of proximal tubules. Conclusions Our findings support the view that MKL1 contributes to the expression of caveolar proteins in healthy kidneys and orchestrates the induction of tubular caveolar proteins in renal injury. Electronic supplementary material The online version of this article (10.1186/s12882-017-0738-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Krzysztof M Krawczyk
- Department of Translational Medicine, Clinical Pathology, Lund University, SUS Malmö, Jan Waldenströms gata 59, SE-20502, Malmö, Sweden
| | - Jennifer Hansson
- Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Helén Nilsson
- Department of Translational Medicine, Clinical Pathology, Lund University, SUS Malmö, Jan Waldenströms gata 59, SE-20502, Malmö, Sweden
| | | | - Karl Swärd
- Department of Experimental Medical Science, Lund University, Lund, Sweden.
| | - Martin E Johansson
- Department of Translational Medicine, Clinical Pathology, Lund University, SUS Malmö, Jan Waldenströms gata 59, SE-20502, Malmö, Sweden.
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Tao Z, Meng X, Han YQ, Xue MM, Wu S, Wu P, Yuan Y, Zhu Q, Zhang TJ, Wong CCL. Therapeutic Mechanistic Studies of ShuFengJieDu Capsule in an Acute Lung Injury Animal Model Using Quantitative Proteomics Technology. J Proteome Res 2017; 16:4009-4019. [PMID: 28880561 DOI: 10.1021/acs.jproteome.7b00409] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ShuFengJieDu capsule (SFJDC), a traditional Chinese medicine (TCM) that contains eight medicinal herbs, has been extensively utilized for the treatment of acute lung injury (ALI) and respiratory infections for more than 30 years in China. SFJDC has also been listed in the official guidelines of the China Food and Drug Administration (CFDA) due to its stable clinical manifestations. However, the underlying mechanism of SFJDC during ALI repair remains unclear. In the present study, we explored the protective and therapeutic mechanisms of SFJDC in a rat model by performing qualitative and label-free quantitative proteomics studies. After establishing lipopolysaccharide (LPS)-induced ALI rat models, we profiled macrophage cells isolated from freshly resected rat lung tissues derived from ALI models and ALI rat lung tissue sections using a high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) shotgun proteomics approach to identify changes in the expression levels of proteins of interest. On the basis of our proteomics results and the results of a protein dysregulation analysis of ALI rat lung tissues and rat lung macrophages, AKT1 was selected as a putative key factor that may play an important role in mediating the effects of SFJDC treatment during ALI progression. Follow-up validation studies demonstrated that AKT1 expression effectively regulates various ALI-related molecules, and Gene Ontology analysis indicated that SFJDC-treated ALI rat macrophages were influenced by AKT1-based networks. Gain- and loss-of-function analyses following lentivirus-AKT1 or lentivirus-si-AKT1 infection in macrophages also indicated that AKT1 was essential for the development of ALI due to its ability to regulate oxidative stress, apoptosis, or inflammatory responses. In summary, SFJDC effectively modulated anti-inflammatory and immunomodulation activity during ALI, potentially due to AKT1 regulation during ALI progression. New insights into SFJDC mechanisms may facilitate the development of novel pharmaceutical strategies to control the expression of inflammatory factors.
