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Freppel W, Silva LA, Stapleford KA, Herrero LJ. Pathogenicity and virulence of chikungunya virus. Virulence 2024; 15:2396484. [PMID: 39193780 PMCID: PMC11370967 DOI: 10.1080/21505594.2024.2396484] [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: 02/27/2024] [Revised: 08/09/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted, RNA virus that causes an often-severe musculoskeletal illness characterized by fever, joint pain, and a range of debilitating symptoms. The virus has re-emerged as a global health threat in recent decades, spreading from its origin in Africa across Asia and the Americas, leading to widespread outbreaks impacting millions of people. Despite more than 50 years of research into the pathogenesis of CHIKV, there is still no curative treatment available. Current management of CHIKV infections primarily involves providing supportive care to alleviate symptoms and improve the patient's quality of life. Given the ongoing threat of CHIKV, there is an urgent need to better understand its pathogenesis. This understanding is crucial for deciphering the mechanisms underlying the disease and for developing effective strategies for both prevention and management. This review aims to provide a comprehensive overview of CHIKV and its pathogenesis, shedding light on the complex interactions of viral genetics, host factors, immune responses, and vector-related factors. By exploring these intricate connections, the review seeks to contribute to the knowledge base surrounding CHIKV, offering insights that may ultimately lead to more effective prevention and management strategies for this re-emerging global health threat.
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Affiliation(s)
- Wesley Freppel
- Institute for Biomedicine and Glycomics, Gold Coast Campus, Griffith University, Southport, Australia
| | - Laurie A. Silva
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Kenneth A. Stapleford
- Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA
| | - Lara J. Herrero
- Institute for Biomedicine and Glycomics, Gold Coast Campus, Griffith University, Southport, Australia
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2
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Khamaru S, Mukherjee T, Tung KS, Kumar PS, Bandyopadhyay S, Mahish C, Chattopadhyay S, Chattopadhyay S. Chikungunya virus infection inhibits B16 melanoma-induced immunosuppression of T cells and macrophages mediated by interleukin 10. Microb Pathog 2024; 197:107022. [PMID: 39419458 DOI: 10.1016/j.micpath.2024.107022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/19/2024]
Abstract
Immunosuppression in cancer poses challenges for immunotherapy and highlights the vulnerability of immunocompromised patients to viral infections. This study explored how Chikungunya virus (CHIKV) infection potentially inhibits B16-F10 melanoma-induced immunosuppressive effects on T cells and RAW 264.7 macrophages. We found high expression of CHIKV entry genes in melanoma and other cancers, with B16-F10 cells demonstrating greater susceptibility to CHIKV infection than non-tumorigenic cells. Interestingly, the CHIKV-infected B16-F10 cell culture supernatant (B16-F10-CS) reversed the immunosuppressive effects of uninfected B16-F10-CS on T cells. This reversal was characterised by decreased STAT3 activation and increased MAPK activation in T cells, an effect amplified by interleukin 10 (IL-10) receptor blockade. In RAW 264.7 cells, B16-F10-CS enhanced CHIKV infectivity without triggering activation. However, blocking the IL-10 receptor (IL-10R) in RAW 264.7 reduced CHIKV infection. CHIKV infection and IL-10R blockade synergistically inhibited B16-F10-CS-mediated polarisation of RAW 264.7 cells towards immunosuppressive macrophage. Our findings suggest that CHIKV modulates cancer-induced immunosuppression through IL-10-dependent pathways, providing new insights into viral-cancer interactions. This research may contribute to developing novel antiviral immunotherapies and virotherapies beneficial for cancer patients and immunocompromised individuals.
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Affiliation(s)
- Somlata Khamaru
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
| | - Tathagata Mukherjee
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India; Institute of Life Sciences, Bhubaneswar, India
| | - Kshyama Subhadarsini Tung
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
| | - P Sanjai Kumar
- Institute of Life Sciences, Bhubaneswar, India; Division of Neonatology and Newborn Nursery, University of Wisconsin, Madison, USA
| | - Saumya Bandyopadhyay
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India; Johns Hopkins University School of Medicine, Department of Biological Chemistry, 725 North Wolfe Street, Baltimore, Maryland, USA
| | - Chandan Mahish
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India
| | | | - Subhasis Chattopadhyay
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India; Homi Bhabha National Institute, Training School Complex, Anushaktinagar, Mumbai, India.
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Rawle DJ, Hugo LE, Cox AL, