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George Pryzdial EL, Perrier JR, Rashid MU, West HE, Sutherland MR. Viral coagulation: pushing the envelope. J Thromb Haemost 2024; 22:3366-3382. [PMID: 39260743 DOI: 10.1016/j.jtha.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/27/2024] [Revised: 07/11/2024] [Accepted: 08/19/2024] [Indexed: 09/13/2024]
Abstract
Many virus types affect the blood clotting system with correlations to pathology that range widely from thrombosis to hemorrhage linking to inflammation. Here we overview the intricate crosstalk induced by infection between proteins on the virus encoded by either the host or virus genomes, coagulation proteins, platelets, leukocytes, and endothelial cells. For blood-borne viruses with an outer covering acquired from the host cell, the envelope, a key player may be the cell-derived trigger of coagulation on the virus surface, tissue factor (TF). TF is a multifunctional transmembrane cofactor that accelerates factor (F)VIIa-dependent activation of FX to FXa, leading to clot formation. However, the nascent TF/FVIIa/FXa complex also facilitates G protein-coupled modulation of cells via protease-activated receptor 2. As a viral envelope constituent, TF can bypass the physiological modes of regulation, thereby initiating the activation of neighboring platelets, leukocytes, and endothelial cells. A thromboinflammatory environment is predicted due to feedback amplification in response to cellular release of cytokines, procoagulant proteins, neutrophil extracellular traps, and stimulus-induced accessibility of adhesive receptors, resulting in cellular aggregates. The pathobiological effects of thromboinflammation ultimately contribute to innate and adaptive immunity for viral clearance. In contrast, the preceding stages of viral infection may be enhanced via the TF-protease axis.
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Affiliation(s)
- Edward Louis George Pryzdial
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada.
| | - John Ruggles Perrier
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Mahamud-Ur Rashid
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Henry Euan West
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
| | - Michael Ross Sutherland
- Centre for Blood Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Medical Affairs and Innovation, Canadian Blood Services, Ottawa, Ontario, Canada
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2
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Carter MH, Gribble J, Diller JR, Denison MR, Mirza SA, Chappell JD, Halasa NB, Ogden KM. Human Rotaviruses of Multiple Genotypes Acquire Conserved VP4 Mutations during Serial Passage. Viruses 2024; 16:978. [PMID: 38932271 PMCID: PMC11209247 DOI: 10.3390/v16060978] [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] [Academic Contribution Register] [Received: 05/14/2024] [Revised: 06/06/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Human rotaviruses exhibit limited tropism and replicate poorly in most cell lines. Attachment protein VP4 is a key rotavirus tropism determinant. Previous studies in which human rotaviruses were adapted to cultured cells identified mutations in VP4. However, most such studies were conducted using only a single human rotavirus genotype. In the current study, we serially passaged 50 human rotavirus clinical specimens representing five of the genotypes most frequently associated with severe human disease, each in triplicate, three to five times in primary monkey kidney cells then ten times in the MA104 monkey kidney cell line. From 13 of the 50 specimens, we obtained 25 rotavirus antigen-positive lineages representing all five genotypes, which tended to replicate more efficiently in MA104 cells at late versus early passage. We used Illumina next-generation sequencing and analysis to identify variants that arose during passage. In VP4, variants encoded 28 mutations that were conserved for all P[8] rotaviruses and 12 mutations that were conserved for all five genotypes. These findings suggest there may be a conserved mechanism of human rotavirus adaptation to MA104 cells. In the future, such a conserved adaptation mechanism could be exploited to study human rotavirus biology or efficiently manufacture vaccines.
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Affiliation(s)
- Maximilian H. Carter
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Jennifer Gribble
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Julia R. Diller
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mark R. Denison
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Sara A. Mirza
- Centers for Disease Control and Prevention, Atlanta, GA 30329, USA
| | - James D. Chappell
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Natasha B. Halasa
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Kristen M. Ogden
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
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3
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Trivigno SMG, Guidetti GF, Barbieri SS, Zarà M. Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery. Int J Mol Sci 2023; 24:ijms24087462. [PMID: 37108623 PMCID: PMC10138547 DOI: 10.3390/ijms24087462] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/13/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Platelets are classically recognized for their important role in hemostasis and thrombosis but they are also involved in many other physiological and pathophysiological processes, including infection. Platelets are among the first cells recruited to sites of inflammation and infection and they exert their antimicrobial response actively cooperating with the immune system. This review aims to summarize the current knowledge on platelet receptor interaction with different types of pathogens and the consequent modulations of innate and adaptive immune responses.
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Affiliation(s)
- Silvia M G Trivigno
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
- University School for Advanced Studies, IUSS, 27100 Pavia, Italy
| | | | - Silvia Stella Barbieri
- Unit of Heart-Brain Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
| | - Marta Zarà
- Unit of Heart-Brain Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
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4
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Goswami S, Samanta D, Duraivelan K. Molecular mimicry of host short linear motif-mediated interactions utilised by viruses for entry. Mol Biol Rep 2023; 50:4665-4673. [PMID: 37016039 PMCID: PMC10072811 DOI: 10.1007/s11033-023-08389-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/10/2022] [Accepted: 03/15/2023] [Indexed: 04/06/2023]
Abstract
Viruses are obligate intracellular parasites that depend on host cellular machinery for performing even basic biological functions. One of the many ways they achieve this is through molecular mimicry, wherein the virus mimics a host sequence or structure, thereby being able to hijack the host's physiological interactions for its pathogenesis. Such adaptations are specific recognitions that often confer tissue and species-specific tropisms to the virus, and enable the virus to utilise previously existing host signalling networks, which ultimately aid in further steps of viral infection, such as entry, immune evasion and spread. A common form of sequence mimicry utilises short linear motifs (SLiMs). SLiMs are short-peptide sequences that mediate transient interactions and are major elements in host protein interaction networks. This work is aimed at providing a comprehensive review of current literature of some well-characterised SLiMs that play a role in the attachment and entry of viruses into host cells, which mimic physiological receptor-ligand interactions already present in the host. Considering recent trends in emerging diseases, further research on such motifs involved in viral entry can help in the discovery of previously unknown cellular receptors utilised by viruses, as well as help in the designing of targeted therapeutics such as vaccines or inhibitors directed towards these interactions.
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Affiliation(s)
- Saumyadeep Goswami
- School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India
| | - Dibyendu Samanta
- School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India.
| | - Kheerthana Duraivelan
- Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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5
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Viruses Binding to Host Receptors Interacts with Autophagy. Int J Mol Sci 2023; 24:ijms24043423. [PMID: 36834833 PMCID: PMC9968160 DOI: 10.3390/ijms24043423] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2022] [Revised: 01/19/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Viruses must cross the plasma membrane to infect cells, making them eager to overcome this barrier in order to replicate in hosts. They bind to cell surface receptors as the first step of initiating entry. Viruses can use several surface molecules that allow them to evade defense mechanisms. Various mechanisms are stimulated to defend against viruses upon their entry into cells. Autophagy, one of the defense systems, degrades cellular components to maintain homeostasis. The presence of viruses in the cytosol regulates autophagy; however, the mechanisms by which viral binding to receptors regulates autophagy have not yet been fully established. This review discusses recent findings on autophagy induced by interactions between viruses and receptors. It provides novel perspectives on the mechanism of autophagy as regulated by viruses.
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6
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Hamajima R, Lusiany T, Minami S, Nouda R, Nurdin JA, Yamasaki M, Kobayashi N, Kanai Y, Kobayashi T. A reverse genetics system for human rotavirus G2P[4]. J Gen Virol 2022; 103. [PMID: 36748482 DOI: 10.1099/jgv.0.001816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/23/2022] Open
Abstract
Rotaviruses (RVs) are an important cause of acute gastroenteritis in young children. Recently, versatile plasmid-based reverse genetics systems were developed for several human RV genotypes; however, these systems have not been developed for all commonly circulating human RV genotypes. In this study, we established a reverse genetics system for G2P[4] human RV strain HN126. Nucleotide sequence analysis, including that of the terminal ends of the viral double-stranded RNA genome, revealed that HN126 possessed a DS-1-like genotype constellation. Eleven plasmids, each encoding 11 gene segments of the RV genome, and expression plasmids encoding vaccinia virus RNA capping enzyme (D1R and D12L), Nelson Bay orthoreovirus FAST, and NSP2 and NSP5 of HN126, were transfected into BHK-T7 cells, and recombinant strain HN126 was generated. Using HN126 or simian RV strain SA11 as backbone viruses, reassortant RVs carrying the outer and intermediate capsid proteins (VP4, VP7 and VP6) of HN126 and/or SA11 (in various combinations) were generated. Viral replication analysis of the single, double and triple reassortant viruses suggested that homologous combination of the VP4 and VP7 proteins contributed to efficient virus infectivity and interaction between other viral or cellular proteins. Further studies of reassortant viruses between simian and other human RV strains will contribute to developing an appropriate model for human RV research, as well as suitable backbone viruses for generation of recombinant vaccine candidates.