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Affiliation(s)
| | - Xia Meng
- National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 201210, China
| | - Yan-Qi Han
- Tianjin Institute of Pharmaceutical Research , Tianjin 300193, China
| | | | - Shifei Wu
- National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 201210, China
| | - Ping Wu
- National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 201210, China
| | | | - Qiang Zhu
- Anhui Jiren Pharmaceutical Co., Ltd., Bozhou 236800, China
| | - Tie-Jun Zhang
- Tianjin Institute of Pharmaceutical Research , Tianjin 300193, China
| | - Catherine C L Wong
- National Center for Protein Science (Shanghai), Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 201210, China
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Identification of Rab18 as an Essential Host Factor for BK Polyomavirus Infection Using a Whole-Genome RNA Interference Screen. mSphere 2017; 2:mSphere00291-17. [PMID: 28815213 PMCID: PMC5555678 DOI: 10.1128/mspheredirect.00291-17] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 07/12/2017] [Indexed: 11/20/2022] Open
Abstract
Polyomaviruses bind to a group of specific gangliosides on the plasma membrane of the cell prior to being endocytosed. They then follow a retrograde trafficking pathway to reach the endoplasmic reticulum (ER). The viruses begin to disassemble in the ER and then exit the ER and move to the nucleus. However, the details of intracellular trafficking between the endosome and the ER are largely unknown. By implementing a whole human genome small interfering RNA screen, we identified Rab18, syntaxin 18, and the NRZ complex as key components in endosome-ER trafficking of the human polyomavirus BKPyV. These results serve to further elucidate the route BKPyV takes from outside the cell to its site of replication in the nucleus. BK polyomavirus (BKPyV) is a human pathogen first isolated in 1971. BKPyV infection is ubiquitous in the human population, with over 80% of adults worldwide being seropositive for BKPyV. BKPyV infection is usually asymptomatic; however, BKPyV reactivation in immunosuppressed transplant patients causes two diseases, polyomavirus-associated nephropathy and hemorrhagic cystitis. To establish a successful infection in host cells, BKPyV must travel in retrograde transport vesicles to reach the nucleus. To make this happen, BKPyV requires the cooperation of host cell proteins. To further identify host factors associated with BKPyV entry and intracellular trafficking, we performed a whole-genome small interfering RNA screen on BKPyV infection of primary human renal proximal tubule epithelial cells. The results revealed the importance of Ras-related protein Rab18 and syntaxin 18 for BKPyV infection. Our subsequent experiments implicated additional factors that interact with this pathway and suggest a more detailed model of the intracellular trafficking process, indicating that BKPyV reaches the endoplasmic reticulum (ER) lumen through a retrograde transport pathway between the late endosome and the ER. IMPORTANCE Polyomaviruses bind to a group of specific gangliosides on the plasma membrane of the cell prior to being endocytosed. They then follow a retrograde trafficking pathway to reach the endoplasmic reticulum (ER). The viruses begin to disassemble in the ER and then exit the ER and move to the nucleus. However, the details of intracellular trafficking between the endosome and the ER are largely unknown. By implementing a whole human genome small interfering RNA screen, we identified Rab18, syntaxin 18, and the NRZ complex as key components in endosome-ER trafficking of the human polyomavirus BKPyV. These results serve to further elucidate the route BKPyV takes from outside the cell to its site of replication in the nucleus.
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Bhattacharjee S, Chattaraj S. Entry, infection, replication, and egress of human polyomaviruses: an update. Can J Microbiol 2017; 63:193-211. [DOI: 10.1139/cjm-2016-0519] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Polyomaviruses (PyVs), belonging to the family Polyomaviridae, are a group of small, nonenveloped, double-stranded, circular DNA viruses widely distributed in the vertebrates. PyVs cause no apparent disease in adult laboratory mice but cause a wide variety of tumors when artificially inoculated into neonates or semipermissive animals. A few human PyVs, such as BK, JC, and Merkel cell PyVs, have been unequivocally linked to pathogenesis under conditions of immunosuppression. Infection is thought to occur early in life and persists for the lifespan of the host. Over evolutionary time scales, it appears that PyVs have slowly co-evolved with specific host animal lineages. Host cell surface glycoproteins and glycolipids seem to play a decisive role in the entry stage of viral infection and in channeling the virions to specific intracellular membrane-bound compartments and ultimately to the nucleus, where the genomes are replicated and packaged for release. Therefore the transport of the infecting virion or viral genome to this site of multiplication is an essential process in productive viral infection as well as in latent infection and transformation. This review summarizes the major findings related to the characterization of the nature of the interactions between PyV and host protein and their impact in host cell invasion.
