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Shahrtash SA, Ghnim ZS, Ghaheri M, Adabi J, Hassanzadeh MA, Yasamineh S, Afkhami H, Kheirkhah AH, Gholizadeh O, Moghadam HZ. Recent Advances in the Role of Different Nanoparticles in the Various Biosensors for the Detection of the Chikungunya Virus. Mol Biotechnol 2025; 67:54-79. [PMID: 38393630 DOI: 10.1007/s12033-024-01052-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 12/29/2023] [Indexed: 02/25/2024]
Abstract
Humans contract the Chikungunya virus (CHIKV), an alphavirus transmitted by mosquitoes that induces acute and chronic musculoskeletal discomfort and fever. Millions of cases of the disease have been attributed to CHIKV in the Indian Ocean region since 2004, and the virus has since spread to Europe, the Middle East, and the Pacific. The exponential proliferation of CHIKV in recent times underscores the critical nature of implementing preventative measures and exploring potential control strategies. The principal laboratory test employed to diagnose infection in serum samples collected over six days after the onset of symptoms is the detection of CHIKV or viral RNA. Although two commercially available real-time reverse transcription-polymerase chain reaction products exist, data on their validity are limited. A diagnostic instrument that is rapid, sensitive, specific, and cost-effective is, therefore an absolute necessity, particularly in developing nations. Biosensors have demonstrated considerable potential in the realm of pathogen detection. The rapid and sensitive detection of viruses has been facilitated by the development of numerous types of biosensors, including affinity-based nano-biosensors, graphene affinity-based biosensors, optical nano-biosensors, surface Plasmon Resonance-based optical nano-biosensors, and electrochemical nano-biosensors. Furthermore, the utilization of nanomaterials for signal extension, including but not limited to gold and silver nanoparticles, quantum dots, and iron oxide NPs, has enhanced the precision and sensitivity of biosensors. The developed innovative diagnostic method is time-efficient, precise, and economical; it can be implemented as a point-of-care device. The technique may be implemented in diagnostic laboratories and hospitals to identify patients infected with CHIKV. Throughout this article, we have examined a multitude of CHIKV nano-biosensors and their respective properties. Following a discussion of representative nanotechnologies for biosensors, numerous NPs-assisted CHIKV nano-biosensors are summarized in this article. As a result, we anticipate that this review will furnish a significant foundation for advancing innovative CHIKV nano-biosensors.
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Affiliation(s)
| | | | - Mohammad Ghaheri
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Javid Adabi
- Chemical Engineering Department, Amirkabir University of Technology, Tehran, Iran
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Hamed Afkhami
- Department of Medical Microbiology, Faculty of Medicine, Shahed University of Medical Science, Tehran, Iran
| | - Amir Hossein Kheirkhah
- Department of Tissue Engineering and Applied Cell Science, School of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Omid Gholizadeh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
- Azad Researcher, Virology and Biotechnology, Tehran, Iran.
| | - Hesam Zendehdel Moghadam
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran.
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Lozano-Parra A, Herrera V, Calderón C, Badillo R, Gélvez Ramírez RM, Estupiñán Cárdenas MI, Lozano Jiménez JF, Villar LÁ, Rojas Garrido EM. Chronic Rheumatologic Disease in Chikungunya Virus Fever: Results from a Cohort Study Conducted in Piedecuesta, Colombia. Trop Med Infect Dis 2024; 9:247. [PMID: 39453274 PMCID: PMC11511048 DOI: 10.3390/tropicalmed9100247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 10/26/2024] Open
Abstract
This study aimed to determine the incidence of post-chikungunya chronic rheumatism (pCHIK-CR) and its impact on quality of life (QoL) and chronic fatigue in adults seven years after the 2014-2015 CHIKV outbreak in Piedecuesta, Colombia. We evaluated 78 adults (median age: 30 years, IQR: 21.0; women 60.3%) with confirmed CHIKV infection. In 2022, participants underwent a GALS examination and completed surveys on disability, stiffness, health status, and fatigue. A rheumatologist evaluated patients who reported arthralgia, morning stiffness, and abnormal GALS examination. Chronic fatigue was defined as fatigue persisting for over six months. Seven years after infection, 14.1% of participants were classified as pCHIK-CR cases, 41.0% as having non-inflammatory pain, likely degenerative (NIP-LD), and 44.9% without rheumatic disease (Wo-RM). Patients with pCHIK-CR and NIP-LD exhibited significantly worse QoL compared to Wo-RM cases. Chronic fatigue prevalence increased from 8.6% in Wo-RM patients to 25.0% in NIP-LD and 54.6% in pCHIK-CR cases. This study implemented a comprehensive clinical assessment to objectively estimate and characterize the incidence of chronic rheumatological disease attributed to CHIKV infection. One in seven cases with CHIKV infection develops pCHIK-CR, which impacts both QoL and chronic fatigue. This study contributes to understanding the burden of these arboviruses in the medium term.
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Affiliation(s)
- Anyela Lozano-Parra
- Grupo Epidemiología Clínica, Escuela de Medicina, Universidad Industrial de Santander UIS, Calle 9 Carrera 27, Bucaramanga 680002, Colombia; (A.L.-P.); (V.H.)
| | - Víctor Herrera
- Grupo Epidemiología Clínica, Escuela de Medicina, Universidad Industrial de Santander UIS, Calle 9 Carrera 27, Bucaramanga 680002, Colombia; (A.L.-P.); (V.H.)
| | - Carlos Calderón
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
| | - Reynaldo Badillo
- Departamento Medicina Interna, Universidad de Santander-UDES, Calle 35 # 10-43, Bucaramanga 680006, Colombia;
| | - Rosa Margarita Gélvez Ramírez
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
| | - María Isabel Estupiñán Cárdenas
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
| | - José Fernando Lozano Jiménez
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
| | - Luis Ángel Villar
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
| | - Elsa Marina Rojas Garrido
- Centro de Atención y Diagnóstico de Enfermedades Infecciosas (CDI), Fundación INFOVIDA, Cra. 37 No. 51-126, Bucaramanga 680003, Colombia; (C.C.); (R.M.G.R.); (M.I.E.C.); (J.F.L.J.); (L.Á.V.)
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Urbanski AH, Maso VE, Martins FM, da Costa-Martins AG, do Nascimento Oliveira APB, Nakaya HI. Chikungunya-Driven Gene Expression Linked to Osteoclast Survival and Chronic Arthralgia. Infect Dis Rep 2024; 16:914-922. [PMID: 39311214 PMCID: PMC11417755 DOI: 10.3390/idr16050073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 09/26/2024] Open
Abstract
Chikungunya fever (CHIKF), caused by the Chikungunya virus (CHIKV), manifests as acute febrile illness often associated with polyarthritis and polyarthralgia. Although the acute symptoms resolve within two weeks, many patients experience prolonged joint pain and inflammation, resembling rheumatoid arthritis (RA). This study aimed to identify molecular markers related to joint pain and chronicity in CHIKV-infected individuals by analyzing blood transcriptomes using bulk RNA sequencing. B- and T-cell receptor (BCR and TCR) diversity was assessed through computational analysis of RNA-seq data, revealing a significant reduction in CDR3 diversity in CHIKV-infected individuals compared to healthy controls. This reduced diversity was associated with the upregulation of genes involved in osteoclast differentiation and activation, particularly through the RANK/RANKL signaling pathway. These findings suggest a potential link between immune dysregulation and enhanced osteoclast activity, which may contribute to the persistence of joint pain in chronic CHIKF. Targeting osteoclast-related pathways could offer therapeutic strategies for managing chronic symptoms in CHIKF patients.
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Affiliation(s)
- Alysson Henrique Urbanski
- School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-020, Brazil (V.E.M.); (F.M.M.); (A.G.d.C.-M.); (A.P.B.d.N.O.)
| | - Vanessa E. Maso
- School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-020, Brazil (V.E.M.); (F.M.M.); (A.G.d.C.-M.); (A.P.B.d.N.O.)
| | - Felipe M. Martins
- School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-020, Brazil (V.E.M.); (F.M.M.); (A.G.d.C.-M.); (A.P.B.d.N.O.)
| | - André Guilherme da Costa-Martins
- School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-020, Brazil (V.E.M.); (F.M.M.); (A.G.d.C.-M.); (A.P.B.d.N.O.)
- Micromanufacturing Laboratory, Institute for Technological Research—IPT, São Paulo 05508-901, Brazil
| | | | - Helder I. Nakaya
- School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-020, Brazil (V.E.M.); (F.M.M.); (A.G.d.C.-M.); (A.P.B.d.N.O.)
- Hospital Israelita Albert Einstein, São Paulo 05653-000, Brazil
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de Oliveira Souza R, Duarte Júnior JWB, Della Casa VS, Santoro Rosa D, Renia L, Claser C. Unraveling the complex interplay: immunopathology and immune evasion strategies of alphaviruses with emphasis on neurological implications. Front Cell Infect Microbiol 2024; 14:1421571. [PMID: 39211797 PMCID: PMC11358129 DOI: 10.3389/fcimb.2024.1421571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/09/2024] [Indexed: 09/04/2024] Open
Abstract
Arthritogenic alphaviruses pose a significant public health concern due to their ability to cause joint inflammation, with emerging evidence of potential neurological consequences. In this review, we examine the immunopathology and immune evasion strategies employed by these viruses, highlighting their complex mechanisms of pathogenesis and neurological implications. We delve into how these viruses manipulate host immune responses, modulate inflammatory pathways, and potentially establish persistent infections. Further, we explore their ability to breach the blood-brain barrier, triggering neurological complications, and how co-infections exacerbate neurological outcomes. This review synthesizes current research to provide a comprehensive overview of the immunopathological mechanisms driving arthritogenic alphavirus infections and their impact on neurological health. By highlighting knowledge gaps, it underscores the need for research to unravel the complexities of virus-host interactions. This deeper understanding is crucial for developing targeted therapies to address both joint and neurological manifestations of these infections.