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Affiliation(s)
- Rina Hamajima
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan.,Present address: Laboratory of Sericulture and Entomoresources, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Chikusa, Japan
| | - Tina Lusiany
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Shohei Minami
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Ryotaro Nouda
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Jeffery A Nurdin
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Moeko Yamasaki
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Nobumichi Kobayashi
- Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yuta Kanai
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan
| | - Takeshi Kobayashi
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Japan.,Center for Infectious Disease Education and Research, Osaka University, Suita, Osaka, Japan
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7
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Mohanty SK, Donnelly B, Temple H, Mowery S, Poling H, Meller J, Malik A, McNeal M, Tiao G. Rhesus rotavirus receptor-binding site affects high mobility group box 1 release, altering the pathogenesis of experimental biliary atresia. Hepatol Commun 2022; 6:2702-2714. [PMID: 35866580 PMCID: PMC9512450 DOI: 10.1002/hep4.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/15/2022] [Revised: 05/26/2022] [Accepted: 05/30/2022] [Indexed: 11/10/2022] Open
Abstract
Biliary atresia (BA) is a neonatal inflammatory cholangiopathy that requires surgical intervention by Kasai portoenterostomy to restore biliary drainage. Even with successful portoenterostomy, most patients diagnosed with BA progress to end-stage liver disease, necessitating a liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of neonatal mice induces an inflammatory obstructive cholangiopathy that parallels human BA. The model is triggered by RRV viral protein (VP)4 binding to cholangiocyte cell-surface proteins. High mobility group box 1 (HMGB1) protein is a danger-associated molecular pattern that when released extracellularly moderates innate and adaptive immune response. In this study, we investigated how mutations in three RRV VP4-binding sites, RRVVP4-K187R (sialic acid-binding site), RRVVP4-D308A (integrin α2β1-binding site), and RRVVP4-R446G (heat shock cognate 70 [Hsc70]-binding site), affects infection, HMGB1 release, and the murine model of BA. Newborn pups injected with RRVVP4-K187R and RRVVP4-D308A developed an obstruction within the extrahepatic bile duct similar to wild-type RRV, while those infected with RRVVP4-R446G remained patent. Infection with RRVVP4-R446G induced a lower level of HMGB1 release from cholangiocytes and in the serum of infected pups. RRV infection of HeLa cells lacking Hsc70 resulted in no HMGB1 release, while transfection with wild-type Hsc70 into HeLa Hsc70-deficient cells reestablished HMGB1 release, indicating a mechanistic role for Hsc70 in its release. Conclusion: Binding to Hsc70 contributes to HMGB1 release; therefore, Hsc70 potentially serves as a therapeutic target for BA.
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Affiliation(s)
- Sujit K. Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Haley Temple
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Sarah Mowery
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Holly M. Poling
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Jaroslaw Meller
- Department of Environmental and Public Health SciencesUniversity of CincinnatiCincinnatiOhioUSA
- Division of Biomedical InformaticsCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Astha Malik
- Division of Gastroenterology, Hepatology, and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Monica McNeal
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Division of Infectious DiseasesCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
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8
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The Underestimated Role of Platelets in Severe Infection a Narrative Review. Cells 2022; 11:cells11030424. [PMID: 35159235 PMCID: PMC8834344 DOI: 10.3390/cells11030424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/06/2021] [Revised: 01/16/2022] [Accepted: 01/23/2022] [Indexed: 12/13/2022] Open
Abstract
Beyond their role in hemostasis, platelets have emerged as key contributors in the immune response; accordingly, the occurrence of thrombocytopenia during sepsis/septic shock is a well-known risk factor of mortality and a marker of disease severity. Recently, some studies elucidated that the response of platelets to infections goes beyond a simple fall in platelets count; indeed, sepsis-induced thrombocytopenia can be associated with—or even anticipated by—several changes, including an altered morphological pattern, receptor expression and aggregation. Of note, alterations in platelet function and morphology can occur even with a normal platelet count and can modify, depending on the nature of the pathogen, the pattern of host response and the severity of the infection. The purpose of this review is to give an overview on the pathophysiological interaction between platelets and pathogens, as well as the clinical consequences of platelet dysregulation. Furthermore, we try to clarify how understanding the nature of platelet dysregulation may help to optimize the therapeutic approach.
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9
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Amimo JO, Raev SA, Chepngeno J, Mainga AO, Guo Y, Saif L, Vlasova AN. Rotavirus Interactions With Host Intestinal Epithelial Cells. Front Immunol 2021; 12:793841. [PMID: 35003114 PMCID: PMC8727603 DOI: 10.3389/fimmu.2021.793841] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/12/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
Rotavirus (RV) is the foremost enteric pathogen associated with severe diarrheal illness in young children (<5years) and animals worldwide. RV primarily infects mature enterocytes in the intestinal epithelium causing villus atrophy, enhanced epithelial cell turnover and apoptosis. Intestinal epithelial cells (IECs) being the first physical barrier against RV infection employs a range of innate immune strategies to counteract RVs invasion, including mucus production, toll-like receptor signaling and cytokine/chemokine production. Conversely, RVs have evolved numerous mechanisms to escape/subvert host immunity, seizing translation machinery of the host for effective replication and transmission. RV cell entry process involve penetration through the outer mucus layer, interaction with cell surface molecules and intestinal microbiota before reaching the IECs. For successful cell attachment and entry, RVs use sialic acid, histo-blood group antigens, heat shock cognate protein 70 and cell-surface integrins as attachment factors and/or (co)-receptors. In this review, a comprehensive summary of the existing knowledge of mechanisms underlying RV-IECs interactions, including the role of gut microbiota, during RV infection is presented. Understanding these mechanisms is imperative for developing efficacious strategies to control RV infections, including development of antiviral therapies and vaccines that target specific immune system antagonists within IECs.
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Affiliation(s)
- Joshua Oluoch Amimo
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Animal Production, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - Sergei Alekseevich Raev
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Juliet Chepngeno
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Alfred Omwando Mainga
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
- Department of Public Health, Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - Yusheng Guo
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Linda Saif
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
| | - Anastasia N. Vlasova
- Center for Food Animal Health, Department of Animal Sciences, College of Food Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, United States
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10
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Diller JR, Carter MH, Kanai Y, Sanchez SV, Kobayashi T, Ogden KM. Monoreassortant rotaviruses of multiple G types are differentially neutralized by sera from infants vaccinated with ROTARIX® and RotaTeq®. J Infect Dis 2021; 224:1720-1729. [PMID: 34628500 DOI: 10.1093/infdis/jiab479] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/21/2021] [Accepted: 09/16/2021] [Indexed: 12/30/2022] Open
Abstract
Rotavirus is a leading cause of pediatric diarrheal mortality. The rotavirus outer capsid consists of VP7 and VP4 proteins, which respectively determine viral G and P type and are primary targets of neutralizing antibodies. To elucidate VP7-specific neutralizing antibody responses, we engineered monoreassortant rotaviruses each containing a human VP7 segment from a sequenced clinical specimen or a vaccine strain in an identical genetic background. We quantified replication and neutralization of engineered viruses using sera from infants vaccinated with monovalent ROTARIX® or multivalent RotaTeq® vaccines. Immunization with RotaTeq® induced broader neutralizing antibody responses than ROTARIX®. Inclusion of a single dose of RotaTeq® in the schedule enhanced G-type neutralization breadth of vaccinated infant sera. Cell type-specific differences in infectivity, replication, and neutralization were detected for some monoreassortant viruses. These findings suggest that rotavirus VP7, independent of VP4, can contribute to cell tropism and the breadth of vaccine-elicited neutralizing antibody responses.
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Affiliation(s)
- Julia R Diller
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Maximilian H Carter
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Yuta Kanai
- Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Shania V Sanchez
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Takeshi Kobayashi
- Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
| | - Kristen M Ogden
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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11
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Tugizov S. Virus-associated disruption of mucosal epithelial tight junctions and its role in viral transmission and spread. Tissue Barriers 2021; 9:1943274. [PMID: 34241579 DOI: 10.1080/21688370.2021.19432749] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 05/25/2023] Open
Abstract
Oropharyngeal, airway, intestinal, and genital mucosal epithelia are the main portals of entry for the majority of human pathogenic viruses. To initiate systemic infection, viruses must first be transmitted across the mucosal epithelium and then spread across the body. However, mucosal epithelia have well-developed tight junctions, which have a strong barrier function that plays a critical role in preventing the spread and dissemination of viral pathogens. Viruses can overcome these barriers by disrupting the tight junctions of mucosal epithelia, which facilitate paracellular viral penetration and initiate systemic disease. Disruption of tight and adherens junctions may also release the sequestered viral receptors within the junctional areas, and liberation of hidden receptors may facilitate viral infection of mucosal epithelia. This review focuses on possible molecular mechanisms of virus-associated disruption of mucosal epithelial junctions and its role in transmucosal viral transmission and spread.
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Affiliation(s)
- Sharof Tugizov
- Department of Medicine, School of Medicine, University of California-San Francisco, San Francisco, CA, USA
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12
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Tugizov S. Virus-associated disruption of mucosal epithelial tight junctions and its role in viral transmission and spread. Tissue Barriers 2021; 9:1943274. [PMID: 34241579 DOI: 10.1080/21688370.2021.1943274] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/27/2022] Open
Abstract
Oropharyngeal, airway, intestinal, and genital mucosal epithelia are the main portals of entry for the majority of human pathogenic viruses. To initiate systemic infection, viruses must first be transmitted across the mucosal epithelium and then spread across the body. However, mucosal epithelia have well-developed tight junctions, which have a strong barrier function that plays a critical role in preventing the spread and dissemination of viral pathogens. Viruses can overcome these barriers by disrupting the tight junctions of mucosal epithelia, which facilitate paracellular viral penetration and initiate systemic disease. Disruption of tight and adherens junctions may also release the sequestered viral receptors within the junctional areas, and liberation of hidden receptors may facilitate viral infection of mucosal epithelia. This review focuses on possible molecular mechanisms of virus-associated disruption of mucosal epithelial junctions and its role in transmucosal viral transmission and spread.