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Affiliation(s)
- Soumen Bhattacharjee
- Cell and Molecular Biology Laboratory, Department of Zoology, University of North Bengal, Raja Rammohunpur, P.O. North Bengal University, Siliguri, District Darjeeling, West Bengal, PIN 734013, India
- Cell and Molecular Biology Laboratory, Department of Zoology, University of North Bengal, Raja Rammohunpur, P.O. North Bengal University, Siliguri, District Darjeeling, West Bengal, PIN 734013, India
| | - Sutanuka Chattaraj
- Cell and Molecular Biology Laboratory, Department of Zoology, University of North Bengal, Raja Rammohunpur, P.O. North Bengal University, Siliguri, District Darjeeling, West Bengal, PIN 734013, India
- Cell and Molecular Biology Laboratory, Department of Zoology, University of North Bengal, Raja Rammohunpur, P.O. North Bengal University, Siliguri, District Darjeeling, West Bengal, PIN 734013, India
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Barth H, Solis M, Kack-Kack W, Soulier E, Velay A, Fafi-Kremer S. In Vitro and In Vivo Models for the Study of Human Polyomavirus Infection. Viruses 2016; 8:E292. [PMID: 27782080 PMCID: PMC5086624 DOI: 10.3390/v8100292] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/22/2016] [Accepted: 10/13/2016] [Indexed: 12/26/2022] Open
Abstract
Developments of genome amplification techniques have rapidly expanded the family of human polyomaviruses (PyV). Following infection early in life, PyV persist in their hosts and are generally of no clinical consequence. High-level replication of PyV can occur in patients under immunosuppressive or immunomodulatory therapy and causes severe clinical entities, such as progressive multifocal leukoencephalopathy, polyomavirus-associated nephropathy or Merkel cell carcinoma. The characterization of known and newly-discovered human PyV, their relationship to human health, and the mechanisms underlying pathogenesis remain to be elucidated. Here, we summarize the most widely-used in vitro and in vivo models to study the PyV-host interaction, pathogenesis and anti-viral drug screening. We discuss the strengths and limitations of the different models and the lessons learned.
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Affiliation(s)
- Heidi Barth
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
| | - Morgane Solis
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
| | - Wallys Kack-Kack
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
| | - Eric Soulier
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
| | - Aurélie Velay
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
| | - Samira Fafi-Kremer
- Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé, 67000 Strasbourg, France.
- Université de Strasbourg, INSERM, IRM UMR-S 1109, 4 rue Kirschleger, 67000 Strasbourg, France.
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Vigil D, Konstantinov NK, Barry M, Harford AM, Servilla KS, Kim YH, Sun Y, Ganta K, Tzamaloukas AH. BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection. World J Transplant 2016; 6:472-504. [PMID: 27683628 PMCID: PMC5036119 DOI: 10.5500/wjt.v6.i3.472] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/25/2016] [Accepted: 09/08/2016] [Indexed: 02/05/2023] Open
Abstract
Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.
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African horse sickness virus infects BSR cells through macropinocytosis. Virology 2016; 497:217-232. [PMID: 27497184 DOI: 10.1016/j.virol.2016.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 07/11/2016] [Accepted: 07/12/2016] [Indexed: 11/23/2022]
Abstract
Cellular pathways involved in cell entry by African horse sickness virus (AHSV), a member of the Orbivirus genus within the Reoviridae family, have not yet been determined. Here, we show that acidic pH is required for productive infection of BSR cells by AHSV-4, suggesting that the virus is likely internalized by an endocytic pathway. We subsequently analyzed the major endocytic routes using specific inhibitors and determined the consequences for AHSV-4 entry into BSR cells. The results indicated that virus entry is dynamin dependent, but clathrin- and lipid raft/caveolae-mediated endocytic pathways were not used by AHSV-4 to enter and infect BSR cells. Instead, binding of AHSV-4 to BSR cells stimulated uptake of a macropinocytosis-specific cargo and inhibition of Na(+)/H(+) exchangers, actin polymerization and cellular GTPases and kinases involved in macropinocytosis significantly inhibited AHSV-4 infection. Altogether, the data suggest that AHSV-4 infects BSR cells by utilizing macropinocytosis as the primary entry pathway.
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Zhao L, Marciano AT, Rivet CR, Imperiale MJ. Caveolin- and clathrin-independent entry of BKPyV into primary human proximal tubule epithelial cells. Virology 2016; 492:66-72. [PMID: 26901486 DOI: 10.1016/j.virol.2016.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/05/2016] [Accepted: 02/11/2016] [Indexed: 01/23/2023]
Abstract
BK polyomavirus (BKPyV) is a human pathogen that causes polyomavirus-associated nephropathy and hemorrhagic cystitis in transplant patients. Gangliosides and caveolin proteins have previously been reported to be required for BKPyV infection in animal cell models. Recent studies from our lab and others, however, have indicated that the identity of the cells used for infection studies can greatly influence the behavior of the virus. We therefore wished to re-examine BKPyV entry in a physiologically relevant primary cell culture model, human renal proximal tubule epithelial cells. Using siRNA knockdowns, we interfered with expression of UDP-glucose ceramide glucosyltransferase (UGCG), and the endocytic vesicle coat proteins caveolin 1, caveolin 2, and clathrin heavy chain. The results demonstrate that while BKPyV does require gangliosides for efficient infection, it can enter its natural host cells via a caveolin- and clathrin-independent pathway. The results emphasize the importance of studying viruses in a relevant cell culture model.