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Affiliation(s)
- Raquel de Oliveira Souza
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | | | - Victória Simões Della Casa
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Daniela Santoro Rosa
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Laurent Renia
- ASTAR Infectious Diseases Labs (ASTAR ID Labs), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Carla Claser
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
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Silveira-Freitas JEP, Campagnolo ML, dos Santos Cortez M, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. Long chikungunya? An overview to immunopathology of persistent arthralgia. World J Virol 2024; 13:89985. [PMID: 38984075 PMCID: PMC11229846 DOI: 10.5501/wjv.v13.i2.89985] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/09/2024] [Accepted: 04/12/2024] [Indexed: 06/24/2024] Open
Abstract
Chikungunya fever (CF) is caused by an arbovirus whose manifestations are extremely diverse, and it has evolved with significant severity in recent years. The clinical signs triggered by the Chikungunya virus are similar to those of other arboviruses. Generally, fever starts abruptly and reaches high levels, followed by severe polyarthralgia and myalgia, as well as an erythematous or petechial maculopapular rash, varying in severity and extent. Around 40% to 60% of affected individuals report persistent arthralgia, which can last from months to years. The symptoms of CF mainly represent the tissue tropism of the virus rather than the immunopathogenesis triggered by the host's immune system. The main mechanisms associated with arthralgia have been linked to an increase in T helper type 17 cells and a consequent increase in receptor activator of nuclear factor kappa-Β ligand and bone resorption. This review suggests that persistent arthralgia results from the presence of viral antigens post-infection and the constant activation of signaling lymphocytic activation molecule family member 7 in synovial macrophages, leading to local infiltration of CD4+ T cells, which sustains the inflammatory process in the joints through the secretion of pro-inflammatory cytokines. The term "long chikungunya" was used in this review to refer to persistent arthralgia since, due to its manifestation over long periods after the end of the viral infection, this clinical condition seems to be characterized more as a sequel than as a symptom, given that there is no active infection involved.
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Affiliation(s)
| | | | | | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Campus Anísio Teixeira, Vitória da Conquista, Bahia 45029-094, Brazil
| | - Ana Carla Zarpelon-Schutz
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa de Pós-graduação em Biotecnologia, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
| | - Kádima Nayara Teixeira
- Campus Toledo, Universidade Federal do Paraná, Toledo, Paraná 85919-899, Brazil
- Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular, Palotina, Universidade Federal do Paraná-Setor Palotina, Paraná 85950-000, Brazil
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Liao X, Xin J, Yu Z, Yan W, Li C, Cao L, Zhang H, Wang W. Unlocking the antiviral potential of rosmarinic acid against chikungunya virus via IL-17 signaling pathway. Front Cell Infect Microbiol 2024; 14:1396279. [PMID: 38800832 PMCID: PMC11127627 DOI: 10.3389/fcimb.2024.1396279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024] Open
Abstract
Background The Chikungunya virus is an Alphavirus that belongs to the Togaviridae family and is primarily transmitted by mosquitoes. It causes acute infection characterized by fever, headache, and arthralgia. Some patients also experience persistent chronic osteoarthritis-like symptoms. Dedicated antiviral treatments are currently unavailable for CHIKV. This study aims to explore the potential anti-CHIKV effect of rosmarinic acid using network pharmacology. Methods This study employed network pharmacology to predict and verify the molecular targets and pathways associated with ROSA in the context of CHIKV. The analysis outcomes were further validated using molecular docking and in vitro experiments. Results The analysis of CHIKV targets using the Kyoto Encyclopedia of Genes and Genomes and MCODE identified IL-17 as an important pathogenic pathway in CHIKV infection. Among the 30 targets of ROSA against CHIKV, nearly half were found to be involved in the IL-17 signaling pathway. This suggests that ROSA may help the host in resisting CHIKV invasion by modulating this pathway. Molecular docking validation results showed that ROSA can stably bind to 10 core targets out of the 30 identified targets. In an in vitro CHIKV infection model developed using 293T cells, treatment with 60 μM ROSA significantly improved the survival rate of infected cells, inhibited 50% CHIKV proliferation after CHIKV infection, and reduced the expression of TNF-α in the IL-17 signaling pathway. Conclusion This study provides the first confirmation of the efficacy of ROSA in suppressing CHIKV infection through the IL-17 signaling pathway. The findings warrant further investigation to facilitate the development of ROSA as a potential treatment for CHIKV infection.
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Affiliation(s)
- Xinfei Liao
- Wenzhou Polytechnic, Wenzhou, Zhejiang, China
| | - Jialiang Xin
- Institute of Virology, Wenzhou University, Wenzhou, Zhejiang, China
| | - Ziping Yu
- Institute of Virology, Wenzhou University, Wenzhou, Zhejiang, China
| | - Weiming Yan
- Institute of Virology, Wenzhou University, Wenzhou, Zhejiang, China
| | - Chenghui Li
- College of Agriculture, Yanbian University, Yanji, Jilin, China
| | - Liang Cao
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - He Zhang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - Wei Wang
- Institute of Virology, Wenzhou University, Wenzhou, Zhejiang, China
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
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Anestino TA, Queiroz-Junior CM, Cruz AMF, Souza DG, Madeira MFM. The impact of arthritogenic viruses in oral tissues. J Appl Microbiol 2024; 135:lxae029. [PMID: 38323434 DOI: 10.1093/jambio/lxae029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/14/2023] [Accepted: 02/05/2024] [Indexed: 02/08/2024]
Abstract
Arthritis and periodontitis are inflammatory diseases that share several immunopathogenic features. The expansion in the study of virus-induced arthritis has shed light on how this condition could impact other parts of the human body, including the mouth. Viral arthritis is an inflammatory joint disease caused by several viruses, most notably the alphaviruses Chikungunya virus (CHIKV), Sindbis virus (SINV), Ross River virus (RRV), Mayaro virus (MAYV), and O'nyong'nyong virus (ONNV). These viruses can induce an upsurge of matrix metalloproteinases and immune-inflammatory mediators such as Interleukin-6 (IL6), IL-1β, tumor necrosis factor, chemokine ligand 2, and receptor activator of nuclear factor kappa-B ligand in the joint and serum of infected individuals. This can lead to the influx of inflammatory cells to the joints and associated muscles as well as osteoclast activation and differentiation, culminating in clinical signs of swelling, pain, and bone resorption. Moreover, several data indicate that these viral infections can affect other sites of the body, including the mouth. The human oral cavity is a rich and diverse microbial ecosystem, and viral infection can disrupt the balance of microbial species, causing local dysbiosis. Such events can result in oral mucosal damage and gingival bleeding, which are indicative of periodontitis. Additionally, infection by RRV, CHIKV, SINV, MAYV, or ONNV can trigger the formation of osteoclasts and upregulate pro-osteoclastogenic inflammatory mediators, interfering with osteoclast activation. As a result, these viruses may be linked to systemic conditions, including oral manifestations. Therefore, this review focuses on the involvement of alphavirus infections in joint and oral health, acting as potential agents associated with oral mucosal inflammation and alveolar bone loss. The findings of this review demonstrate how alphavirus infections could be linked to the comorbidity between arthritis and periodontitis and may provide a better understanding of potential therapeutic management for both conditions.
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Affiliation(s)
- Thales Augusto Anestino
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, CEP: 31270-901, Brazil
| | - Celso Martins Queiroz-Junior
- Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, CEP: 31270-901, Brazil
| | - Amanda Medeiros Frota Cruz
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, CEP: 31270-901, Brazil
| | - Daniele G Souza
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, CEP: 31270-901, Brazil
| | - Mila Fernandes Moreira Madeira
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, CEP: 31270-901, Brazil
- Department of Oral Biology, Biomedical Research Institute, University at Buffalo, Buffalo, NY, 14203, United States
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Santos FM, Costa VRDM, de Araújo S, de Sousa CDF, Moreira TP, Gonçalves MR, dos Santos ACPM, Ferreira HAS, Costa PAC, Barrioni BR, Bargi-Souza P, Pereira MDM, Nogueira ML, Souza DDG, Guimarães PPG, Teixeira MM, Queiroz-Junior CM, Costa VV. Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease. J Virol 2024; 98:e0110223. [PMID: 38169294 PMCID: PMC10805060 DOI: 10.1128/jvi.01102-23] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 12/02/2023] [Indexed: 01/05/2024] Open
Abstract
Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, wild-type (WT) C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF, and CCL2. Higher levels of CCL2 at the local and systemic levels were followed by the significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, the absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying the bone pathology of MAYV, in which MAYV infection promotes a pro-osteoclastogenic microenvironment mediated by CCL2, IL-6, and TNF, which induces the migration and differentiation of osteoclast precursor cells. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and the identification future of specific therapeutic targets in MAYV-induced disease.IMPORTANCEThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. The infection of wild-type (WT) C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor, there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated with alphavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.
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Affiliation(s)
- Franciele Martins Santos
- Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Victor Rodrigues de Melo Costa
- Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Simone de Araújo
- Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Carla Daiane Ferreira de Sousa
- Department of Microbiology, Host Microorganism Interaction Laboratory, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Thaiane Pinto Moreira
- Department of Microbiology, Host Microorganism Interaction Laboratory, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Matheus Rodrigues Gonçalves
- Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anna Clara Paiva Menezes dos Santos
- Department of Microbiology, Host Microorganism Interaction Laboratory, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Pedro Augusto Carvalho Costa
- Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Breno Rocha Barrioni
- Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Paula Bargi-Souza
- Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Marivalda de Magalhães Pereira
- Department of Metallurgical and Materials Engineering, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Maurício Lacerda Nogueira
- Virology Research Laboratory, São José do Rio Preto School of Medicine (FAMERP), São José do Rio Preto, São Paulo, Brazil
| | - Danielle da Glória Souza
- Department of Microbiology, Host Microorganism Interaction Laboratory, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Mauro Martins Teixeira
- Department of Biochemistry and Immunology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Celso Martins Queiroz-Junior
- Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Vivian Vasconcelos Costa
- Department of Morphology, Drug Research and Development Center, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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Taylor M, Rayner JO. Immune Response to Chikungunya Virus: Sex as a Biological Variable and Implications for Natural Delivery via the Mosquito. Viruses 2023; 15:1869. [PMID: 37766276 PMCID: PMC10538149 DOI: 10.3390/v15091869] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne virus with significant public health implications around the world. Climate change, as well as rapid urbanization, threatens to expand the population range of Aedes vector mosquitoes globally, increasing CHIKV cases worldwide in return. Epidemiological data suggests a sex-dependent response to CHIKV infection. In this review, we draw attention to the importance of studying sex as a biological variable by introducing epidemiological studies from previous CHIKV outbreaks. While the female sex appears to be a risk factor for chronic CHIKV disease, the male sex has recently been suggested as a risk factor for CHIKV-associated death; however, the underlying mechanisms for this phenotype are unknown. Additionally, we emphasize the importance of including mosquito salivary components when studying the immune response to CHIKV. As with other vector-transmitted pathogens, CHIKV has evolved to use these salivary components to replicate more extensively in mammalian hosts; however, the response to natural transmission of CHIKV has not been fully elucidated.
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Affiliation(s)
| | - Jonathan O. Rayner
- Department of Microbiology & Immunology, Whiddon College of Medicine, University of South Alabama, Mobile, AL 36688, USA;
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10
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Avila-Trejo AM, Rodríguez-Páez LI, Alcántara-Farfán V, Aguilar-Faisal JL. Multiple Factors Involved in Bone Damage Caused by Chikungunya Virus Infection. Int J Mol Sci 2023; 24:13087. [PMID: 37685893 PMCID: PMC10488091 DOI: 10.3390/ijms241713087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Chronic cases of chikungunya fever represent a public health problem in countries where the virus circulates. The disease is prolonged, in some cases, for years, resulting in disabling pain and bone erosion among other bone and joint problems. As time progresses, tissue damage is persistent, although the virus has not been found in blood or joints. The pathogenesis of these conditions has not been fully explained. Additionally, it has been considered that there are multiple factors that might intervene in the viral pathogenesis of the different conditions that develop. Other mechanisms involved in osteoarthritic diseases of non-viral origin could help explain how damage is produced in chronic conditions. The aim of this review is to analyze the molecular and cellular factors that could be involved in the tissue damage generated by different infectious conditions of the chikungunya virus.