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Affiliation(s)
- Sharof Tugizov
- Department of Medicine, School of Medicine, University of California-San Francisco, San Francisco, CA, USA
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13
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Yang J, Park J, Koehler M, Simpson J, Luque D, Rodríguez JM, Alsteens D. Rotavirus Binding to Cell Surface Receptors Directly Recruiting α
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Integrin. ADVANCED NANOBIOMED RESEARCH 2021. [DOI: 10.1002/anbr.202100077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/21/2023] Open
Affiliation(s)
- Jinsung Yang
- Louvain Institute of Biomolecular Science and Technology Université Catholique de Louvain Louvain-la-Neuve 1348 Belgium
| | | | - Melanie Koehler
- Louvain Institute of Biomolecular Science and Technology Université Catholique de Louvain Louvain-la-Neuve 1348 Belgium
| | - Joshua Simpson
- Louvain Institute of Biomolecular Science and Technology Université Catholique de Louvain Louvain-la-Neuve 1348 Belgium
| | - Daniel Luque
- Centro Nacional de Microbiología/ISCIII Madrid 28220 Spain
| | | | - David Alsteens
- Louvain Institute of Biomolecular Science and Technology Université Catholique de Louvain Louvain-la-Neuve 1348 Belgium
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14
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Erdei A, Kovács KG, Nagy-Baló Z, Lukácsi S, Mácsik-Valent B, Kurucz I, Bajtay Z. New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4. Immunol Lett 2021; 237:42-57. [PMID: 34186155 DOI: 10.1016/j.imlet.2021.06.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/18/2021] [Revised: 06/17/2021] [Accepted: 06/23/2021] [Indexed: 10/21/2022]
Abstract
The involvement of complement in the regulation of antibody responses has been known for long. By now several additional B cell functions - including cytokine production and antigen presentation - have also been shown to be regulated by complement proteins. Most of these important activities are mediated by receptors interacting with activation fragments of the central component of the complement system C3, such as C3b, iC3b and C3d, which are covalently attached to antigens and immune complexes. This review summarizes the role of complement receptors interacting with these ligands, namely CR1 (CD35), CR2 (CD21), CR3 (CD11b/CD18) and CR4 (CD11c/CD18) expressed by B cells in health and disease. Although we focus on human B lymphocytes, we also aim to call the attention to important differences between human and mouse systems.
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Affiliation(s)
- Anna Erdei
- Department of Immunology, Eötvös Loránd University, Budapest, Hungary; MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.
| | - Kristóf G Kovács
- Department of Immunology, Eötvös Loránd University, Budapest, Hungary
| | - Zsuzsa Nagy-Baló
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary
| | - Szilvia Lukácsi
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary
| | | | - István Kurucz
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary
| | - Zsuzsa Bajtay
- Department of Immunology, Eötvös Loránd University, Budapest, Hungary; MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary
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15
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Arias CF, López S. Rotavirus cell entry: not so simple after all. Curr Opin Virol 2021; 48:42-48. [PMID: 33887683 DOI: 10.1016/j.coviro.2021.03.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/20/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 01/25/2023]
Abstract
Rotaviruses are important agents of severe gastroenteritis in young children, and show a very selective cell and tissue tropism, as well as significant age and host restriction. In the last few years, these properties have been associated with the initial interaction of the virus with histo-blood group antigens on the cell surface, although post-attachment interactions have also been found to define the susceptibility to infection of human enteroids. These initial interactions seem also to determine the virus entry pathway, as well as the induction of signaling cascades that influence the virus intracellular vesicular traffic and escape from endosomes. Here we review the current knowledge of the different stages of the virus entry journey.
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Affiliation(s)
- Carlos F Arias
- Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, Mexico.
| | - Susana López
- Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, Mexico
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16
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Tarris G, de Rougemont A, Charkaoui M, Michiels C, Martin L, Belliot G. Enteric Viruses and Inflammatory Bowel Disease. Viruses 2021; 13:v13010104. [PMID: 33451106 PMCID: PMC7828589 DOI: 10.3390/v13010104] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/23/2020] [Revised: 01/04/2021] [Accepted: 01/08/2021] [Indexed: 12/16/2022] Open
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.
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Affiliation(s)
- Georges Tarris
- Department of Pathology, University Hospital of Dijon, F 21000 Dijon, France; (G.T.); (L.M.)
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
| | - Alexis de Rougemont
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
| | - Maëva Charkaoui
- Department of Hepatogastroenterology, University Hospital of Dijon, F 21000 Dijon, France; (M.C.); (C.M.)
| | - Christophe Michiels
- Department of Hepatogastroenterology, University Hospital of Dijon, F 21000 Dijon, France; (M.C.); (C.M.)
| | - Laurent Martin
- Department of Pathology, University Hospital of Dijon, F 21000 Dijon, France; (G.T.); (L.M.)
| | - Gaël Belliot
- National Reference Centre for Gastroenteritis Viruses, Laboratory of Virology, University Hospital of Dijon, F 21000 Dijon, France;
- Correspondence: ; Tel.: +33-380-293-171; Fax: +33-380-293-280
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17
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Kanai Y, Onishi M, Kawagishi T, Pannacha P, Nurdin JA, Nouda R, Yamasaki M, Lusiany T, Khamrin P, Okitsu S, Hayakawa S, Ebina H, Ushijima H, Kobayashi T. Reverse Genetics Approach for Developing Rotavirus Vaccine Candidates Carrying VP4 and VP7 Genes Cloned from Clinical Isolates of Human Rotavirus. J Virol 2020; 95:e01374-20. [PMID: 33087468 PMCID: PMC7944460 DOI: 10.1128/jvi.01374-20] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/13/2020] [Accepted: 10/15/2020] [Indexed: 12/21/2022] Open
Abstract
Species A rotaviruses (RVs) are a leading cause of severe acute gastroenteritis in infants and children younger than 5 years. Currently available RV vaccines were adapted from wild-type RV strains by serial passage of cultured cells or by reassortment between human and animal RV strains. These traditional methods require large-scale screening and genotyping to obtain vaccine candidates. Reverse genetics is a tractable, rapid, and reproducible approach to generating recombinant RV vaccine candidates carrying any VP4 and VP7 genes that provide selected antigenicity. Here, we developed a vaccine platform by generating recombinant RVs carrying VP4 (P[4] and P[8]), VP7 (G1, G2, G3, G8, and G9), and/or VP6 genes cloned from human RV clinical samples using the simian RV SA11 strain (G3P[2]) as a backbone. Neutralization assays using monoclonal antibodies and murine antisera revealed that recombinant VP4 and VP7 monoreassortant viruses exhibited altered antigenicity. However, replication of VP4 monoreassortant viruses was severely impaired. Generation of recombinant RVs harboring a chimeric VP4 protein for SA11 and human RV gene components revealed that the VP8* fragment was responsible for efficient infectivity of recombinant RVs. Although this system must be improved because the yield of vaccine viruses directly affects vaccine manufacturing costs, reverse genetics requires less time than traditional methods and enables rapid production of safe and effective vaccine candidates.IMPORTANCE Although vaccines have reduced global RV-associated hospitalization and mortality over the past decade, the multisegmented genome of RVs allows reassortment of VP4 and VP7 genes from different RV species and strains. The evolutionary dynamics of novel RV genotypes and their constellations have led to great genomic and antigenic diversity. The reverse genetics system is a powerful tool for manipulating RV genes, thereby controlling viral antigenicity, growth capacity, and pathogenicity. Here, we generated recombinant simian RVs (strain SA11) carrying heterologous VP4 and VP7 genes cloned from clinical isolates and showed that VP4- or VP7-substituted chimeric viruses can be used for antigenic characterization of RV outer capsid proteins and as improved seed viruses for vaccine production.
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Affiliation(s)
- Yuta Kanai
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Misa Onishi
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Takahiro Kawagishi
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Pimfhun Pannacha
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Jeffery A Nurdin
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Ryotaro Nouda
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Moeko Yamasaki
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Tina Lusiany
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
| | - Pattara Khamrin
- Department of Microbiology, Chiang Mai University, Faculty of Medicine, Chiang Mai, Thailand
- Center of Excellence in Emerging and Re-emerging Diarrheal Viruses, Chiang Mai University, Chiang Mai, Thailand
| | - Shoko Okitsu
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Satoshi Hayakawa
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Hirotaka Ebina
- Biken Center for Innovative Vaccine Research and Development, The Research Foundation for Microbial Diseases of Osaka University (BIKEN), Suita, Osaka, Japan
| | - Hiroshi Ushijima
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan
| | - Takeshi Kobayashi
- Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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18
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Kumar NA, Kunnakkadan U, Thomas S, Johnson JB. In the Crosshairs: RNA Viruses OR Complement? Front Immunol 2020; 11:573583. [PMID: 33133089 PMCID: PMC7550403 DOI: 10.3389/fimmu.2020.573583] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/17/2020] [Accepted: 08/24/2020] [Indexed: 12/02/2022] Open
Abstract
Complement, a part of the innate arm of the immune system, is integral to the frontline defense of the host against innumerable pathogens, which includes RNA viruses. Among the major groups of viruses, RNA viruses contribute significantly to the global mortality and morbidity index associated with viral infection. Despite multiple routes of entry adopted by these viruses, facing complement is inevitable. The initial interaction with complement and the nature of this interaction play an important role in determining host resistance versus susceptibility to the viral infection. Many RNA viruses are potent activators of complement, often resulting in virus neutralization. Yet, another facet of virus-induced activation is the exacerbation in pathogenesis contributing to the overall morbidity. The severity in disease and death associated with RNA virus infections shows a tip in the scale favoring viruses. Growing evidence suggest that like their DNA counterparts, RNA viruses have co-evolved to master ingenious strategies to remarkably restrict complement. Modulation of host genes involved in antiviral responses contributed prominently to the adoption of unique strategies to keep complement at bay, which included either down regulation of activation components (C3, C4) or up regulation of complement regulatory proteins. All this hints at a possible “hijacking” of the cross-talk mechanism of the host immune system. Enveloped RNA viruses have a selective advantage of not only modulating the host responses but also recruiting membrane-associated regulators of complement activation (RCAs). This review aims to highlight the significant progress in the understanding of RNA virus–complement interactions.
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Affiliation(s)
- Nisha Asok Kumar
- Viral Disease Biology, Department of Pathogen Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, India.,Manipal Academy of Higher Education, Manipal, India
| | - Umerali Kunnakkadan
- Viral Disease Biology, Department of Pathogen Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, India.,Department of Biotechnology, University of Kerala, Thiruvananthapuram, India
| | - Sabu Thomas
- Cholera and Biofilm Research Lab, Department of Pathogen Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, India
| | - John Bernet Johnson
- Viral Disease Biology, Department of Pathogen Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, India
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19
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Page MJ, Pretorius E. A Champion of Host Defense: A Generic Large-Scale Cause for Platelet Dysfunction and Depletion in Infection. Semin Thromb Hemost 2020; 46:302-319. [PMID: 32279287 PMCID: PMC7339151 DOI: 10.1055/s-0040-1708827] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Thrombocytopenia is commonly associated with sepsis and infections, which in turn are characterized by a profound immune reaction to the invading pathogen. Platelets are one of the cellular entities that exert considerable immune, antibacterial, and antiviral actions, and are therefore active participants in the host response. Platelets are sensitive to surrounding inflammatory stimuli and contribute to the immune response by multiple mechanisms, including endowing the endothelium with a proinflammatory phenotype, enhancing and amplifying leukocyte recruitment and inflammation, promoting the effector functions of immune cells, and ensuring an optimal adaptive immune response. During infection, pathogens and their products influence the platelet response and can even be toxic. However, platelets are able to sense and engage bacteria and viruses to assist in their removal and destruction. Platelets greatly contribute to host defense by multiple mechanisms, including forming immune complexes and aggregates, shedding their granular content, and internalizing pathogens and subsequently being marked for removal. These processes, and the nature of platelet function in general, cause the platelet to be irreversibly consumed in the execution of its duty. An exaggerated systemic inflammatory response to infection can drive platelet dysfunction, where platelets are inappropriately activated and face immunological destruction. While thrombocytopenia may arise by condition-specific mechanisms that cause an imbalance between platelet production and removal, this review evaluates a generic large-scale mechanism for platelet depletion as a repercussion of its involvement at the nexus of responses to infection.
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Affiliation(s)
- Martin J Page
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Etheresia Pretorius
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
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20
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Mohanty SK, Lobeck I, Donnelly B, Dupree P, Walther A, Mowery S, Coots A, Bondoc A, Sheridan RM, Poling HM, Temple H, McNeal M, Sestak K, Bansal R, Tiao G. Rotavirus Reassortant-Induced Murine Model of Liver Fibrosis Parallels Human Biliary Atresia. Hepatology 2020; 71:1316-1330. [PMID: 31442322 PMCID: PMC7384231 DOI: 10.1002/hep.30907] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/23/2019] [Accepted: 08/15/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a devastating neonatal cholangiopathy that progresses to fibrosis and end-stage liver disease by 2 years of age. Portoenterostomy may reestablish biliary drainage, but, despite drainage, virtually all afflicted patients develop fibrosis and progress to end-stage liver disease requiring liver transplantation for survival. APPROACH AND RESULTS In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling human BA and has been used to study mechanistic aspects of the disease. Unfortunately, nearly all RRV-infected pups succumb by day of life 14. Thus, in this study we generated an RRV-TUCH rotavirus reassortant (designated as TR(VP2,VP4) ) that when injected into newborn mice causes an obstructive jaundice phenotype with lower mortality rates. Of the mice that survived, 63% developed Ishak stage 3-5 fibrosis with histopathological signs of inflammation/fibrosis and bile duct obstruction. CONCLUSIONS This model of rotavirus-induced neonatal fibrosis will provide an opportunity to study disease pathogenesis and has potential to be used in preclinical studies with an objective to identify therapeutic targets that may alter the course of BA.
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Affiliation(s)
- Sujit K. Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Inna Lobeck
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Phylicia Dupree
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Ashley Walther
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Sarah Mowery
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Abigail Coots
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Alexander Bondoc
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Rachel M. Sheridan
- Division of Pathology and Laboratory MedicineCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Holly M. Poling
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Haley Temple
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Monica McNeal
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOH,Division of Infectious DiseasesCincinnati Children’s Hospital Medical CenterCincinnatiOH
| | - Karol Sestak
- Tulane National Primate Research CenterCovingtonLA
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Technical Medical CentreUniversity of TwenteEnschedethe Netherlands
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children’s Hospital Medical CenterCincinnatiOH
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21
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Lukácsi S, Mácsik-Valent B, Nagy-Baló Z, Kovács KG, Kliment K, Bajtay Z, Erdei A. Utilization of complement receptors in immune cell-microbe interaction. FEBS Lett 2020; 594:2695-2713. [PMID: 31989596 DOI: 10.1002/1873-3468.13743] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/06/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/19/2022]
Abstract
The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade. Not all pathogens are lysed however and, if opsonized by a variety of molecules, they undergo phagocytosis and disposal inside immune cells. The most important complement-derived opsonins are C1q, the first component of the classical pathway, MBL, the initiator of the lectin pathway and C3-derived activation fragments, including C3b, iC3b and C3d, which all serve as ligands for their corresponding receptors. In this review, we discuss how complement receptors are utilized by various immune cells to tackle invading microbes, or by pathogens to evade host response.
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Affiliation(s)
- Szilvia Lukácsi
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary
| | | | - Zsuzsa Nagy-Baló
- Department of Immunology, Eötvös Loránd University, Budapest, Hungary
| | - Kristóf G Kovács
- Department of Immunology, Eötvös Loránd University, Budapest, Hungary
| | | | - Zsuzsa Bajtay
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.,Department of Immunology, Eötvös Loránd University, Budapest, Hungary
| | - Anna Erdei
- MTA-ELTE Immunology Research Group, Eötvös Loránd University, Budapest, Hungary.,Department of Immunology, Eötvös Loránd University, Budapest, Hungary
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22
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Rodríguez JM, Luque D. Structural Insights into Rotavirus Entry. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1215:45-68. [PMID: 31317495 DOI: 10.1007/978-3-030-14741-9_3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 12/04/2022]
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23
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Ghosh S, Malik YS, Kobayashi N. Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future. Curr Drug Metab 2018; 19:170-191. [PMID: 28901254 PMCID: PMC5971199 DOI: 10.2174/1389200218666170912161449] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/04/2016] [Revised: 09/25/2016] [Accepted: 03/19/2017] [Indexed: 12/20/2022]
Abstract
Background: Noroviruses and rotaviruses are important viral etiologies of severe gastroenteritis. Noroviruses are the primary cause of nonbacterial diarrheal outbreaks in humans, whilst rotaviruses are a major cause of childhood diarrhea. Although both enteric pathogens substantially impact human health and economies, there are no approved drugs against noroviruses and rotaviruses so far. On the other hand, whilst the currently licensed rotavirus vaccines have been successfully implemented in over 100 countries, the most advanced norovirus vaccine has recently completed phase-I and II trials. Methods: We performed a structured search of bibliographic databases for peer-reviewed research litera-ture on advances in the fields of norovirus and rotavirus therapeutics and immunoprophylaxis. Results: Technological advances coupled with a proper understanding of viral morphology and replication over the past decade has facilitated pioneering research on therapeutics and immunoprophylaxis against noroviruses and rotaviruses, with promising outcomes in human clinical trials of some of the drugs and vaccines. This review focuses on the various developments in the fields of norovirus and rotavirus thera-peutics and immunoprophylaxis, such as potential antiviral drug molecules, passive immunotherapies (oral human immunoglobulins, egg yolk and bovine colostral antibodies, llama-derived nanobodies, and anti-bodies expressed in probiotics, plants, rice grains and insect larvae), immune system modulators, probiot-ics, phytochemicals and other biological substances such as bovine milk proteins, therapeutic nanoparti-cles, hydrogels and viscogens, conventional viral vaccines (live and inactivated whole virus vaccines), and genetically engineered viral vaccines (reassortant viral particles, virus-like particles (VLPs) and other sub-unit recombinant vaccines including multi-valent viral vaccines, edible plant vaccines, and encapsulated viral particles). Conclusions: This review provides important insights into the various approaches to therapeutics and im-munoprophylaxis against noroviruses and rotaviruses..
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Affiliation(s)
- Souvik Ghosh
- Department of Biomedical Sciences, Ross University School of Veterinary Medicine, St. Kitts and Nevis, West Indies.,Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
| | - Yashpal Singh Malik
- Indian Veterinary Research Institute, Izatnagar 243 122, Uttar Pradesh, India
| | - Nobumichi Kobayashi
- Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
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24
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Maginnis MS. Virus-Receptor Interactions: The Key to Cellular Invasion. J Mol Biol 2018; 430:2590-2611. [PMID: 29924965 PMCID: PMC6083867 DOI: 10.1016/j.jmb.2018.06.024] [Citation(s) in RCA: 205] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/25/2018] [Revised: 06/04/2018] [Accepted: 06/08/2018] [Indexed: 11/05/2022]
Abstract
Virus–receptor interactions play a key regulatory role in viral host range, tissue tropism, and viral pathogenesis. Viruses utilize elegant strategies to attach to one or multiple receptors, overcome the plasma membrane barrier, enter, and access the necessary host cell machinery. The viral attachment protein can be viewed as the “key” that unlocks host cells by interacting with the “lock”—the receptor—on the cell surface, and these lock-and-key interactions are critical for viruses to successfully invade host cells. Many common themes have emerged in virus–receptor utilization within and across virus families demonstrating that viruses often target particular classes of molecules in order to mediate these events. Common viral receptors include sialylated glycans, cell adhesion molecules such as immunoglobulin superfamily members and integrins, and phosphatidylserine receptors. The redundancy in receptor usage suggests that viruses target particular receptors or “common locks” to take advantage of their cellular function and also suggests evolutionary conservation. Due to the importance of initial virus interactions with host cells in viral pathogenesis and the redundancy in viral receptor usage, exploitation of these strategies would be an attractive target for new antiviral therapeutics.
Viral receptors are key regulators of host range, tissue tropism, and viral pathogenesis. Many viruses utilize common viral receptors including sialic acid, cell adhesion molecules such as immunoglobulin superfamily members and integrins, and phosphatidylserine receptors. Detailed molecular interactions between viruses and receptors have been defined through elegant biochemical analyses including glycan array screens, structural–functional analyses, and cell-based approaches providing tremendous insights into these initial events in viral infection. Commonalities in virus–receptor interactions present promising targets for the development of broad-spectrum antiviral therapies.
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Affiliation(s)
- Melissa S Maginnis
- Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469-5735, USA.
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25
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Wen YH, Chen DP. Human platelet antigens in disease. Clin Chim Acta 2018; 484:87-90. [PMID: 29802830 DOI: 10.1016/j.cca.2018.05.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/06/2018] [Revised: 05/05/2018] [Accepted: 05/07/2018] [Indexed: 12/16/2022]
Abstract
Platelets have various functions and participate in primary hemostasis, inflammation, and immune responses. Human platelet antigens (HPAs) are alloantigens expressed on the platelet membrane. Each HPA represent one of six platelet glycoproteins GPIIb, GPIIIa, GPIa, GPIbα, GPIbβ, and CD109, and six biallelic systems are grouped. A single nucleotide polymorphism (SNP) in the gene sequence causes a single amino acid substitution of relevant platelet glycoprotein with the exception of HPA-14bw. High-throughput next-generation sequencing-based method has been developed, which enable accurately identification of HPA polymorphisms. The roles of HPA in disease were reviewed. HPAs mediate platelet-microorganism and platelet-malignant cell interactions, and they also participate in pathogenesis of hemorrhagic fever with renal syndrome and infective endocarditis. The exploration of HPA polymorphisms in association with disease susceptibility of individuals will benefit prevention or management of disease.
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Affiliation(s)
- Ying-Hao Wen
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ding-Ping Chen
- Department of Laboratory Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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26
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Giansanti F, Flavell DJ, Angelucci F, Fabbrini MS, Ippoliti R. Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins. Toxins (Basel) 2018; 10:toxins10020082. [PMID: 29438358 PMCID: PMC5848183 DOI: 10.3390/toxins10020082] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/16/2017] [Revised: 01/29/2018] [Accepted: 02/11/2018] [Indexed: 02/06/2023] Open
Abstract
Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti-cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins.
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Affiliation(s)
- Francesco Giansanti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, I-67100 L'Aquila, Italy.
| | - David J Flavell
- The Simon Flavell Leukaemia Research Laboratory (Leukaemia Busters), Southampton General Hospital, Southampton, SO16 8AT, UK.
| | - Francesco Angelucci
- Department of Life, Health and Environmental Sciences, University of L'Aquila, I-67100 L'Aquila, Italy.
| | | | - Rodolfo Ippoliti
- Department of Life, Health and Environmental Sciences, University of L'Aquila, I-67100 L'Aquila, Italy.
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Beyond the Matrix: The Many Non-ECM Ligands for Integrins. Int J Mol Sci 2018; 19:ijms19020449. [PMID: 29393909 PMCID: PMC5855671 DOI: 10.3390/ijms19020449] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/31/2017] [Revised: 01/21/2018] [Accepted: 01/30/2018] [Indexed: 12/17/2022] Open
Abstract
The traditional view of integrins portrays these highly conserved cell surface receptors as mediators of cellular attachment to the extracellular matrix (ECM), and to a lesser degree, as coordinators of leukocyte adhesion to the endothelium. These canonical activities are indispensable; however, there is also a wide variety of integrin functions mediated by non-ECM ligands that transcend the traditional roles of integrins. Some of these unorthodox roles involve cell-cell interactions and are engaged to support immune functions such as leukocyte transmigration, recognition of opsonization factors, and stimulation of neutrophil extracellular traps. Other cell-cell interactions mediated by integrins include hematopoietic stem cell and tumor cell homing to target tissues. Integrins also serve as cell-surface receptors for various growth factors, hormones, and small molecules. Interestingly, integrins have also been exploited by a wide variety of organisms including viruses and bacteria to support infectious activities such as cellular adhesion and/or cellular internalization. Additionally, the disruption of integrin function through the use of soluble integrin ligands is a common strategy adopted by several parasites in order to inhibit blood clotting during hematophagy, or by venomous snakes to kill prey. In this review, we strive to go beyond the matrix and summarize non-ECM ligands that interact with integrins in order to highlight these non-traditional functions of integrins.
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Activation of PI3K, Akt, and ERK during early rotavirus infection leads to V-ATPase-dependent endosomal acidification required for uncoating. PLoS Pathog 2018; 14:e1006820. [PMID: 29352319 PMCID: PMC5792019 DOI: 10.1371/journal.ppat.1006820] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/29/2017] [Revised: 01/31/2018] [Accepted: 12/15/2017] [Indexed: 11/19/2022] Open
Abstract
The cellular PI3K/Akt and/or MEK/ERK signaling pathways mediate the entry process or endosomal acidification during infection of many viruses. However, their roles in the early infection events of group A rotaviruses (RVAs) have remained elusive. Here, we show that late-penetration (L-P) human DS-1 and bovine NCDV RVA strains stimulate these signaling pathways very early in the infection. Inhibition of both signaling pathways significantly reduced production of viral progeny due to blockage of virus particles in the late endosome, indicating that neither of the two signaling pathways is involved in virus trafficking. However, immunoprecipitation assays using antibodies specific for pPI3K, pAkt, pERK and the subunit E of the V-ATPase co-immunoprecipitated the V-ATPase in complex with pPI3K, pAkt, and pERK. Moreover, Duolink proximity ligation assay revealed direct association of the subunit E of the V-ATPase with the molecules pPI3K, pAkt, and pERK, indicating that both signaling pathways are involved in V-ATPase-dependent endosomal acidification. Acidic replenishment of the medium restored uncoating of the RVA strains in cells pretreated with inhibitors specific for both signaling pathways, confirming the above results. Isolated components of the outer capsid proteins, expressed as VP4-VP8* and VP4-VP5* domains, and VP7, activated the PI3K/Akt and MEK/ERK pathways. Furthermore, psoralen-UV-inactivated RVA and CsCl-purified RVA triple-layered particles triggered activation of the PI3K/Akt and MEK/ERK pathways, confirming the above results. Our data demonstrate that multistep binding of outer capsid proteins of L-P RVA strains with cell surface receptors phosphorylates PI3K, Akt, and ERK, which in turn directly interact with the subunit E of the V-ATPase to acidify the late endosome for uncoating of RVAs. This study provides a better understanding of the RVA-host interaction during viral uncoating, which is of importance for the development of strategies aiming at controlling or preventing RVA infections. Viral particles must transport their genome into the cytoplasm or the nucleus of host cells to initiate successful infection. Knowledge of how viruses may pirate host cell signaling cascades or molecules to promote their own replication can facilitate the development of antiviral drugs. Group A rotavirus (RVA) is a major etiological agent of acute gastroenteritis in young children and the young of various mammals. RVA enters cells by a complex multistep process. However, the cellular signaling cascades or molecules that facilitate these processes are incompletely understood. Here, we demonstrate that infection with late-penetration RVA strains results in phosphorylation of PI3K, Akt, and ERK signaling molecules at an early stage of infection, a process mediated by the multistep binding of RVAs outer capsid proteins. Specific inhibitors for PI3K/Akt and MEK/ERK signaling pathways trap the viral particles in late endosome, and acidic replenishment restores and releases them. Moreover, the RVA-induced phosphorylated PI3K, Akt, and ERK directly interact with the subunit E of the V-ATPase proton pump, required for endosomal acidification and RVA uncoating. Understanding how RVA-induced early activation of cellular signaling molecules mediates the V-ATPase-dependent endosomal acidification required for uncoating of viral particles opens up opportunities for targeted interventions against rotavirus entry.
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Díaz-Salinas MA, Casorla LA, López T, López S, Arias CF. Most rotavirus strains require the cation-independent mannose-6-phosphate receptor, sortilin-1, and cathepsins to enter cells. Virus Res 2017; 245:44-51. [PMID: 29275103 PMCID: PMC7173016 DOI: 10.1016/j.virusres.2017.12.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/10/2017] [Revised: 12/04/2017] [Accepted: 12/06/2017] [Indexed: 12/27/2022]
Abstract
Rotaviruses require the TGN to LE transporter CI-M6PR for cell entry. Sortilin-1 was identified as a cell factor involved in rotavirus replication. Rotaviruses require cathepsins also to enter Caco-2 cells. Cathepsins, endosomal acid proteases, are transported from the trans-Golgi network to late endosomes by the mannose-6-phosphate receptor (M6PR). We have previously demonstrated that some rotavirus strains, like UK, Wa, WI61, DS-1, and YM, require the cation-dependent (CD-) M6PR and cathepsins to enter from late endosomes to the cytoplasm in MA104 cells, while other strains, like the simian strain RRV, which enter cells from maturing endosomes, do not. However, the role of other trans-Golgi network-late endosome transporters, such as the cation-independent (CI-) M6PR and sortillin-1, has not been evaluated. In this work, we found that several rotavirus strains that require the CD-M6PR for cell entry are also dependent on CI-M6PR and sortilin-1. Furthermore, we showed that the infectivity of all these rotavirus strains also requires cathepsins to enter not only MA104 cells, but also human intestinal Caco-2 cells. This study identifies sortilin-1 as a novel cell factor necessary for the infectivity of a virus; in addition, our results strongly suggest that cathepsins could be common cell factors needed for the infectivity of most rotavirus strains.
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Affiliation(s)
- Marco A Díaz-Salinas
- Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
| | - Luis A Casorla
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
| | - Tomás López
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
| | - Susana López
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico
| | - Carlos F Arias
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos 62210, Mexico.
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A Point Mutation in the Rhesus Rotavirus VP4 Protein Generated through a Rotavirus Reverse Genetics System Attenuates Biliary Atresia in the Murine Model. J Virol 2017; 91:JVI.00510-17. [PMID: 28515290 DOI: 10.1128/jvi.00510-17] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2017] [Accepted: 05/08/2017] [Indexed: 12/25/2022] Open
Abstract
Rotavirus infection is one of the most common causes of diarrheal illness in humans. In neonatal mice, rhesus rotavirus (RRV) can induce biliary atresia (BA), a disease resulting in inflammatory obstruction of the extrahepatic biliary tract and intrahepatic bile ducts. We previously showed that the amino acid arginine (R) within the sequence SRL (amino acids 445 to 447) in the RRV VP4 protein is required for viral binding and entry into biliary epithelial cells. To determine if this single amino acid (R) influences the pathogenicity of the virus, we generated a recombinant virus with a single amino acid mutation at this site through a reverse genetics system. We demonstrated that the RRV mutant (RRVVP4-R446G) produced less symptomatology and replicated to lower titers both in vivo and in vitro than those seen with wild-type RRV, with reduced binding in cholangiocytes. Our results demonstrate that a single amino acid change in the RRV VP4 gene influences cholangiocyte tropism and reduces pathogenicity in mice.IMPORTANCE Rotavirus is the leading cause of diarrhea in humans. Rhesus rotavirus (RRV) can also lead to biliary atresia (a neonatal human disease) in mice. We developed a reverse genetics system to create a mutant of RRV (RRVVP4-R446G) with a single amino acid change in the VP4 protein compared to that of wild-type RRV. In vitro, the mutant virus had reduced binding and infectivity in cholangiocytes. In vivo, it produced fewer symptoms and lower mortality in neonatal mice, resulting in an attenuated form of biliary atresia.
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Mohanty SK, Donnelly B, Lobeck I, Walther A, Dupree P, Coots A, Meller J, McNeal M, Sestak K, Tiao G. The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia. Hepatology 2017; 65:1278-1292. [PMID: 27859498 PMCID: PMC5360466 DOI: 10.1002/hep.28947] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/02/2016] [Accepted: 11/08/2016] [Indexed: 12/24/2022]
Abstract
UNLABELLED Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end-stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4-derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRV's ability to infect cholangiocytes. This virus-cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV-injected mice. CONCLUSION The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2017;65:1278-1292).
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Affiliation(s)
- Sujit K. Mohanty
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Bryan Donnelly
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Inna Lobeck
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Ashley Walther
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Phylicia Dupree
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Abigail Coots
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Jaroslaw Meller
- Department of Environmental HealthUniversity of Cincinnati & Division of Biomedical Informatics, Cincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Monica McNeal
- Division of Infectious DiseasesCincinnati Children's Hospital Medical CenterCincinnatiOH
| | - Karol Sestak
- Tulane National Primate Research CenterCovingtonLA
| | - Greg Tiao
- Department of Pediatric and Thoracic SurgeryCincinnati Children's Hospital Medical CenterCincinnatiOH
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Abstract
Virus–platelet interplay is complex. Diverse virus types have been shown to associate with numerous distinct platelet receptors. This association can benefit the virus or the host, and thus the platelet is somewhat of a renegade. Evidence is accumulating to suggest that viruses are capable of entering platelets. For at least one type of RNA virus (dengue virus), the platelet has the necessary post-translational and packaging machinery required for production of replicative viral progeny. As a facilitator of immunity, the platelet also participates in eradicating the virus by direct and indirect mechanisms involving presentation of the pathogen to the innate and adaptive immune systems, thus enhancing inflammation by release of cytokines and other agonists. Virus-induced thrombocytopenia is caused by tangential imbalance of thrombopoeisis, autoimmunity, and loss of platelet function and integrity.
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Abstract
INTRODUCTION Acquired thrombocytopenia recognizes a myriad of causes. Among these, infectious diseases play a relevant role since a low platelet count is commonplace along with other abnormal laboratory data. Areas covered: This narrative review, after a brief presentation of the possible pathogenic mechanisms, is focused on the most prevalent infections associated with thrombocytopenia, namely those attributable to hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Helicobacter pylori. Expert commentary: An underlying HCV or HIV infection should always be suspected in patients at risk who present with isolated thrombocytopenia. The eradication of Helicobacter pylori is advisable in infected patients with secondary immune thrombocytopenia, because this will increase the platelet count in a substantial number of cases, thus avoiding more aggressive and prolonged treatments.
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Affiliation(s)
- Massimo Franchini
- a Department of Hematology and Transfusion Medicine , Carlo Poma Hospital , Mantova , Italy
| | - Dino Veneri
- b Department of Medicine, Section of Haematology , University of Verona , Verona , Italy
| | - Giuseppe Lippi
- c Section of Clinical Biochemistry , University of Verona , Verona , Italy
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Glycan Specificity of P[19] Rotavirus and Comparison with Those of Related P Genotypes. J Virol 2016; 90:9983-9996. [PMID: 27558427 PMCID: PMC5068545 DOI: 10.1128/jvi.01494-16] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/27/2016] [Accepted: 08/21/2016] [Indexed: 12/24/2022] Open
Abstract
The P[19] genotype belongs to the P[II] genogroup of group A rotaviruses (RVs). However, unlike the other P[II] RVs, which mainly infect humans, P[19] RVs commonly infect animals (pigs), making P[19] unique for the study of RV diversity and host ranges. Through in vitro binding assays and saturation transfer difference (STD) nuclear magnetic resonance (NMR), we found that P[19] could bind mucin cores 2, 4, and 6, as well as type 1 histo-blood group antigens (HBGAs). The common sequences of these glycans serve as minimal binding units, while additional residues, such as the A, B, H, and Lewis epitopes of the type 1 HBGAs, can further define the binding outcomes and therefore likely the host ranges for P[19] RVs. This complex binding property of P[19] is shared with the other three P[II] RVs (P[4], P[6], and P[8]) in that all of them recognized the type 1 HBGA precursor, although P[4] and P[8], but not P[6], also bind to mucin cores. Moreover, while essential for P[4] and P[8] binding, the addition of the Lewis epitope blocked P[6] and P[19] binding to type 1 HBGAs. Chemical-shift NMR of P[19] VP8* identified a ligand binding interface that has shifted away from the known RV P-genotype binding sites but is conserved among all P[II] RVs and two P[I] RVs (P[10] and P[12]), suggesting an evolutionary connection among these human and animal RVs. Taken together, these data are important for hypotheses on potential mechanisms for RV diversity, host ranges, and cross-species transmission. IMPORTANCE In this study, we found that our P[19] strain and other P[II] RVs recognize mucin cores and the type 1 HBGA precursors as the minimal functional units and that additional saccharides adjacent to these units can alter binding outcomes and thereby possibly host ranges. These data may help to explain why some P[II] RVs, such as P[6] and P[19], commonly infect animals but rarely humans, while others, such as the P[4] and P[8] RVs, mainly infect humans and are predominant over other P genotypes. Elucidation of the molecular bases for strain-specific host ranges and cross-species transmission of these human and animal RVs is important to understand RV epidemiology and disease burden, which may impact development of control and prevention strategies against RV gastroenteritis.
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Cevallos Porta D, López S, Arias CF, Isa P. Polarized rotavirus entry and release from differentiated small intestinal cells. Virology 2016; 499:65-71. [PMID: 27639572 DOI: 10.1016/j.virol.2016.09.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/21/2016] [Revised: 09/06/2016] [Accepted: 09/08/2016] [Indexed: 01/26/2023]
Abstract
Rotaviruses infect mature enterocytes from small intestine, however most data about their cellular entry are from studies carried out in non-intestinal polarized or non-polarized cell lines. In this work the entry of porcine rotavirus YM strain into small intestinal cell line IPEC-J2 was studied. It was found that YM and the human rotavirus Wa strain infect preferentially from the basolateral cell surface. Cell infection from the apical and basolateral surfaces was dependent on the presence of cholesterol. The treatment with neuraminidase, sucrose, and bafilomycin suggests that there are differences in the receptor usage and entry mechanism of the virus from the apical and basolateral surface. While cell entry is more efficient from basolateral surface, the viruses egressed mainly from the apical cell side.
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Affiliation(s)
- Diego Cevallos Porta
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Col. Chamilpa, Cuernavaca, Morelos CP 62210, Mexico.
| | - Susana López
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Col. Chamilpa, Cuernavaca, Morelos CP 62210, Mexico.
| | - Carlos F Arias
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Col. Chamilpa, Cuernavaca, Morelos CP 62210, Mexico.
| | - Pavel Isa
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Col. Chamilpa, Cuernavaca, Morelos CP 62210, Mexico.
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Abstract
Rotavirus, a member of the family Reoviridae, was identified as the leading etiological agent of severe gastroenteritis in infants and young children in 1973. The rotavirus genome is composed of 11 gene segments of double-stranded (ds)RNA. During the last 40 years, a large amount of basic research on rotavirus structure, genome, antigen, replication, pathogenesis, epidemiology, immune responses, and evolution has been accumulated. This article reviews the fundamental aspects of rotavirology including recent important achievements in research.
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Guerrero CA, Acosta O. Inflammatory and oxidative stress in rotavirus infection. World J Virol 2016; 5:38-62. [PMID: 27175349 PMCID: PMC4861870 DOI: 10.5501/wjv.v5.i2.38] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/12/2015] [Revised: 10/23/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
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Coulson BS. Expanding diversity of glycan receptor usage by rotaviruses. Curr Opin Virol 2015; 15:90-6. [PMID: 26363995 DOI: 10.1016/j.coviro.2015.08.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2015] [Revised: 08/11/2015] [Accepted: 08/26/2015] [Indexed: 11/16/2022]
Abstract
Rotaviruses are major etiologic agents of severe gastroenteritis in human and animals, infecting the mature intestinal epithelium. Their attachment to host cell glycans is mediated through the virion spike protein. This is considered to be crucial for successful host cell invasion by rotaviruses. Recent studies have greatly expanded our understanding of the diversity of glycans commonly recognized by rotaviruses, to include the ganglioside GM1a and histo-blood group antigens. Here, these new findings are integrated with advances in knowledge of spike protein structure, rotavirus entry mechanisms and innate intestinal immunity to provide an overview of the variety of rotavirus glycan receptors and their roles in cell penetration, host tropism and pathogenesis.
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Affiliation(s)
- Barbara S Coulson
- Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth St., Melbourne, Victoria 3000, Australia.
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Civra A, Giuffrida MG, Donalisio M, Napolitano L, Takada Y, Coulson BS, Conti A, Lembo D. Identification of Equine Lactadherin-derived Peptides That Inhibit Rotavirus Infection via Integrin Receptor Competition. J Biol Chem 2015; 290:12403-14. [PMID: 25814665 PMCID: PMC4424369 DOI: 10.1074/jbc.m114.620500] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/21/2014] [Revised: 03/24/2015] [Indexed: 11/06/2022] Open
Abstract
Human rotavirus is the leading cause of severe gastroenteritis in infants and children under the age of 5 years in both developed and developing countries. Human lactadherin, a milk fat globule membrane glycoprotein, inhibits human rotavirus infection in vitro, whereas bovine lactadherin is not active. Moreover, it protects breastfed infants against symptomatic rotavirus infections. To explore the potential antiviral activity of lactadherin sourced by equines, we undertook a proteomic analysis of milk fat globule membrane proteins from donkey milk and elucidated its amino acid sequence. Alignment of the human, bovine, and donkey lactadherin sequences revealed the presence of an Asp-Gly-Glu (DGE) α2β1 integrin-binding motif in the N-terminal domain of donkey sequence only. Because integrin α2β1 plays a critical role during early steps of rotavirus host cell adhesion, we tested a minilibrary of donkey lactadherin-derived peptides containing DGE sequence for anti-rotavirus activity. A 20-amino acid peptide containing both DGE and RGD motifs (named pDGE-RGD) showed the greatest activity, and its mechanism of antiviral action was characterized; pDGE-RGD binds to integrin α2β1 by means of the DGE motif and inhibits rotavirus attachment to the cell surface. These findings suggest the potential anti-rotavirus activity of equine lactadherin and support the feasibility of developing an anti-rotavirus peptide that acts by hindering virus-receptor binding.
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Affiliation(s)
- Andrea Civra
- From the Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Regione Gonzole, 10, 10043 Orbassano, Torino, Italy
| | - Maria Gabriella Giuffrida
- the Institute of Sciences of Food Production-National Research Council (ISPA-CNR), c/o Bioindustry Park "SilvanoFumero", 10100 CollerettoGiacosa, Torino, Italy
| | - Manuela Donalisio
- From the Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Regione Gonzole, 10, 10043 Orbassano, Torino, Italy
| | - Lorenzo Napolitano
- the Institute of Sciences of Food Production-National Research Council (ISPA-CNR), c/o Bioindustry Park "SilvanoFumero", 10100 CollerettoGiacosa, Torino, Italy
| | - Yoshikazu Takada
- the Department of Dermatology and Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California 95817, and
| | - Barbara S Coulson
- the Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia
| | - Amedeo Conti
- the Institute of Sciences of Food Production-National Research Council (ISPA-CNR), c/o Bioindustry Park "SilvanoFumero", 10100 CollerettoGiacosa, Torino, Italy
| | - David Lembo
- From the Department of Clinical and Biological Sciences, University of Torino, S. Luigi Gonzaga Hospital, Regione Gonzole, 10, 10043 Orbassano, Torino, Italy,
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Assinger A. Platelets and infection - an emerging role of platelets in viral infection. Front Immunol 2014; 5:649. [PMID: 25566260 PMCID: PMC4270245 DOI: 10.3389/fimmu.2014.00649] [Citation(s) in RCA: 266] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/27/2014] [Accepted: 12/05/2014] [Indexed: 12/23/2022] Open
Abstract
Platelets are anucleate blood cells that play a crucial role in the maintenance of hemostasis. While platelet activation and elevated platelet counts (thrombocytosis) are associated with increased risk of thrombotic complications, low platelet counts (thrombocytopenia) and several platelet function disorders increase the risk of bleeding. Over the last years, more and more evidence has emerged that platelets and their activation state can also modulate innate and adaptive immune responses and low platelet counts have been identified as a surrogate marker for poor prognosis in septic patients. Viral infections often coincide with platelet activation. Host inflammatory responses result in the release of platelet activating mediators and a pro-oxidative and pro-coagulant environment, which favors platelet activation. However, viruses can also directly interact with platelets and megakaryocytes and modulate their function. Furthermore, platelets can be activated by viral antigen-antibody complexes and in response to some viruses B-lymphocytes also generate anti-platelet antibodies. All these processes contributing to platelet activation result in increased platelet consumption and removal and often lead to thrombocytopenia, which is frequently observed during viral infection. However, virus-induced platelet activation does not only modulate platelet count but also shape immune responses. Platelets and their released products have been reported to directly and indirectly suppress infection and to support virus persistence in response to certain viruses, making platelets a double-edged sword during viral infections. This review aims to summarize the current knowledge on platelet interaction with different types of viruses, the viral impact on platelet activation, and platelet-mediated modulations of innate and adaptive immune responses.
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Affiliation(s)
- Alice Assinger
- Department of Physiology and Pharmacology, Medical University of Vienna , Vienna , Austria ; Department of Medicine, Center for Molecular Medicine, Karolinska University Hospital , Stockholm , Sweden
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Elaid S, Libersou S, Ouldali M, Morellet N, Desbat B, Alves ID, Lepault J, Bouaziz S. A peptide derived from the rotavirus outer capsid protein VP7 permeabilizes artificial membranes. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1838:2026-35. [PMID: 24746450 DOI: 10.1016/j.bbamem.2014.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/08/2013] [Revised: 04/02/2014] [Accepted: 04/07/2014] [Indexed: 01/02/2023]
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Abstract
Noroviruses (NoVs) and rotaviruses (RVs), the two most important causes of viral acute gastroenteritis, are found to recognise histo-blood group antigens (HBGAs) as receptors or ligands for attachment. Human HBGAs are highly polymorphic containing ABO, secretor and Lewis antigens. In addition, both NoVs and RVs are highly diverse in how they recognise these HBGAs. Structural analysis of the HBGA-binding interfaces of NoVs revealed a conserved central binding pocket (CBP) interacting with a common major binding saccharide (MaBS) of HBGAs and a variable surrounding region interacting with additional minor binding saccharides. The conserved CBP indicates a strong selection of NoVs by the host HBGAs, whereas the variable surrounding region explains the diverse recognition patterns of different HBGAs by NoVs and RVs as functional adaptations of the viruses to human HBGAs. Diverse recognition of HBGAs has also been found in bacterial pathogen Helicobacter pylori. Thus, exploratory research into whether such diverse recognitions also occur for other viral and bacterial pathogens that recognise HBGAs is warranted.
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Relative roles of GM1 ganglioside, N-acylneuraminic acids, and α2β1 integrin in mediating rotavirus infection. J Virol 2014; 88:4558-71. [PMID: 24501414 DOI: 10.1128/jvi.03431-13] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED N-acetyl- and N-glycolylneuraminic acids (Sia) and α2β1 integrin are frequently used by rotaviruses as cellular receptors through recognition by virion spike protein VP4. The VP4 subunit VP8*, derived from Wa rotavirus, binds the internal N-acetylneuraminic acid on ganglioside GM1. Wa infection is increased by enhanced internal Sia access following terminal Sia removal from main glycan chains with sialidase. The GM1 ligand cholera toxin B (CTB) reduces Wa infectivity. Here, we found sialidase treatment increased cellular GM1 availability and the infectivity of several other human (including RV-3) and animal rotaviruses, typically rendering them susceptible to methyl α-d-N-acetylneuraminide treatment, but did not alter α2β1 usage. CTB reduced the infectivity of these viruses. Aceramido-GM1 inhibited Wa and RV-3 infectivity in untreated and sialidase-treated cells, and GM1 supplementation increased their infectivity, demonstrating the importance of GM1 for infection. Wa recognition of α2β1 and internal Sia were at least partially independent. Rotavirus usage of GM1 was mapped to VP4 using virus reassortants, and RV-3 VP8* bound aceramido-GM1 by saturation transfer difference nuclear magnetic resonance (STD NMR). Most rotaviruses recognizing terminal Sia did not use GM1, including RRV. RRV VP8* interacted minimally with aceramido-GM1 by STD NMR. Unusually, TFR-41 rotavirus infectivity depended upon terminal Sia and GM1. Competition of CTB, Sia, and/or aceramido-GM1 with cell binding by VP8* from representative rotaviruses showed that rotavirus Sia and GM1 preferences resulted from VP8*-cell binding. Our major finding is that infection by human rotaviruses of commonly occurring VP4 serotypes involves VP8* binding to cell surface GM1 glycan, typically including the internal N-acetylneuraminic acid. IMPORTANCE Rotaviruses, the major cause of severe infantile gastroenteritis, recognize cell surface receptors through virus spike protein VP4. Several animal rotaviruses are known to bind sialic acids at the termini of main carbohydrate chains. Conversely, only a single human rotavirus is known to bind sialic acid. Interestingly, VP4 of this rotavirus bound to sialic acid that forms a branch on the main carbohydrate chain of the GM1 ganglioside. Here, we use several techniques to demonstrate that other human rotaviruses exhibit similar GM1 usage properties. Furthermore, binding by VP4 to cell surface GM1, involving branched sialic acid recognition, is shown to facilitate infection. In contrast, most animal rotaviruses that bind terminal sialic acids did not utilize GM1 for VP4 cell binding or infection. These studies support a significant role for GM1 in mediating host cell invasion by human rotaviruses.
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Zamani K, Lohrasebi T, Sabet MS, Malboobi MA, Mousavi A. Expression pattern and subcellular localization of Arabidopsis purple acid phosphatase AtPAP9. Gene Expr Patterns 2013; 14:9-18. [PMID: 24012521 DOI: 10.1016/j.gep.2013.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/27/2012] [Revised: 08/09/2013] [Accepted: 08/12/2013] [Indexed: 11/29/2022]
Abstract
Purple acid phosphatase (PAP; EC 3.1.3.2) enzymes are metallophosphoesterases that hydrolysis phosphate ester bonds in a wide range of substrates. Twenty-nine PAP-encoding loci have been identified in the Arabidopsis genome, many of which have multiple transcript variants expressed in response to diverse environmental conditions. Having analyzed T-DNA insertion mutants, we have provided strong pieces of evidence that AtPAP9 locus encodes at least two types of transcripts, designated as AtPAP9-1 and AtPAP9-2. These transcript variants expressed distinctly during the course of growth in medium containing sufficient phosphate or none. Further histochemical analysis by the use of AtPAP9-1 promoter fused to β-glucuronidase reporter gene indicated the expression of this gene is regulated in a tissue-specific manner. AtPAP9-1 was highly expressed in stipule and vascular tissue, particularly in response to fungal infection. Subcellular localization of AtPAP9-1:green fluorescent fusion protein showed that it must be involved in plasma membrane and cell wall adhesion.
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Affiliation(s)
- Katayoun Zamani
- Department of Plant Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box 14965/161, Tehran, Islamic Republic of Iran.
| | - Tahmineh Lohrasebi
- Department of Plant Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box 14965/161, Tehran, Islamic Republic of Iran.
| | - Mohammad S Sabet
- Department of Plant Breeding and Biotechnology, Faculty of Agriculture, Tarbiat Modares University, P. O. Box 14115-336, Tehran, Islamic Republic of Iran.
| | - Mohammad A Malboobi
- Department of Plant Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box 14965/161, Tehran, Islamic Republic of Iran.
| | - Amir Mousavi
- Department of Plant Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box 14965/161, Tehran, Islamic Republic of Iran.
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Gupalo E, Kuk C, Qadura M, Buriachkovskaia L, Othman M. Platelet-adenovirus vs. inert particles interaction: effect on aggregation and the role of platelet membrane receptors. Platelets 2012; 24:383-91. [PMID: 22812520 DOI: 10.3109/09537104.2012.703792] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/18/2022]
Abstract
Platelets are involved in host defense via clearance of bacteria from the circulation, interaction with virus particles, and uptake of various size particulates. There is a growing interest in micro- and nanoparticles for drug delivery and there is evidence that the properties of these particles critically influence their interaction and uptake by various tissues and cells including platelets. Virus mediated gene therapy applications are still challenged by the resultant thrombocytopenia and the mechanism(s) of platelet-foreign particles interaction remains unclear. We studied the specifics of platelet interaction with an active biological agent (adenovirus) and inert latex microspheres (MS) and investigated the role of platelet proteins in this interaction. We show that activated and not resting platelets internalize MS, without influencing platelet aggregation. In contrast, adenovirus induces and potentiates ADP-induced platelet aggregation and results in rapid expression of P-selectin. Platelets then internalize adenovirus and viral particles appear inside the open canalicular system. Inhibition of platelet αIIbβ3, GPIbα, and P-selectin decreases both platelet aggregation and internalization of MS. Inhibition of αIIbβ3 and αVβ3 does not abolish adenovirus platelet internalization and adenovirus-induced platelet activation is maintained. Our study demonstrates that platelets react differentially with foreign particles and that αIIbβ3 is a key player in platelet engulfing of foreign particles but not in mediating adenovirus internalization. Other platelet candidate molecules remain to be investigated as potential targets for management of adenovirus-induced thrombocytopenia.
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Affiliation(s)
- Elena Gupalo
- Institute of Experimental Cardiology, Cardiology Research Complex, Moscow, Russia
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Rotavirus VP4 and VP7-Derived Synthetic Peptides as Potential Substrates of Protein Disulfide Isomerase Lead to Inhibition of Rotavirus Infection. Int J Pept Res Ther 2012. [DOI: 10.1007/s10989-012-9314-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/28/2022]
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Abstract
The distal portion of rotavirus (RV) VP4 spike protein (VP8*) is implicated in binding to cellular receptors, thereby facilitating viral attachment and entry. While VP8* of some animal RVs engage sialic acid, human RVs often attach to and enter cells in a sialic acid-independent manner. A recent study demonstrated that the major human RVs (P[4], P[6], and P[8]) recognize human histo-blood group antigens (HBGAs). In this study, we performed a phylogenetic analysis of RVs and showed further variations of RV interaction with HBGAs. On the basis of the VP8* sequences, RVs are grouped into five P genogroups (P[I] to P[V]), of which P[I], P[IV], and P[V] mainly infect animals, P[II] infects humans, and P[III] infects both animals and humans. The sialic acid-dependent RVs (P[1], P[2], P[3], and P[7]) form a subcluster within P[I], while all three major P genotypes of human RVs (P[4], P[6], and P[8]) are clustered in P[II]. We then characterized three human RVs (P[9], P[14], and P[25]) in P[III] and observed a new pattern of binding to the type A antigen which is distinct from that of the P[II] RVs. The binding was demonstrated by hemagglutination and saliva binding assay using recombinant VP8* and native RVs. Homology modeling and mutagenesis study showed that the locations of the carbohydrate binding interfaces are shared with the sialic acid-dependent RVs, although different amino acids are involved. The P[III] VP8* proteins also bind the A antigens of the porcine and bovine mucins, suggesting the A antigen as a possible factor for cross-species transmission of RVs. Our study suggests that HBGAs play an important role in RV infection and evolution.
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Calderon MN, Guerrero CA, Acosta O, Lopez S, Arias CF. Inhibiting rotavirus infection by membrane-impermeant thiol/disulfide exchange blockers and antibodies against protein disulfide isomerase. Intervirology 2012; 55:451-64. [PMID: 22398681 DOI: 10.1159/000335262] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/23/2010] [Accepted: 11/21/2011] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVES Determining the effect of membrane-impermeant thiol/disulfide exchange inhibitors on rhesus rotavirus infectivity in MA104 cells and investigating protein disulfide isomerase (PDI) as a potential target for these inhibitors. METHODS Cells were treated with DTNB [5,5-dithio-bis-(2-nitrobenzoic acid)], bacitracin or anti-PDI antibodies and then infected with virus. Triple-layered particles (TLPs) were also pretreated with inhibitors before inoculation. The effects of these inhibitors on α-sarcin co-entry, virus binding to cells and PDI-TLP interaction were also examined. FACS analysis, cell-surface protein biotin-labeling, lipid-raft isolation and ELISA were performed to determine cell-surface PDI expression. RESULTS Infectivity became reduced by 50% when cells or TLPs were treated with 1 or 6 mM DTNB, respectively; infectivity became reduced by 50% by 20 mM bacitracin treatment of cells whereas TLPs were insensitive to bacitracin treatment; anti-PDI antibodies decreased viral infectivity by about 45%. The presence of DTNB (2.5 mM) or bacitracin (20 mM) was unable to prevent virus binding to cells and rotavirus-induced α-sarcin co-entry. CONCLUSIONS It was concluded that thiol/disulfide exchange was involved in rotavirus entry process and that cell-surface PDI was at least a potential target for DTNB and bacitracin-induced infectivity inhibition.
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Affiliation(s)
- Martha N Calderon
- Chemistry Department, Science Faculty, Universidad Nacional de Colombia, Bogotá, Colombia
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