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Affiliation(s)
- Linbo Zhao
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Anthony T Marciano
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Courtney R Rivet
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Michael J Imperiale
- Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
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A Preliminary Study Into the Significance of Intrarenal Reflux in BK Virus Nephropathy After Kidney Transplantation. Transplant Direct 2016; 2:e64. [PMID: 27500256 PMCID: PMC4946493 DOI: 10.1097/txd.0000000000000575] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 12/16/2015] [Indexed: 12/13/2022] Open
Abstract
Background The BK virus typically colonizes the lower urinary tract and is the causative agent in BK virus nephropathy (BKVN), which can progress to allograft dysfunction and graft loss. Urinary reflux in kidney allografts is induced by vesicoureteral reflux or disturbances in intrarenal reflux (IRR), believed to be associated with BKVN. This study was designed to elucidate the relationship between BKVN and IRR. Methods We examined 30 renal transplant recipients histologically diagnosed with BKVN using anti-Simian virus 40 immunohistochemistry and 60 clinically matched control recipients. The BKVN patients were divided into stable (n = 12) and progressive (n = 18) groups according to allograft kidney function 1 year after diagnosis. Histological rejection scores according to the pathological classification of rejection in renal allografts (Banff classification), histological BKVN stages, and histological polyomavirus load levels (pvl) proposed by the Banff working group were evaluated. The IRR was quantified by histological reflux scores defined with retention and reflux of immunostained Tamm-Horsfall protein in renal tubules and glomeruli. Results Higher reflux scores were observed in the BKVN group compared with that in the control group. No differences in clinical parameters were observed between the BKVN and control groups. Reflux scores and pvl were significantly higher in the progressive group than in the stable BKVN group with no significant difference in BK stage observed between groups. Reflux scores were found to be significantly correlated with pvl. Conclusions Our preliminary study suggested that IRR might be a predisposing and prognostic factor in BKVN.
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Mbianda C, El-Meanawy A, Sorokin A. Mechanisms of BK virus infection of renal cells and therapeutic implications. J Clin Virol 2015; 71:59-62. [PMID: 26295751 DOI: 10.1016/j.jcv.2015.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
Abstract
BK virus (BKV) causes BKV nephritis in renal transplant patients and contributes significantly to the increase of probability of graft loss. BKV, being latent in the urogenital tract, is likely to be transported with the donor kidney to recipients and following reactivation replicates in the nucleus of renal epithelial tubular cells. BKV daughter viruses are released and enter other renal epithelial cells to spread infection. There are still a lot of unknown factors about the mechanism and kinetics of BKV infection. The treatment of BKV infection, with exception of reduction in immunosuppression which increases the risk of allograft rejection, is almost exclusively limited to application of anti-viral drugs with rather inconsistent results. The shortcomings of anti-viral therapies demand the understanding of early steps of infection of permissive cells by BK virus in hope that adequate interventional therapies preventing infection of cells with BK virus could be developed. This review describes the BKV entry in target human cells, intracellular trafficking pathways of BKV particles and potential therapeutic implications based on understanding of mechanisms of BKV infection of renal cells.
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Affiliation(s)
- Christiane Mbianda
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Ashraf El-Meanawy
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Andrey Sorokin
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Gabardi S, Ramasamy S, Kim M, Klasek R, Carter D, Mackenzie MR, Chandraker A, Tan CS. Impact of HMG-CoA reductase inhibitors on the incidence of polyomavirus-associated nephropathy in renal transplant recipients with human BK polyomavirus viremia. Transpl Infect Dis 2015; 17:536-43. [PMID: 25989423 PMCID: PMC4529764 DOI: 10.1111/tid.12402] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/27/2015] [Accepted: 04/17/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. PATIENTS AND METHODS A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. RESULTS Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). CONCLUSIONS Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.