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Affiliation(s)
- Amanda M. Avila-Trejo
- Laboratorio de Bioquímica Farmacológica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (A.M.A.-T.); (L.I.R.-P.); (V.A.-F.)
- Laboratorio de Medicina de Conservación, Secretaría de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Lorena I. Rodríguez-Páez
- Laboratorio de Bioquímica Farmacológica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (A.M.A.-T.); (L.I.R.-P.); (V.A.-F.)
| | - Verónica Alcántara-Farfán
- Laboratorio de Bioquímica Farmacológica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico; (A.M.A.-T.); (L.I.R.-P.); (V.A.-F.)
| | - J. Leopoldo Aguilar-Faisal
- Laboratorio de Medicina de Conservación, Secretaría de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico
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11
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Bezerra WP, Moizéis RNC, Salmeron ACA, Pereira HWB, de Araújo JMG, Guedes PMM, Fernandes JV, Nascimento MSL. Innate immune response in patients with acute Chikungunya disease. Med Microbiol Immunol 2023:10.1007/s00430-023-00771-y. [PMID: 37285099 DOI: 10.1007/s00430-023-00771-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 05/29/2023] [Indexed: 06/08/2023]
Abstract
Chikungunya disease (CHIKD) is an arbovirose that presents with high morbidity, mainly due to arthralgia. Inflammatory mediators including IL-6, IL-1β, GM-CSF and others have been implicated in the pathogenesis of CHIKD, whilst type I interferons can be associated with better outcomes. The role of pattern recognition receptors has been studied incompletely. Here, we evaluated the expression of RNA-specific PRRs, their adaptor molecules and downstream cytokines in acute CHIKD patients. Twenty-eight patients were recruited during the 3rd-5th day after the symptoms onset for clinical examination, peripheral blood collection and qRT-PCR analysis of PBMC to compare to the healthy control group (n = 20). We observed common symptoms of acute CHIKD, with fever, arthralgia, headache and myalgia being the most frequent. Compared with uninfected controls, acute CHIKV infection upregulates the expression of the receptors TLR3, RIG-I and MDA5, and also the adaptor molecule TRIF. Regarding cytokine expression, we found an upregulation of IL-6, IL-12, IFN-α, IFN-β and IFN-γ, which are related directly to the inflammatory or antiviral response. The TLR3-TRIF axis correlated with high expression of IL-6 and IFN-α. Interestingly, greater expression of MDA5, IL-12 and IFN-α was related to lower viral loads in CHIKD acute patients. Together, these findings help to complete the picture of innate immune activation during acute CHIKD, while confirming the induction of strong antiviral responses. Drawing the next steps in the understanding of the immunopathology and virus clearance mechanisms of CHIKD should be of utter importance in the aid of the development of effective treatment to reduce the severity of this debilitating disease.
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Affiliation(s)
- Wallace Pitanga Bezerra
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - Raíza Nara Cunha Moizéis
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - Amanda Costa Ayres Salmeron
- Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaiba, Rio Grande do Norte, Brazil
| | - Hannaly Wana Bezerra Pereira
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - Josélio Maria Galvão de Araújo
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - Paulo Marcos Matta Guedes
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - José Veríssimo Fernandes
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil
| | - Manuela Sales Lima Nascimento
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte. Natal, Rio Grande do Norte, Natal, Rio Grande Do Norte, 59078-970, Brazil.
- Edmond and Lily Safra International Institute of Neuroscience, Santos Dumont Institute, Macaiba, Rio Grande do Norte, Brazil.
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12
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Henderson Sousa F, Ghaisani Komarudin A, Findlay-Greene F, Bowolaksono A, Sasmono RT, Stevens C, Barlow PG. Evolution and immunopathology of chikungunya virus informs therapeutic development. Dis Model Mech 2023; 16:dmm049804. [PMID: 37014125 PMCID: PMC10110403 DOI: 10.1242/dmm.049804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023] Open
Abstract
Chikungunya virus (CHIKV), a mosquito-borne alphavirus, is an emerging global threat identified in more than 60 countries across continents. The risk of CHIKV transmission is rising due to increased global interactions, year-round presence of mosquito vectors, and the ability of CHIKV to produce high host viral loads and undergo mutation. Although CHIKV disease is rarely fatal, it can progress to a chronic stage, during which patients experience severe debilitating arthritis that can last from several weeks to months or years. At present, there are no licensed vaccines or antiviral drugs for CHIKV disease, and treatment is primarily symptomatic. This Review provides an overview of CHIKV pathogenesis and explores the available therapeutic options and the most recent advances in novel therapeutic strategies against CHIKV infections.
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Affiliation(s)
- Filipa Henderson Sousa
- School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Edinburgh EH11 4BN, UK
- Centre for Discovery Brain Sciences and UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH16 4SB, UK
| | - Amalina Ghaisani Komarudin
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency, Cibinong Science Center, Cibinong, Kabupaten Bogor 16911, Indonesia
| | - Fern Findlay-Greene
- School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Edinburgh EH11 4BN, UK
| | - Anom Bowolaksono
- Cellular and Molecular Mechanisms in Biological System (CEMBIOS) Research Group, Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok 16424, Indonesia
| | - R. Tedjo Sasmono
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency, Cibinong Science Center, Cibinong, Kabupaten Bogor 16911, Indonesia
| | - Craig Stevens
- School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Edinburgh EH11 4BN, UK
| | - Peter G. Barlow
- School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Edinburgh EH11 4BN, UK
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13
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Khongwichit S, Chansaenroj J, Chirathaworn C, Poovorawan Y. Chikungunya virus infection: molecular biology, clinical characteristics, and epidemiology in Asian countries. J Biomed Sci 2021; 28:84. [PMID: 34857000 PMCID: PMC8638460 DOI: 10.1186/s12929-021-00778-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 11/21/2021] [Indexed: 02/03/2023] Open
Abstract
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne human pathogen that causes chikungunya fever, which is typically accompanied by severe joint pain. In Asia, serological evidence indicated that CHIKV first emerged in 1954. From the 1950’s to 2005, sporadic CHIKV infections were attributed to the Asian genotype. However, the massive outbreak of CHIKV in India and the Southwest Indian Ocean Islands in 2005 has since raised chikungunya as a worldwide public health concern. The virus is spreading globally, but mostly in tropical and subtropical regions, particularly in South and Southeast Asia. The emergence of the CHIKV East/Central/South African genotype-Indian Ocean lineage (ECSA-IOL) has caused large outbreaks in South and Southeast Asia affected more than a million people over a decade. Notably, the massive CHIKV outbreaks before 2016 and the more recent outbreak in Asia were driven by distinct ECSA lineages. The first significant CHIKV ECSA strains harbored the Aedes albopictus-adaptive mutation E1: A226V. More recently, another mass CHIKV ECSA outbreak in Asia started in India and spread beyond South and Southeast Asia to Kenya and Italy. This virus lacked the E1: A226V mutation but instead harbored two novel mutations (E1: K211E and E2: V264A) in an E1: 226A background, which enhanced its fitness in Aedes aegypti. The emergence of a novel ECSA strain may lead to a more widespread geographical distribution of CHIKV in the future. This review summarizes the current CHIKV situation in Asian countries and provides a general overview of the molecular virology, disease manifestation, diagnosis, prevalence, genotype distribution, evolutionary relationships, and epidemiology of CHIKV infection in Asian countries over the past 65 years. This knowledge is essential in guiding the epidemiological study, control, prevention of future CHIKV outbreaks, and the development of new vaccines and antivirals targeting CHIKV.
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Affiliation(s)
- Sarawut Khongwichit
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Jira Chansaenroj
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Chintana Chirathaworn
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.,Tropical Medicine Cluster, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
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14
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Pott F, Postmus D, Brown RJP, Wyler E, Neumann E, Landthaler M, Goffinet C. Single-cell analysis of arthritogenic alphavirus-infected human synovial fibroblasts links low abundance of viral RNA to induction of innate immunity and arthralgia-associated gene expression. Emerg Microbes Infect 2021; 10:2151-2168. [PMID: 34723780 PMCID: PMC8604527 DOI: 10.1080/22221751.2021.2000891] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/25/2022]
Abstract
Infection by (re-)emerging RNA arboviruses including Chikungunya virus (CHIKV) and Mayaro virus primarily cause acute febrile disease and transient polyarthralgia. However, in a significant subset of infected individuals, debilitating arthralgia persists for weeks over months up to years. The underlying immunopathogenesis of chronification of arthralgia upon primary RNA-viral infection remains unclear. Here, we analysed cell-intrinsic responses to ex vivo arthritogenic alphaviral infection of primary human synovial fibroblasts isolated from knee joints, one the most affected joint types during acute and chronic CHIKV disease. Synovial fibroblasts were susceptible and permissive to alphaviral infection. Base-line and exogenously added type I interferon (IFN) partially and potently restricted infection, respectively. RNA-seq revealed a CHIKV infection-induced transcriptional profile that comprised upregulation of expression of several hundred IFN-stimulated and arthralgia-mediating genes. Single-cell virus-inclusive RNA-seq uncovered a fine-tuned switch from induction to repression of cell-intrinsic immune responses depending on the abundance of viral RNA in an individual cell. Specifically, responses were most pronounced in cells displaying low-to-intermediate amounts of viral RNA and absence of virus-encoded, fluorescent reporter protein expression, arguing for efficient counteraction of innate immunity in cells expressing viral antagonists at sufficient quantities. In summary, cell-intrinsic sensing of viral RNA that potentially persists or replicates at low levels in synovial fibroblasts and other target cell types in vivo may contribute to the chronic arthralgia induced by alphaviral infections. Our findings might advance our understanding of the immunopathophysiology of long-term pathogenesis of RNA-viral infections.