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Affiliation(s)
- S Gabardi
- Department of Transplant Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - S Ramasamy
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - M Kim
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Department of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - R Klasek
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - D Carter
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - M R Mackenzie
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - A Chandraker
- Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - C S Tan
- Harvard Medical School, Boston, Massachusetts, USA
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
- Division of Infectious Disease, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Moriyama T, Takei T, Itabashi M, Uchida K, Tsuchiya K, Nitta K. Caveolae May Enable Albumin to Enter Human Renal Glomerular Endothelial Cells. J Cell Biochem 2015; 116:1060-9. [DOI: 10.1002/jcb.25061] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 12/18/2014] [Indexed: 11/10/2022]
Affiliation(s)
- Takahito Moriyama
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
| | - Takashi Takei
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
| | - Mitsuyo Itabashi
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
| | - Keiko Uchida
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
| | - Ken Tsuchiya
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
| | - Kosaku Nitta
- Department of Medicine, Kidney CenterTokyo Women's Medical UniversityTokyoJapan
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The impact of APOL1, CAV1, and ABCB1 gene variants on outcomes in kidney transplantation: donor and recipient effects. Pediatr Nephrol 2014; 29:1485-92. [PMID: 23748364 PMCID: PMC3809028 DOI: 10.1007/s00467-013-2531-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 05/21/2013] [Accepted: 05/22/2013] [Indexed: 12/13/2022]
Abstract
Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long-term graft survival rates.
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Divers J, Núñez M, High KP, Murea M, Rocco MV, Ma L, Bowden DW, Hicks PJ, Spainhour M, Ornelles DA, Kleiboeker SB, Duncan K, Langefeld CD, Turner J, Freedman BI. JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy. Kidney Int 2013; 84:1207-13. [PMID: 23677244 PMCID: PMC3844025 DOI: 10.1038/ki.2013.173] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 02/20/2013] [Accepted: 03/01/2013] [Indexed: 01/22/2023]
Abstract
Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with non-diabetic nephropathy using linear and non-linear mixed models to account for familial relationships. The four groups evaluated were APOL1 0/1 versus 2 risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients while HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin to creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m2 and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.
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Affiliation(s)
- Jasmin Divers
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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Jia KT, Wu YY, Liu ZY, Mi S, Zheng YW, He J, Weng SP, Li SC, He JG, Guo CJ. Mandarin fish caveolin 1 interaction with major capsid protein of infectious spleen and kidney necrosis virus and its role in early stages of infection. J Virol 2013; 87:3027-3038. [PMID: 23283951 PMCID: PMC3592132 DOI: 10.1128/jvi.00552-12] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Accepted: 12/15/2012] [Indexed: 12/31/2022] Open
Abstract
Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the genus Megalocytivirus from the family Iridoviridae. ISKNV is one of the major agents that cause mortality and economic losses to the freshwater fish culture industry in Asian countries, particularly for mandarin fish (Siniperca chuatsi). In the present study, we report that the interaction of mandarin fish caveolin 1 (mCav-1) with the ISKNV major capsid protein (MCP) was detected by using a virus overlay assay and confirmed by pulldown assay and coimmunoprecipitation. This interaction was independent of the classic caveolin 1 scaffolding domain (CSD), which is responsible for interacting with several signaling proteins and receptors. Confocal immunofluorescence microscopy showed that ISKNV MCP colocalized with mCav-1 in the perinuclear region of virus-infected mandarin fish fry (MFF-1) cells, which appeared as soon as 4 h postinfection. Subcellular fractionation analysis showed that ISKNV MCP was associated with caveolae in the early stages of viral infection. RNA interference silencing of mCav-1 did not change virus-cell binding but efficiently inhibited the entry of virions into the cell. Taken together, these results suggested that mCav-1 plays an important role in the early stages of ISKNV infection.
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Affiliation(s)
- Kun-Tong Jia
- MOE Key Laboratory of Aquatic Product Safety/State Key Laboratory for Biocontrol, School of Marine Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yan-Yan Wu
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhao-Yu Liu
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shu Mi
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yi-Wen Zheng
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Jian He
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shao-Ping Weng
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shengwen Calvin Li
- CHOC Children's Hospital, University of California—Irvine, Orange, California, USA
| | - Jian-Guo He
- MOE Key Laboratory of Aquatic Product Safety/State Key Laboratory for Biocontrol, School of Marine Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chang-Jun Guo
- MOE Key Laboratory of Aquatic Product Safety/State Key Laboratory for Biocontrol, School of Marine Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
- School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
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Pino L, Rijo E, Nohales G, Frances A, Ubre A, Arango O. Bladder transitional cell carcinoma and BK virus in a young kidney transplant recipient. Transpl Infect Dis 2012; 15:E25-7. [PMID: 23231013 DOI: 10.1111/tid.12042] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 09/12/2012] [Accepted: 09/13/2012] [Indexed: 11/28/2022]
Abstract
Kidney transplant recipients have a heightened risk of developing neoplasms. Immunosuppressive treatments decrease the incidence of transplant rejection but increase the risk of infections, including BK virus (BKV). This infection is acquired in childhood and remains latent in the renal and urinary epithelium. In cases of immunodeficiency, BKV has been implicated as a tumor virus, but the role of BKV in cancer is a controversial topic and is difficult to determine. In the tumor cells, it is possible to detect fragments of the viral genome that could alter the control mechanisms of the cell cycle and DNA repair. We report the case of a kidney transplant recipient who developed BKV nephropathy and carcinoma of the bladder, supporting a possible role for BKV in the oncogenic pathway in this clinical setting, but the role of BKV in cancer remains a controversial topic and difficult to determine.
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Affiliation(s)
- L Pino
- Department of Urology, Hospital del Mar, Barcelona, Spain
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Rift Valley fever virus strain MP-12 enters mammalian host cells via caveola-mediated endocytosis. J Virol 2012; 86:12954-70. [PMID: 22993156 DOI: 10.1128/jvi.02242-12] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Rift Valley fever virus (RVFV) is a zoonotic pathogen capable of causing serious morbidity and mortality in both humans and livestock. The lack of efficient countermeasure strategies, the potential for dispersion into new regions, and the pathogenesis in humans and livestock make RVFV a serious public health concern. The receptors, cellular factors, and entry pathways used by RVFV and other members of the family Bunyaviridae remain largely uncharacterized. Here we provide evidence that RVFV strain MP-12 uses dynamin-dependent caveola-mediated endocytosis for cell entry. Caveolae are lipid raft domains composed of caveolin (the main structural component), cholesterol, and sphingolipids. Caveola-mediated endocytosis is responsible for the uptake of a wide variety of host ligands, as well as bacteria, bacterial toxins, and a number of viruses. To determine the cellular entry mechanism of RVFV, we used small-molecule inhibitors, RNA interference (RNAi), and dominant negative (DN) protein expression to inhibit the major mammalian cell endocytic pathways. Inhibitors and RNAi specific for macropinocytosis and clathrin-mediated endocytosis had no effect on RVFV infection. In contrast, inhibitors of caveola-mediated endocytosis, and RNAi targeted to caveolin-1 and dynamin, drastically reduced RVFV infection in multiple cell lines. Expression of DN caveolin-1 also reduced RVFV infection significantly, while expression of DN EPS15, a protein required for the assembly of clathrin-coated pits, and DN PAK-1, an obligate mediator of macropinocytosis, had no significant impact on RVFV infection. These results together suggest that the primary mechanism of RVFV MP-12 uptake is dynamin-dependent, caveolin-1-mediated endocytosis.
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Bennett SM, Broekema NM, Imperiale MJ. BK polyomavirus: emerging pathogen. Microbes Infect 2012; 14:672-83. [PMID: 22402031 PMCID: PMC3568954 DOI: 10.1016/j.micinf.2012.02.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 02/03/2012] [Accepted: 02/07/2012] [Indexed: 02/07/2023]
Abstract
BK polyomavirus (BKPyV) is a small double-stranded DNA virus that is an emerging pathogen in immunocompromised individuals. BKPyV is widespread in the general population, but primarily causes disease when immune suppression leads to reactivation of latent virus. Polyomavirus-associated nephropathy and hemorrhagic cystitis in renal and bone marrow transplant patients, respectively, are the most common diseases associated with BKPyV reactivation and lytic infection. In this review, we discuss the clinical relevance, effects on the host, virus life cycle, and current treatment protocols.