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Affiliation(s)
- Fabian Pott
- Institute of Virology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Dylan Postmus
- Institute of Virology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | | | - Emanuel Wyler
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Elena Neumann
- Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Bad Nauheim, Germany
| | - Markus Landthaler
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
- IRI Life Sciences, Institut für Biologie, Humboldt Universität zu Berlin, Berlin, Germany
| | - Christine Goffinet
- Institute of Virology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
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15
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Constant LEC, Rajsfus BF, Carneiro PH, Sisnande T, Mohana-Borges R, Allonso D. Overview on Chikungunya Virus Infection: From Epidemiology to State-of-the-Art Experimental Models. Front Microbiol 2021; 12:744164. [PMID: 34675908 PMCID: PMC8524093 DOI: 10.3389/fmicb.2021.744164] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/07/2021] [Indexed: 12/27/2022] Open
Abstract
Chikungunya virus (CHIKV) is currently one of the most relevant arboviruses to public health. It is a member of the Togaviridae family and alphavirus genus and causes an arthritogenic disease known as chikungunya fever (CHIKF). It is characterized by a multifaceted disease, which is distinguished from other arbovirus infections by the intense and debilitating arthralgia that can last for months or years in some individuals. Despite the great social and economic burden caused by CHIKV infection, there is no vaccine or specific antiviral drugs currently available. Recent outbreaks have shown a change in the severity profile of the disease in which atypical and severe manifestation lead to hundreds of deaths, reinforcing the necessity to understand the replication and pathogenesis processes. CHIKF is a complex disease resultant from the infection of a plethora of cell types. Although there are several in vivo models for studying CHIKV infection, none of them reproduces integrally the disease signature observed in humans, which is a challenge for vaccine and drug development. Therefore, understanding the potentials and limitations of the state-of-the-art experimental models is imperative to advance in the field. In this context, the present review outlines the present knowledge on CHIKV epidemiology, replication, pathogenesis, and immunity and also brings a critical perspective on the current in vitro and in vivo state-of-the-art experimental models of CHIKF.
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Affiliation(s)
- Larissa E. C. Constant
- Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratório de Biotecnologia e Bioengenharia Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bia F. Rajsfus
- Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratório de Biotecnologia e Bioengenharia Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro H. Carneiro
- Laboratório de Biotecnologia e Bioengenharia Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tháyna Sisnande
- Laboratório de Biotecnologia e Bioengenharia Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ronaldo Mohana-Borges
- Laboratório de Biotecnologia e Bioengenharia Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Diego Allonso
- Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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16
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Gupta S, Mishra KP, Gupta R, Singh SB. Andrographolide - A prospective remedy for chikungunya fever and viral arthritis. Int Immunopharmacol 2021; 99:108045. [PMID: 34435582 DOI: 10.1016/j.intimp.2021.108045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 08/01/2021] [Accepted: 08/01/2021] [Indexed: 12/14/2022]
Abstract
AIM Andrographolide, the major bioactive compound of the plant Andrographis paniculata, exerts anti-inflammatory, cyto-, neuro- and hepato-protective effects. Traditional remedies for infectious diseases include A. paniculata for maladies like fever, pain, rashes which are associated with chikungunya and other arboviral diseases. Since andrographolide and A. paniculata have potent antiviral properties, the present review aims to provide a comprehensive report of symptoms and immunological molecules involved in chikungunya virus (CHIKV) infection and the therapeutic role of andrographolide in the mitigation of chikungunya and associated symptoms. MATERIALS AND METHODS Studies on the therapeutic role of A. paniculata and andrographolide in chikungunya and other viral infections published between 1991 and 2021 were searched on various databases. RESULTS AND DISCUSSION The havoc created by chikungunya is due to the associated debilitating symptoms including arthralgia and myalgia which sometimes remains for years. The authors reviewed and summarized the various symptoms and immunological molecules related to CHIKV replication and associated inflammation, oxidative and unfolded protein stress, apoptosis and arthritis. Additionally, the authors suggested andrographolide as a remedy for chikungunya and other arboviral infections by highlighting its role in the regulation of molecules involved in unfolded protein response pathway, immunomodulation, inflammation, virus multiplication, oxidative stress, apoptosis and arthritis. CONCLUSION The present review demonstrated the major complications associated with chikungunya and the role of andrographolide in alleviating the chikungunya associated symptoms to encourage further investigations using this promising compound towards early development of an anti-CHIKV drug. Chemical Compound studied: andrographolide (PubChem CID: 5318517).
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Affiliation(s)
- Swati Gupta
- Division of Epidemiology and Communicable Diseases, Indian Council of Medical Research (ICMR), Ansari Nagar, New Delhi 110029, India.
| | - K P Mishra
- Defence Research and Development Organization (DRDO)-HQ, Rajaji Marg, New Delhi 110011, India
| | - Rupali Gupta
- Department of Neurology, Duke University Medical Center, Durham, NC, United States
| | - S B Singh
- National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
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17
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Kril V, Aïqui-Reboul-Paviet O, Briant L, Amara A. New Insights into Chikungunya Virus Infection and Pathogenesis. Annu Rev Virol 2021; 8:327-347. [PMID: 34255544 DOI: 10.1146/annurev-virology-091919-102021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for major outbreaks of disease since 2004 in the Indian Ocean islands, South east Asia, and the Americas. CHIKV causes debilitating musculoskeletal disorders in humans that are characterized by fever, rash, polyarthralgia, and myalgia. The disease is often self-limiting and nonlethal; however, some patients experience atypical or severe clinical manifestations, as well as a chronic rheumatic syndrome. Unfortunately, no efficient antivirals against CHIKV infection are available so far, highlighting the importance of deepening our knowledge of CHIKV host cell interactions and viral replication strategies. In this review, we discuss recent breakthroughs in the molecular mechanisms that regulate CHIKV infection and lay down the foundations to understand viral pathogenesis. We describe the role of the recently identified host factors co-opted by the virus for infection and pathogenesis, and emphasize the importance of CHIKV nonstructural proteins in both replication complex assembly and host immune response evasion. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Vasiliya Kril
- Biology of Emerging Virus Team, INSERM U944, CNRS UMR 7212, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis, 75010 Paris, France;
| | - Olivier Aïqui-Reboul-Paviet
- RNA Viruses and Metabolism Team, CNRS UMR 9004, Institut de Recherche en Infectiologie de Montpellier, University of Montpellier, 34293 Montpellier, France;
| | - Laurence Briant
- RNA Viruses and Metabolism Team, CNRS UMR 9004, Institut de Recherche en Infectiologie de Montpellier, University of Montpellier, 34293 Montpellier, France;
| | - Ali Amara
- Biology of Emerging Virus Team, INSERM U944, CNRS UMR 7212, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis, 75010 Paris, France;
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18
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Hibl BM, Dailey Garnes NJM, Kneubehl AR, Vogt MB, Spencer Clinton JL, Rico-Hesse RR. Mosquito-bite infection of humanized mice with chikungunya virus produces systemic disease with long-term effects. PLoS Negl Trop Dis 2021; 15:e0009427. [PMID: 34106915 PMCID: PMC8189471 DOI: 10.1371/journal.pntd.0009427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 05/02/2021] [Indexed: 12/13/2022] Open
Abstract
Chikungunya virus (CHIKV) is an emerging, mosquito-borne alphavirus responsible for acute to chronic arthralgias and neuropathies. Although it originated in central Africa, recent reports of disease have come from many parts of the world, including the Americas. While limiting human CHIKV cases through mosquito control has been used, it has not been entirely successful. There are currently no licensed vaccines or treatments specific for CHIKV disease, thus more work is needed to develop effective countermeasures. Current animal research on CHIKV is often not representative of human disease. Most models use CHIKV needle inoculation via unnatural routes to create immediate viremia and localized clinical signs; these methods neglect the natural route of transmission (the mosquito vector bite) and the associated human immune response. Since mosquito saliva has been shown to have a profound effect on viral pathogenesis, we evaluated a novel model of infection that included the natural vector, Aedes species mosquitoes, transmitting CHIKV to mice containing components of the human immune system. Humanized mice infected by 3-6 mosquito bites showed signs of systemic infection, with demonstrable viremia (by qRT-PCR and immunofluorescent antibody assay), mild to moderate clinical signs (by observation, histology, and immunohistochemistry), and immune responses consistent with human infection (by flow cytometry and IgM ELISA). This model should give a better understanding of human CHIKV disease and allow for more realistic evaluations of mechanisms of pathogenesis, prophylaxis, and treatments.
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Affiliation(s)
- Brianne M. Hibl
- Center for Comparative Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Natalie J. M. Dailey Garnes
- Section of Infectious Disease, Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Section of Pediatric Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Alexander R. Kneubehl
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Megan B. Vogt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jennifer L. Spencer Clinton
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Rebecca R. Rico-Hesse
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail:
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19
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Irinotecan (CPT-11) Canonical Anti-Cancer Drug Can also Modulate Antiviral and Pro-Inflammatory Responses of Primary Human Synovial Fibroblasts. Cells 2021; 10:cells10061431. [PMID: 34201243 PMCID: PMC8230279 DOI: 10.3390/cells10061431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/21/2021] [Accepted: 05/24/2021] [Indexed: 11/29/2022] Open
Abstract
Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O’nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1β was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1β treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.
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20
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Paiva IA, Badolato-Corrêa J, Familiar-Macedo D, de-Oliveira-Pinto LM. Th17 Cells in Viral Infections-Friend or Foe? Cells 2021; 10:cells10051159. [PMID: 34064728 PMCID: PMC8151546 DOI: 10.3390/cells10051159] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.
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21
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Sukkaew A, Suksatu A, Roytrakul S, Smith DR, Ubol S. Proteomic analysis of CHIKV-infected human fibroblast-like synoviocytes: Identification of host factors potentially associated with CHIKV replication and cellular pathogenesis. Microbiol Immunol 2020; 64:445-457. [PMID: 32246487 DOI: 10.1111/1348-0421.12793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 01/02/2023]
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne virus that causes arthralgic fever. Fibroblast-like synoviocytes play a key role in joint damage in inflammatory arthritides and can additionally serve as target cells for CHIKV infection. To gain a better understanding of CHIKV-induced arthralgia, the interaction between CHIKV and synoviocytes was investigated at the protein level. A gel-enhanced liquid chromatography-mass spectrometry (GeLC-MS/MS) approach was used to examine protein expression from primary human fibroblast-like synoviocytes (HFLS) infected with clinical isolates of CHIKV at 12 and 24 hr post infection. Our analysis identified 259 and 241 proteins of known function that were differentially expressed (>1.5 or <-1.5 fold change) following CHIKV infection at 12 and 24 hpi, respectively. These proteins are involved in cellular homeostasis, including cellular trafficking, cytoskeletal organization, immune response, metabolic process, and protein modification. Some of these proteins have previously been reported to participate in arthralgia/arthritis and the death of infected cells. Our results provide information on the CHIKV-induced modulation of cellular proteins of HFLS at an early stage of infection, as well as highlighting biological processes associated with CHIKV infection in the main target cells of the joint.
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Affiliation(s)
- Apamas Sukkaew
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Ampa Suksatu
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Sittiruk Roytrakul
- Proteomics Research Laboratory, Genome Institute, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand
| | - Duncan R Smith
- Center for Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand.,Institute of Molecular Bioscience, Mahidol University Salaya Campus, Nakorn Pathom, Thailand
| | - Sukathida Ubol
- Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.,Center for Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
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22
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Schrauf S, Tschismarov R, Tauber E, Ramsauer K. Current Efforts in the Development of Vaccines for the Prevention of Zika and Chikungunya Virus Infections. Front Immunol 2020; 11:592. [PMID: 32373111 PMCID: PMC7179680 DOI: 10.3389/fimmu.2020.00592] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 03/13/2020] [Indexed: 01/07/2023] Open
Abstract
Arboviruses represent major challenges to public health, particularly in tropical, and subtropical regions, and a substantial risk to other parts of the world as respective vectors extend their habitats. In recent years, two viruses transmitted by Aedes mosquitoes, Chikungunya and Zika virus, have gathered increased interest. After decades of regionally constrained outbreaks, both viruses have recently caused explosive outbreaks on an unprecedented scale, causing immense suffering and massive economic burdens in affected regions. Chikungunya virus causes an acute febrile illness that often transitions into a chronic manifestation characterized by debilitating arthralgia and/or arthritis in a substantial subset of infected individuals. Zika infection frequently presents as a mild influenza-like illness, often subclinical, but can cause severe complications such as congenital malformations in pregnancy and neurological disorders, including Guillain-Barré syndrome. With no specific treatments or vaccines available, vector control remains the most effective measure to manage spread of these diseases. Given that both viruses cause antibody responses that confer long-term, possibly lifelong protection and that such responses are cross-protective against the various circulating genetic lineages, the development of Zika and Chikungunya vaccines represents a promising route for disease control. In this review we provide a brief overview on Zika and Chikungunya viruses, the etiology and epidemiology of the illnesses they cause and the host immune response against them, before summarizing past and current efforts to develop vaccines to alleviate the burden caused by these emerging diseases. The development of the urgently needed vaccines is hampered by several factors including the unpredictable epidemiology, feasibility of rapid clinical trial implementation during outbreaks and regulatory pathways. We will give an overview of the current developments.
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23
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Rheumatic manifestations of chikungunya: emerging concepts and interventions. Nat Rev Rheumatol 2019; 15:597-611. [DOI: 10.1038/s41584-019-0276-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 12/15/2022]
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24
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Valdés López JF, Velilla PA, Urcuqui-Inchima S. Chikungunya Virus and Zika Virus, Two Different Viruses Examined with a Common Aim: Role of Pattern Recognition Receptors on the Inflammatory Response. J Interferon Cytokine Res 2019; 39:507-521. [DOI: 10.1089/jir.2019.0058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
| | - Paula Andrea Velilla
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
| | - Silvio Urcuqui-Inchima
- Grupo Inmunovirología, Facultad de Medicina, Universidad de Antioquia UdeA, Medellín, Colombia
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25
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Bengue M, Ferraris P, Baronti C, Diagne CT, Talignani L, Wichit S, Liegeois F, Bisbal C, Nougairède A, Missé D. Mayaro Virus Infects Human Chondrocytes and Induces the Expression of Arthritis-Related Genes Associated with Joint Degradation. Viruses 2019; 11:v11090797. [PMID: 31470617 PMCID: PMC6783875 DOI: 10.3390/v11090797] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 08/26/2019] [Accepted: 08/27/2019] [Indexed: 12/18/2022] Open
Abstract
Mayaro virus (MAYV) is an emerging arthritogenic alphavirus belonging to the Togaviridae family. Infection leads to a dengue-like illness accompanied by severe polyarthralgia. However, the molecular and cellular mechanisms of arthritis as a result of MAYV infection remain poorly understood. In the present study, we assess the susceptibility of human chondrocytes (HC), fibroblast-like synoviocytes and osteoblasts that are the major cell types involved in osteoarthritis, to infection with MAYV. We show that these cells are highly permissive to MAYV infection and that viral RNA copy number and viral titers increase over time in infected cells. Knowing that HC are the primary cells in articular cartilage and are essential for maintaining the cartilaginous matrix, gene expression studies were conducted in MAYV-infected primary HC using polymerase chain reaction (PCR) arrays. The infection of the latter cells resulted in an induction in the expression of several matrix metalloproteinases (MMP) including MMP1, MMP7, MMP8, MMP10, MMP13, MMP14 and MMP15 which could be involved in the destruction of articular cartilage. Infected HC were also found to express significantly increased levels of various IFN-stimulated genes and arthritogenic mediators such as TNF-α and IL-6. In conclusion, MAYV-infected primary HC overexpress arthritis-related genes, which may contribute to joint degradation and pathogenesis.
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Affiliation(s)
- Michèle Bengue
- MIVEGEC, IRD, Univ. Montpellier, CNRS, 34394 Montpellier, France
| | - Pauline Ferraris
- MIVEGEC, IRD, Univ. Montpellier, CNRS, 34394 Montpellier, France
| | - Cécile Baronti
- Unité des virus émergents, Aix Marseille Univ-IRD 190, Inserm 1207-IHU Méditerranée Infection, 13385 Marseille, France
| | | | - Loïc Talignani
- MIVEGEC, IRD, Univ. Montpellier, CNRS, 34394 Montpellier, France
| | - Sineewanlaya Wichit
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Florian Liegeois
- MIVEGEC, IRD, Univ. Montpellier, CNRS, 34394 Montpellier, France
| | - Catherine Bisbal
- PhyMedExp, CNRS UMR 9214, INSERM U1046, University of Montpellier, 34295 Montpellier, France
| | - Antoine Nougairède
- Unité des virus émergents, Aix Marseille Univ-IRD 190, Inserm 1207-IHU Méditerranée Infection, 13385 Marseille, France
| | - Dorothée Missé
- MIVEGEC, IRD, Univ. Montpellier, CNRS, 34394 Montpellier, France.
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26
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Limthongkul J, Mapratiep N, Apichirapokey S, Suksatu A, Midoeng P, Ubol S. Insect anionic septapeptides suppress DENV replication by activating antiviral cytokines and miRNAs in primary human monocytes. Antiviral Res 2019; 168:1-8. [PMID: 31075349 DOI: 10.1016/j.antiviral.2019.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 04/10/2019] [Accepted: 04/24/2019] [Indexed: 01/06/2023]
Abstract
Dengue viruses (DENVs) have threatened 2/3 of the world population for decades. Thus, combating DENV infection with either antiviral therapy or protective vaccination is an urgent goal. In the present study, we investigated the anti-DENV activity of insect cell-derived anionic septapeptides from C6/36 mosquito cell cultures persistently infected with DENV. These molecules were previously shown to protect C6/36 and Vero cells against DENV infection. We found that treatment with these septapeptides strongly and rapidly downregulated the multiplication of DENV-1 16007, DENV-3 16562, and DENV-4 1036 but not that of DENV-2 16681 in primary human monocytes. This inhibitory effect was likely mediated through various routes including the increased production of antiviral cytokines (IFN-I), activation of mononuclear cell migration, and upregulation of the expression of antiviral miRNAs (has-miR-30e*, has-miR-133a, and has-miR-223) and inflammation-related miRNAs (has-miR-146a and has-miR-147). In conclusion, anionic septapeptides exerted anti-DENV activity in human monocytes through the upregulation of innate immune responses and the activation of several previously reported antiviral and inflammation-related miRNAs.
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Affiliation(s)
- Jitra Limthongkul
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok, 10400, Thailand.
| | - Nithipong Mapratiep
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok, 10400, Thailand.
| | - Suttikarn Apichirapokey
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok, 10400, Thailand.
| | - Ampa Suksatu
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok, 10400, Thailand.
| | - Panuwat Midoeng
- Army Institute of Pathology, Phramongkutklao Hospital, Bangkok, Thailand.
| | - Sukathida Ubol
- Department of Microbiology, Faculty of Science, Mahidol University, 272 Rama 6 Road, Bangkok, 10400, Thailand.
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27
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Nayak TK, Mamidi P, Sahoo SS, Kumar PS, Mahish C, Chatterjee S, Subudhi BB, Chattopadhyay S, Chattopadhyay S. P38 and JNK Mitogen-Activated Protein Kinases Interact With Chikungunya Virus Non-structural Protein-2 and Regulate TNF Induction During Viral Infection in Macrophages. Front Immunol 2019; 10:786. [PMID: 31031770 PMCID: PMC6473476 DOI: 10.3389/fimmu.2019.00786] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 03/25/2019] [Indexed: 02/02/2023] Open
Abstract
Chikungunya virus (CHIKV), a mosquito-borne Alphavirus, is endemic in different parts of the globe. The host macrophages are identified as the major cellular reservoirs of CHIKV during infection and this virus triggers robust TNF production in the host macrophages, which might be a key mediator of virus induced inflammation. However, the molecular mechanism underneath TNF induction is not understood yet. Accordingly, the Raw264.7 cells, a mouse macrophage cell line, were infected with CHIKV to address the above-mentioned question. It was observed that CHIKV induces both p38 and JNK phosphorylation in macrophages in a time-dependent manner and p-p38 inhibitor, SB203580 is effective in reducing infection even at lower concentration as compared to the p-JNK inhibitor, SP600125. However, inhibition of p-p38 and p-JNK decreased CHIKV induced TNF production in the host macrophages. Moreover, CHIKV induced macrophage derived TNF was found to facilitate TCR driven T cell activation. Additionally, it was noticed that the expressions of key transcription factors involved mainly in antiviral responses (p-IRF3) and TNF production (p-c-jun) were induced significantly in the CHIKV infected macrophages as compared to the corresponding mock cells. Further, it was demonstrated that CHIKV mediated TNF production in the macrophages is dependent on p38 and JNK MAPK pathways linking p-c-jun transcription factor. Interestingly, it was found that CHIKV nsP2 interacts with both p-p38 and p-JNK MAPKs in the macrophages. This observation was supported by the in silico protein-protein docking analysis which illustrates the specific amino acids responsible for the nsP2-MAPKs interactions. A strong polar interaction was predicted between Thr-180 (within the phosphorylation lip) of p38 and Gln-273 of nsP2, whereas, no such polar interaction was predicted for the phosphorylation lip of JNK which indicates the differential roles of p-p38 and p-JNK during CHIKV infection in the host macrophages. In summary, for the first time it has been shown that CHIKV triggers robust TNF production in the host macrophages via both p-p38 and p-JNK/p-c-jun pathways and the interaction of viral protein, nsP2 with these MAPKs during infection. Hence, this information might shed light in rationale-based drug designing strategies toward a possible control measure of CHIKV infection in future.