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Affiliation(s)
- Shauna M. Bennett
- Program in Cellular and Molecular Biology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
| | - Nicole M. Broekema
- Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
| | - Michael J. Imperiale
- Program in Cellular and Molecular Biology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
- Department of Microbiology and Immunology, University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
- Comprehensive Cancer Center University of Michigan Medical School, 1150 West Medical Center Drive, 5724 Medical Science II, Ann Arbor, MI 48109-5620, USA
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48
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Guo Q, Shen N, Yuan K, Li J, Wu H, Zeng Y, Fox J, Bansal AK, Singh BB, Gao H, Wu M. Caveolin-1 plays a critical role in host immunity against Klebsiella pneumoniae by regulating STAT5 and Akt activity. Eur J Immunol 2012; 42:1500-1511. [PMID: 22678904 PMCID: PMC3644991 DOI: 10.1002/eji.201142051] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Caveolin-1 (Cav1) is a structural protein of caveolae. Although Cav1 is associated with certain bacterial infections, it is unknown whether Cav1 is involved in host immunity against Klebsiella pneumoniae, the third most commonly isolated microorganism from bacterial sepsis patients. Here, we showed that cav1 knockout mice succumbed to K. pneumoniae infection with markedly decreased survival rates, increased bacterial burdens, intensified tissue injury, hyperactive proinflammatory cytokines, and systemic bacterial dissemination as compared with WT mice. Knocking down Cav1 by a dominant negative approach in lung epithelial MLE-12 cells resulted in similar outcomes (decreased bacterial clearance and increased proinflammatory cytokine production). Furthermore, we revealed that STAT5 influences the GSK3β-β-catenin-Akt pathway, which contributes to the intensive inflammatory response and rapid infection dissemination seen in Cav1 deficiency. Collectively, our findings indicate that Cav1 may offer resistance to K. pneumoniae infection, by affecting both systemic and local production of proinflammatory cytokines via the actions of STAT5 and the GSK3β-β-catenin-Akt pathway.
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Affiliation(s)
- Qiang Guo
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
- Department of Rheumatology Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Nan Shen
- Department of Rheumatology Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Kefei Yuan
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
| | - Jiaxin Li
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
- Department of Hepatobiliary and Pancreatic Surgery West China Hospital, Sichuan University, Chengdu, China
| | - Hong Wu
- Department of Hepatobiliary and Pancreatic Surgery West China Hospital, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Hepatobiliary and Pancreatic Surgery West China Hospital, Sichuan University, Chengdu, China
| | - John Fox
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
| | - Arvind K. Bansal
- Pulmonary, Critical Care and Sleep Medicine, the Altru Hospital, Grand Forks, North Dakota, USA
| | - Brij B. Singh
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
| | - Hongwei Gao
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Min Wu
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, North Dakota, USA
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Ribeiro A, Wörnle M, Motamedi N, Anders HJ, Gröne EF, Nitschko H, Kurktschiev P, Debiec H, Kretzler M, Cohen CD, Gröne HJ, Schlöndorff D, Schmid H. Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy. Kidney Int 2012; 81:100-11. [PMID: 21918500 DOI: 10.1038/ki.2011.311] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.
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Affiliation(s)
- Andrea Ribeiro
- Medizinische Poliklinik Campus Innenstadt, Klinikum der LMU, Munich, Germany
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50
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Function of membrane rafts in viral lifecycles and host cellular response. Biochem Res Int 2011; 2011:245090. [PMID: 22191032 PMCID: PMC3235436 DOI: 10.1155/2011/245090] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 08/31/2011] [Accepted: 09/27/2011] [Indexed: 12/31/2022] Open
Abstract
Membrane rafts are small (10–200 nm) sterol- and sphingolipid-enriched domains that compartmentalize cellular processes. Membrane rafts play an important role in viral infection cycles and viral virulence. Viruses are divided into four main classes, enveloped DNA virus, enveloped RNA virus, nonenveloped DNA virus, and nonenveloped RNA virus. General virus infection cycle is also classified into two sections, the early stage (entry process) and the late stage (assembly, budding, and release processes of virus particles). In the viral cycle, membrane rafts act as a scaffold of many cellular signal transductions, which are associated with symptoms caused by viral infections. In this paper, we describe the functions of membrane rafts in viral lifecycles and host cellular response according to each virus classification, each stage of the virus lifecycle, and each virus-induced signal transduction.
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