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Affiliation(s)
- Tapas Kumar Nayak
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar, India
| | - Prabhudutta Mamidi
- Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Subhransu Sekhar Sahoo
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar, India
| | - P Sanjai Kumar
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar, India
| | - Chandan Mahish
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar, India
| | | | - Bharat Bhusan Subudhi
- School of Pharmaceutical Sciences, Siksha O Anusandhan University, Bhubaneswar, India
| | - Soma Chattopadhyay
- Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India
| | - Subhasis Chattopadhyay
- School of Biological Sciences, National Institute of Science Education and Research, HBNI, Bhubaneswar, India
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28
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A bioinformatics investigation into the pharmacological mechanisms of the effect of Fufang Danshen on pain based on methodologies of network pharmacology. Sci Rep 2019; 9:5913. [PMID: 30976033 PMCID: PMC6459854 DOI: 10.1038/s41598-019-40694-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 12/20/2018] [Indexed: 12/31/2022] Open
Abstract
Fufang Danshen (FFDS), a Chinese medicine formula widely used in the clinic, has proven therapeutic effects on pain relief. However, the mechanisms of these effects have not been elucidated. Here, we performed a systematic analysis to discover the mechanisms of FFDS in attenuating pain to gain a better understanding of FFDS in the treatment of other diseases accompanied by pain. Relevance analysis showed that Salvia miltiorrhizae was the best studied herb in FFDS. Most compounds in FFDS have good bioavailability, and we collected 223 targets for 35 compounds in FFDS. These targets were significantly enriched in many pathways related to pain and can be classified as signal transduction, endocrine system, nervous system and lipid metabolism. We compared Salvia miltiorrhizae and Panax notoginseng and found that they can significantly affect different pathways. Moreover, ten pain disease proteins and 45 therapeutic targets can be directly targeted by FFDS. All 45 therapeutic targets have direct or indirect connections with pain disease proteins. Forty-six pain disease proteins can be indirectly affected by FFDS, especially through heat shock cognate 71 kDa protein (HSPA8) and transcription factor AP-1 (JUN). A total of 109 targets of FFDS were identified as significant targets.
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29
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Matusali G, Colavita F, Bordi L, Lalle E, Ippolito G, Capobianchi MR, Castilletti C. Tropism of the Chikungunya Virus. Viruses 2019; 11:v11020175. [PMID: 30791607 PMCID: PMC6410217 DOI: 10.3390/v11020175] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/16/2019] [Accepted: 02/17/2019] [Indexed: 12/12/2022] Open
Abstract
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne virus that displays a large cell and organ tropism, and causes a broad range of clinical symptoms in humans. It is maintained in nature through both urban and sylvatic cycles, involving mosquito vectors and human or vertebrate animal hosts. Although CHIKV was first isolated in 1953, its pathogenesis was only more extensively studied after its re-emergence in 2004. The unexpected spread of CHIKV to novel tropical and non-tropical areas, in some instances driven by newly competent vectors, evidenced the vulnerability of new territories to this infectious agent and its associated diseases. The comprehension of the exact CHIKV target cells and organs, mechanisms of pathogenesis, and spectrum of both competitive vectors and animal hosts is pivotal for the design of effective therapeutic strategies, vector control measures, and eradication actions.
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Affiliation(s)
- Giulia Matusali
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Francesca Colavita
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Licia Bordi
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Eleonora Lalle
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Giuseppe Ippolito
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Maria R Capobianchi
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
| | - Concetta Castilletti
- National Institute for Infectious Diseases "Lazzaro Spallanzani" IRCCS, 00149 Rome, Italy.
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30
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Tanabe ISB, Tanabe ELL, Santos EC, Martins WV, Araújo IMTC, Cavalcante MCA, Lima ARV, Câmara NOS, Anderson L, Yunusov D, Bassi ÊJ. Cellular and Molecular Immune Response to Chikungunya Virus Infection. Front Cell Infect Microbiol 2018; 8:345. [PMID: 30364124 PMCID: PMC6191487 DOI: 10.3389/fcimb.2018.00345] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 09/11/2018] [Indexed: 11/13/2022] Open
Abstract
Chikungunya virus (CHIKV) is a re-emergent arthropod-borne virus (arbovirus) that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia. In the last decade, CHIKV has become a serious public health problem causing several outbreaks around the world. Despite the fact that CHIKV has been around since 1952, our knowledge about immunopathology, innate and adaptive immune response involved in this infectious disease is incomplete. In this review, we provide an updated summary of the current knowledge about immune response to CHIKV and about soluble immunological markers associated with the morbidity, prognosis and chronicity of this arbovirus disease. In addition, we discuss the progress in the research of new vaccines for preventing CHIKV infection and the use of monoclonal antibodies as a promising therapeutic strategy.
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Affiliation(s)
- Ithallo S B Tanabe
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Eloiza L L Tanabe
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Elane C Santos
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Wanessa V Martins
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Isadora M T C Araújo
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Maria C A Cavalcante
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Ana R V Lima
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
| | - Niels O S Câmara
- Laboratório de Imunobiologia dos Transplantes, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Leticia Anderson
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil.,Centro Universitário CESMAC, Maceió, Brazil
| | - Dinar Yunusov
- Cold Spring Harbor Laboratory, Genome Research Center, Woodbury, NY, United States
| | - Ênio J Bassi
- IMUNOREG-Grupo de Pesquisa em Regulação da Resposta Imune, Laboratório de Pesquisas em Virologia e Imunologia, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, Maceió, Brazil
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31
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Immunomodulatory drug methotrexate used to treat patients with chronic inflammatory rheumatisms post-chikungunya does not impair the synovial antiviral and bone repair responses. PLoS Negl Trop Dis 2018; 12:e0006634. [PMID: 30074983 PMCID: PMC6093699 DOI: 10.1371/journal.pntd.0006634] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 08/15/2018] [Accepted: 06/22/2018] [Indexed: 02/08/2023] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted RNA alphavirus causing major outbreaks of infectious chronic inflammatory rheumatisms (CIR). Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug has been used successfully to treat patients suffering from rheumatoid-like arthritis post-CHIK but its immunomodulatory activity in the context of viral persistence has been a matter of concerns. We herein used a model of primary human synovial fibroblasts (HSF) and the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic infectious settings in the joints of CHIKV infected patients. The innate antiviral immune and inflammatory responses were investigated in response to MTX used at the therapeutic concentration of 1 μM. We found that MTX did not affect cellular viability as indicated by the LDH release assay. By quantitative RT-PCR, we observed that HSF responded robustly to PIC by increasing ISG15 and IFNβ mRNA levels. Furthermore, PIC upregulated the mRNA expression of two of the major pattern recognition receptors, RIG-I and MDA5 involved in the innate immune detection of viral RNA. MTX did not impact the antiviral response of PIC on ISG15, IFNβ, RIG-I and MDA5 mRNA expressions. MTX alone or combined with PIC did not affect the expression of proinflammatory CCL2 and CXCL8 chemokines. PIC strongly upregulated the mRNA and protein expression of osteoclastogenic factors (IL-6, GM-CSF but not RANKL). Critically, MTX treatment alone or combined with PIC did not affect the expression of all three tested osteoclastogenic cytokines. We found that MTX alone did not increase the capacity of CHIKV to infect and replicate in HSF. In conclusion, our study argues for a beneficial effect of MTX to treat CIR post-CHIKV given that it does not critically impact the antiviral, the proinflammatory and the bone tissue remodeling responses of synovial cells. Chikungunya is a mosquito-borne virus (CHIKV) and has been incriminated in the development of arthralgia (pain of the joint) and arthritis particularly in elderly patients. Methotrexate (MTX) has been used widely to effectively treat these chronic rheumatic symptoms. Using a model of primary human joint fibroblasts (HSF), we investigated the capacity of the MTX immunosuppressive drug to affect the immune antiviral and inflammatory responses essential to clear the virus while allowing bone tissue repair. This study is important given that CHIKV and its RNA were shown to persist in the joint for months to years post infection and leading to injuries through ill-characterized mechanisms. The molecule PIC was used to mimic the effect of viral RNA. Interestingly, we found that MTX did not affect the expression of several proinflammatory and bone repair factors by HSF. Remarkably, MTX did not also impair the antiviral response of synovial fibroblasts. Our study revealed for the first time that MTX treatment should be considered as safe even in the context of viral persistence associated with chronic inflammation. MTX will not affect the capacity of the synovial tissue to maintain antiviral mechanism, to control inflammation and to promote bone tissue repair.
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Moizéis RNC, Fernandes TAADM, Guedes PMDM, Pereira HWB, Lanza DCF, de Azevedo JWV, Galvão JMDA, Fernandes JV. Chikungunya fever: a threat to global public health. Pathog Glob Health 2018; 112:182-194. [PMID: 29806537 PMCID: PMC6147074 DOI: 10.1080/20477724.2018.1478777] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Chikungunya fever is an emerging arbovirus infection, representing a serious public health problem. Its etiological agent is the Chikungunya virus (CHIKV). Transmission of this virus is mainly vector by mosquitoes of the genus Aedes, although transmission by blood transfusions and vertical transmission has also been reported. The disease presents high morbidity caused mainly by the arthralgia and arthritis generated. Cardiovascular and neurological manifestations have also been reported. The severity of the infection seems to be directly associated with the action of the virus, but also with the decompensation of preexisting comorbidities. Currently, there are no therapeutic products neither vaccines licensed to the infection CHIKV control, although several vaccine candidates are being evaluated and human polyvalent immunoglobulins anti-CHIKV had been tested. Antibodies can protect against the infection, but in sub-neutralizing concentrations can augment virus infection and exacerbate disease severity. So, the prevention still depends on the use of personal protection measures and vector control, which are only minimally effective.
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Affiliation(s)
- Raíza Nara Cunha Moizéis
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | | | - Paulo Marcos da Matta Guedes
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal do Rio Grande do Norte, Natal, Brazil
- Departamento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | | | | | | | - Josélio Maria de Araújo Galvão
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal do Rio Grande do Norte, Natal, Brazil
- Departamento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil
| | - José Veríssimo Fernandes
- Programa de Pós-Graduação em Biologia Parasitária, Universidade Federal do Rio Grande do Norte, Natal, Brazil
- Departamento de Microbiologia e Parasitologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil
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Sukkaew A, Thanagith M, Thongsakulprasert T, Mutso M, Mahalingam S, Smith DR, Ubol S. Heterogeneity of clinical isolates of chikungunya virus and its impact on the responses of primary human fibroblast-like synoviocytes. J Gen Virol 2018. [PMID: 29517478 DOI: 10.1099/jgv.0.001039] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Low-passage clinical isolates of chikungunya virus (CHIKV) were found to be a mixture of large- and small-plaque viruses, with small-plaque viruses being the predominant species. To investigate the contribution of plaque variants to the pathology of the joint, primary human fibroblast-like synoviocytes (HFLS) were used. Large- and small-plaque viruses were purified from two clinical isolates, CHIKV-031C and CHIKV-033C, and were designated CHIKV-031L and CHIKV-031S and CHIKV-033L and CHIKV-033S, respectively. The replication efficiencies of these viruses in HFLSs were compared and it was found that CHIKV-031S and CHIKV-033S replicated with the highest efficiency, while the parental clinical isolates had the lowest efficiency. Interestingly, the cytopathic effects (CPE) induced by these viruses correlated with neither the efficiency of replication nor the plaque size. The small-plaque viruses and the clinical isolates induced cell death rapidly, while large-plaque viruses induced slow CPE in which only 50 % of the cells in infected cultures were rounded up and detached on day 5 of infection. The production of proinflammatory cytokines and chemokines from infected HFLSs was evaluated. The results showed that the large-plaque viruses and the clinical isolates, but not small-plaque variants, were potent inducers of IL-6, IL-8 and MCP-1, and were able to migrate monocytes/macrophages efficiently. Sequencing data revealed a number of differences in amino acid sequences between the small- and large-plaque viruses. The results suggest that it is common for clinical isolates of CHIKV to be heterogeneous, while the variants may have distinct roles in the pathology of the joint.
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Affiliation(s)
- Apamas Sukkaew
- Department of Microbiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchatewi, Bangkok 10400, Thailand
| | | | | | - Margit Mutso
- Institute for Glycomics, Griffith University, Southport, Gold Coast, QLD, Australia
| | - Suresh Mahalingam
- Institute for Glycomics, Griffith University, Southport, Gold Coast, QLD, Australia
| | - Duncan R Smith
- Center for Emerging and Neglected Infectious Diseases, Mahidol University, Salaya Campus, Nakornpathom, Thailand.,Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakornpathom, Thailand
| | - Sukathida Ubol
- Center for Emerging and Neglected Infectious Diseases, Mahidol University, Salaya Campus, Nakornpathom, Thailand.,Department of Microbiology, Faculty of Science, Mahidol University, Rama 6 Rd., Ratchatewi, Bangkok 10400, Thailand
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Ganesan VK, Duan B, Reid SP. Chikungunya Virus: Pathophysiology, Mechanism, and Modeling. Viruses 2017; 9:v9120368. [PMID: 29194359 PMCID: PMC5744143 DOI: 10.3390/v9120368] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 11/21/2017] [Accepted: 11/23/2017] [Indexed: 12/15/2022] Open
Abstract
Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, is recurring in epidemic waves. In the past decade and a half, the disease has resurged in several countries around the globe, with outbreaks becoming increasingly severe. Though CHIKV was first isolated in 1952, there remain significant gaps in knowledge of CHIKV biology, pathogenesis, transmission, and mechanism. Diagnosis is largely simplified and based on symptoms, while treatment is supportive rather than curative. Here we present an overview of the disease, the challenges that lie ahead for future research, and what directions current studies are headed towards, with emphasis on improvement of current animal models and potential use of 3D models.
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Affiliation(s)
- Vaishnavi K Ganesan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
- Department of Surgery, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - St Patrick Reid
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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Amdekar S, Parashar D, Alagarasu K. Chikungunya Virus-Induced Arthritis: Role of Host and Viral Factors in the Pathogenesis. Viral Immunol 2017; 30:691-702. [PMID: 28910194 DOI: 10.1089/vim.2017.0052] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Chikungunya virus (CHIKV), a member of Alphavirus genus, is responsible for chikungunya fever (CHIKF), which is characterized by the presence of fever, rash, myalgia, and arthralgia. Reemergence of CHIKV has become a significant public health concern in Asian and African countries and is newly emerging in the Middle East, Pacific, American, and European countries. Cytokines, innate (monocytes, natural killer cells) and adaptive immune response (role of B cells and T cells i.e. CD4+ and CD8+), and/or viral factors contribute to CHIKV-induced arthritis. Vector factors such as vector competence (that includes extrinsic and intrinsic factors) and effect of genome mutations on viral replication and fitness in mosquitoes are responsible for the spread of virus, although they are not directly responsible for CHIKV-induced arthritis. CHIKV-induced arthritis mimics arthritis by involving joints and a common pattern of leukocyte infiltrate, cytokine production, and complement activation. Successful establishment of CHIKV infection and induction of arthritis depends on its ability to manipulate host cellular processes or host factors. CHIKV-induced joint damage is due to host inflammatory response mediated by macrophages, T cells, and antibodies, as well as the possible persistence of the virus in hidden sites. This review provides insight into mechanisms of CHIKV-induced arthritis. Understanding the pathogenesis of CHIKV-induced arthritis will help in developing novel strategies to predict and prevent the disease in virus-infected subjects and combat the disease, thereby decreasing the worldwide burden of the disease.
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Affiliation(s)
- Sarika Amdekar
- Dengue/Chikungunya Group, ICMR-National Institute of Virology , Pune, India
| | - Deepti Parashar
- Dengue/Chikungunya Group, ICMR-National Institute of Virology , Pune, India
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36
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Abstract
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus in the family Togaviridae that causes outbreaks of debilitating acute and chronic arthralgia in humans. Although historically associated with localized outbreaks in Africa and Asia, recent epidemics in the Indian Ocean region and the Americas have led to the recognition that CHIKV is capable of moving into previously unaffected areas and causing significant levels of human suffering. The severity of CHIKV rheumatic disease, which can severely impact life quality of infected individuals for weeks, months, or even years, combined with the explosive nature of CHIKV outbreaks and its demonstrated ability to quickly spread into new regions, has led to renewed interest in developing strategies for the prevention or treatment of CHIKV-induced disease. Therefore, this chapter briefly discusses the biology of CHIKV and the factors contributing to CHIKV dissemination, while also discussing the pathogenesis of CHIKV-induced disease and summarizing the status of efforts to develop safe and effective therapies and vaccines against CHIKV and related viruses.
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Abstract
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that causes acute and chronic arthritis. The virus reemerged in the Indian Ocean islands in 2005-2006 and is responsible for outbreaks in the Caribbean islands and the Americas since late 2013. Despite the wealth of research over the past 10 years, there are no commercially available antiviral drugs or vaccines. Treatment usually involves analgesics, anti-inflammatory drugs, and supportive care. Most studies have been focused on understanding the pathogenesis of CHIKV infection through clinical observation and with animal models. In this review, the clinical manifestations of CHIKV that define the disease and the use of relevant animal models, from mice to nonhuman primates, are discussed. Understanding key cellular factors in CHIKV infection and the interplay with the immune system will aid in the development of preventive and therapeutic approaches to combat this painful viral disease in humans.
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Affiliation(s)
- Lisa F P Ng
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648; .,Institute of Infection and Global Health, University of Liverpool, Liverpool L69 3BX, United Kingdom
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Nayak TK, Mamidi P, Kumar A, Singh LPK, Sahoo SS, Chattopadhyay S, Chattopadhyay S. Regulation of Viral Replication, Apoptosis and Pro-Inflammatory Responses by 17-AAG during Chikungunya Virus Infection in Macrophages. Viruses 2017; 9:v9010003. [PMID: 28067803 PMCID: PMC5294972 DOI: 10.3390/v9010003] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 12/15/2022] Open
Abstract
Chikungunya virus (CHIKV) infection has re-emerged as a major public health concern due to its recent worldwide epidemics and lack of control measures. Although CHIKV is known to infect macrophages, regulation of CHIKV replication, apoptosis and immune responses towards macrophages are not well understood. Accordingly, the Raw264.7 cells, a mouse macrophage cell line, were infected with CHIKV and viral replication as well as new viral progeny release was assessed by flow cytometry and plaque assay, respectively. Moreover, host immune modulation and apoptosis were studied through flow cytometry, Western blot and ELISA. Our current findings suggest that expression of CHIKV proteins were maximum at 8 hpi and the release of new viral progenies were remarkably increased around 12 hpi. The induction of Annexin V binding, cleaved caspase-3, cleaved caspase-9 and cleaved caspase-8 in CHIKV infected macrophages suggests activation of apoptosis through both intrinsic and extrinsic pathways. The pro-inflammatory mediators (TNF and IL-6) MHC-I/II and B7.2 (CD86) were also up-regulated during infection over time. Further, 17-AAG, a potential HSP90 inhibitor, was found to regulate CHIKV infection, apoptosis and pro-inflammatory cytokine/chemokine productions of host macrophages significantly. Hence, the present findings might bring new insight into the therapeutic implication in CHIKV disease biology.
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Affiliation(s)
- Tapas K Nayak
- School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, HBNI, Jatni, Khurda, Odisha 752050, India.
| | - Prabhudutta Mamidi
- Infectious Disease Biology, Institute of Life Sciences, (Autonomous Institute of Department of Biotechnology, Government of India), Nalco Square, Bhubaneswar, Odisha 751023, India.
| | - Abhishek Kumar
- Infectious Disease Biology, Institute of Life Sciences, (Autonomous Institute of Department of Biotechnology, Government of India), Nalco Square, Bhubaneswar, Odisha 751023, India.
| | - Laishram Pradeep K Singh
- School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, HBNI, Jatni, Khurda, Odisha 752050, India.
| | - Subhransu S Sahoo
- School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, HBNI, Jatni, Khurda, Odisha 752050, India.
| | - Soma Chattopadhyay
- Infectious Disease Biology, Institute of Life Sciences, (Autonomous Institute of Department of Biotechnology, Government of India), Nalco Square, Bhubaneswar, Odisha 751023, India.
| | - Subhasis Chattopadhyay
- School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, HBNI, Jatni, Khurda, Odisha 752050, India.
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Goupil BA, Mores CN. A Review of Chikungunya Virus-induced Arthralgia: Clinical Manifestations, Therapeutics, and Pathogenesis. Open Rheumatol J 2016; 10:129-140. [PMID: 28077980 PMCID: PMC5204064 DOI: 10.2174/1874312901610010129] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 11/08/2016] [Accepted: 11/09/2016] [Indexed: 11/22/2022] Open
Abstract
Background: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that circulates predominantly in tropical and subtropical regions, potentially affecting over 1 billion people. Recently, an outbreak began in the western hemisphere and has resulted in over 1.8 million reported suspected cases. Infection often results in severe fever, rash and debilitating polyarthralgia lasting weeks to months. Additionally, the current literature reports that CHIKV can result in a severe chronic arthralgia and/or arthritis that can last months to years following the initial infection. Objective: The purpose of this review is to evaluate the literature and summarize the current state of knowledge regarding CHIKV-associated disease, including clinical presentation, diagnosis, risk factors for development of severe disease, treatment, and pathogenesis in human patients. Additionally, recommendations are presented regarding avenues for clinical research to help further elucidate the pathogenesis of joint disease associated with CHIKV infection. Conclusion: While there is an association between initial CHIKV infection and acute disease, a causal relationship with development of chronic arthralgia has not been established at this time. Potential causes of chronic CHIKV-induced arthritis have been postulated, including viral persistence, induction of autoimmune disease, and exacerbation of pre-existing joint disease. While there are numerous reports of chronic CHIKV-associated arthralgia and/or arthritis, there is currently no evidence of a definitive link between initial infection and development of chronic disease. Additional, prospective clinical research on CHIKV-associated disease is necessary to further determine the potential role of virus and development of chronic joint disease.
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Affiliation(s)
- Brad A Goupil
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Christopher N Mores
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America; Virology and Emerging Infections, US Naval Medical Research Unit No. 6, Lima Pampa, Peru
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The Role of Cellular Immune Responses on Chikungunya Virus Infection-Induced Arthritis. CURRENT TROPICAL MEDICINE REPORTS 2016. [DOI: 10.1007/s40475-016-0074-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Goupil BA, McNulty MA, Martin MJ, McCracken MK, Christofferson RC, Mores CN. Novel Lesions of Bones and Joints Associated with Chikungunya Virus Infection in Two Mouse Models of Disease: New Insights into Disease Pathogenesis. PLoS One 2016; 11:e0155243. [PMID: 27182740 PMCID: PMC4868286 DOI: 10.1371/journal.pone.0155243] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 04/26/2016] [Indexed: 12/13/2022] Open
Abstract
Chikungunya virus is an arbovirus spread predominantly by Aedes aegypti and Ae. albopictus mosquitoes, and causes debilitating arthralgia and arthritis. While these are common manifestations during acute infection and it has been suggested they can recur in patients chronically, gaps in knowledge regarding the pathogenesis still exist. Two established mouse models were utilized (adult IRF 3/7 -/- -/- and wild-type C57BL/6J mice) to evaluate disease manifestations in bones and joints at various timepoints. Novel lesions in C57BL/6J mice consisted of periostitis (91%) and foci of cartilage of necrosis (50% of mice at 21 DPI). Additionally, at 21 DPI, 50% and 75% of mice exhibited periosteal bone proliferation affecting the metatarsal bones, apparent via histology and μCT, respectively. μCT analysis did not reveal any alterations in trabecular bone volume measurements in C57BL/6J mice. Novel lesions demonstrated in IRF 3/7 -/- -/- mice at 5 DPI included focal regions of cartilage necrosis (20%), periosteal necrosis (66%), and multifocal ischemic bone marrow necrosis (100%). Contralateral feet in 100% of mice of both strains had similar, though milder lesions. Additionally, comparison of control IRF 3/7 -/- -/- and wild-type C57BL/6J mice demonstrated differences in cortical bone. These experiments demonstrate novel manifestations of disease similar to those occurring in humans, adding insight into disease pathogenesis, and representing new potential targets for therapeutic interventions. Additionally, results demonstrate the utility of μCT in studies of bone and joint pathology and illustrate differences in bone dynamics between mouse strains.
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Affiliation(s)
- Brad A. Goupil
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Margaret A. McNulty
- Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Matthew J. Martin
- Department of Comparative Biomedical Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Michael K. McCracken
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Rebecca C. Christofferson
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
| | - Christopher N. Mores
- Department of Pathobiological Sciences, Louisiana State University School of Veterinary Medicine, Skip Bertman Drive, Baton Rouge, Louisiana, United States of America
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Gasque P, Couderc T, Lecuit M, Roques P, Ng LFP. Chikungunya virus pathogenesis and immunity. Vector Borne Zoonotic Dis 2016; 15:241-9. [PMID: 25897810 DOI: 10.1089/vbz.2014.1710] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chikungunya virus (CHIKV) is an arbovirus associated with acute and chronic arthralgia that re-emerged in the Indian Ocean islands in 2005-2006 and is currently responsible for the ongoing outbreaks in the Caribbean islands and the Americas. We describe here the acute and chronic clinical manifestations of CHIKV in patients that define the disease. We also review the various animal models that have been developed to study CHIKV infection and pathology and further strengthened the understanding of the cellular and molecular mechanisms of CHIKV infection and immunity. A complete understanding of the immunopathogenesis of CHIKV infection will help develop the needed preventive and therapeutic approaches to combat this arbovirosis.
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Affiliation(s)
- Philippe Gasque
- 1 University of La Reunion , GRI/IRG EA4517, and Centre Hospitalier Universitaire (CHU North Felix-Guyon), Saint-Denis, La Reunion, France
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Roosenhoff R, Anfasa F, Martina B. The pathogenesis of chronic chikungunya: evolving concepts. Future Virol 2016. [DOI: 10.2217/fvl.15.107] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Chikungunya virus (CHIKV) re-emerged and caused an outbreak in the Caribbean and the Americas. CHIKV can cause incapacitating arthralgia, which may be evolved in chronic arthritis that is similar to rheumatoid arthritis that lasts for months or years. This review provides an overview of known and hypothesized mechanisms that CHIKV uses to promote chronic arthritis. We hypothesized that the chronic inflammatory response that is stimulated by persisting CHIKV replication in the joints results in the arthritic symptoms seen in patients. Most hypotheses proposed in this review need to be tested or confirmed, which may help in the development of new specific treatments and vaccines against CHIKV that will not only combat viral persistence but also prevent tissue damage.
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Affiliation(s)
- Rueshandra Roosenhoff
- ARTEMIS One Health Research Institute, Yalelaan 1, 3584 CL, Utrecht, The Netherlands
- Curacao Biomedical & Health Research Institute, Curacao
| | - Fatih Anfasa
- Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Byron Martina
- ARTEMIS One Health Research Institute, Yalelaan 1, 3584 CL, Utrecht, The Netherlands
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
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Lohachanakul J, Phuklia W, Thannagith M, Thongsakulprasert T, Smith DR, Ubol S. Differences in response of primary human myoblasts to infection with recent epidemic strains of Chikungunya virus isolated from patients with and without myalgia. J Med Virol 2015; 87:733-9. [DOI: 10.1002/jmv.24081] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2014] [Indexed: 12/30/2022]
Affiliation(s)
- Jindarat Lohachanakul
- Department of Microbiology; Faculty of Science; Mahidol University; Bangkok Thailand
| | - Weerawat Phuklia
- Department of Microbiology; Faculty of Science; Mahidol University; Bangkok Thailand
| | | | | | - Duncan R. Smith
- Institute of Molecular Biosciences; Mahidol University; Bangkok Thailand
- Center for Emerging and Neglected Infectious Diseases; Mahidol University; Bangkok Thailand
| | - Sukathida Ubol
- Department of Microbiology; Faculty of Science; Mahidol University; Bangkok Thailand
- Center for Emerging and Neglected Infectious Diseases; Mahidol University; Bangkok Thailand
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Arthritogenic alphaviruses: new insights into arthritis and bone pathology. Trends Microbiol 2014; 23:35-43. [PMID: 25449049 DOI: 10.1016/j.tim.2014.09.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 09/18/2014] [Accepted: 09/19/2014] [Indexed: 01/01/2023]
Abstract
Arthritogenic alphaviral infection begins as a febrile illness and often progresses to joint pain and rheumatic symptoms that are described as polyarthritis. Alphaviral arthritis and classical arthritides share many similar cellular and immune mediators involved in their pathogenesis. Recent in vitro and in vivo evidence suggests that bone loss resulting from increased expression of bone resorption mediators may accompany alphaviral infection. In addition, several longitudinal studies have reported more severe and delayed recovery of alphaviral disease in patients with pre-existing arthritic conditions. This review aims to provide insights into alphavirus-induced bone loss and focuses on aspects of disease exacerbation in patients with underlying arthritis and on possible therapeutic targets.
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Rougeron V, Sam IC, Caron M, Nkoghe D, Leroy E, Roques P. Chikungunya, a paradigm of neglected tropical disease that emerged to be a new health global risk. J Clin Virol 2014; 64:144-52. [PMID: 25453326 DOI: 10.1016/j.jcv.2014.08.032] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 08/25/2014] [Indexed: 01/08/2023]
Abstract
Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family that causes chronic and incapacitating arthralgia in human populations. Since its discovery in 1952, CHIKV was responsible for sporadic and infrequent outbreaks. However, since 2005, global Chikungunya outbreaks have occurred, inducing some fatalities and associated with severe and chronic morbidity. Chikungunya is thus considered as an important re-emerging public health problem in both tropical and temperate countries, where the distribution of the Aedes mosquito vectors continues to expand. This review highlights the most recent advances in our knowledge and understanding of the epidemiology, biology, treatment and vaccination strategies of CHIKV.
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Affiliation(s)
- Virginie Rougeron
- Centre International de Recherches Médicales de Franceville, Franceville, Gabon; Unité Mixte de Recherche Maladies Infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle (IRD 224 - CNRS 5290 - UM1-UM2), Institut de Recherche pour le Développement, Montpellier, France
| | - I-Ching Sam
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mélanie Caron
- Centre International de Recherches Médicales de Franceville, Franceville, Gabon
| | - Dieudonné Nkoghe
- Centre International de Recherches Médicales de Franceville, Franceville, Gabon
| | - Eric Leroy
- Centre International de Recherches Médicales de Franceville, Franceville, Gabon; Unité Mixte de Recherche Maladies Infectieuses et Vecteurs: Ecologie, Génétique, Evolution et Contrôle (IRD 224 - CNRS 5290 - UM1-UM2), Institut de Recherche pour le Développement, Montpellier, France
| | - Pierre Roques
- CEA, Institute of Emerging Diseases and Innovative Therapies, Division of Immuno-Virology, Fontenay-aux-Roses, France; Université Paris-Sud 11, UMR E1, Orsay, France.
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Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection. J Virol 2014; 89:581-93. [PMID: 25339772 DOI: 10.1128/jvi.02034-14] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (μCT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.
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Smith DR. Global protein profiling studies of chikungunya virus infection identify different proteins but common biological processes. Rev Med Virol 2014; 25:3-18. [PMID: 25066270 DOI: 10.1002/rmv.1802] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 06/26/2014] [Accepted: 06/26/2014] [Indexed: 12/24/2022]
Abstract
Chikungunya fever (CHIKF) caused by the mosquito-transmitted chikungunya virus (CHIKV) swept into international prominence from late 2005 as an epidemic of CHIKF spread around countries surrounding the Indian Ocean. Although significant advances have been made in understanding the pathobiology of CHIKF, numerous questions still remain. In the absence of commercially available specific drugs to treat the disease, or a vaccine to prevent the diseases, the questions have particular significance. A number of studies have used global proteome analysis to increase our understanding of the process of CHIKV infection using a number of different experimental techniques and experimental systems. In all, over 700 proteins have been identified in nine different analyses by five different groups as being differentially regulated. Remarkably, only a single protein, eukaryotic elongation factor 2, has been identified by more than two different groups as being differentially regulated during CHIKV infection. This review provides a critical overview of the studies that have used global protein profiling to understand CHIKV infection and shows that while a broad consensus is emerging on which biological processes are altered during CHIKV infection, this consensus is poorly supported in terms of consistent identification of any key proteins mediating those biological processes.
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Affiliation(s)
- Duncan R Smith
- Institute of Molecular Biosciences, Mahidol University, Bangkok, Thailand; Center for Emerging and Neglected Infectious Diseases, Mahidol University, Bangkok, Thailand
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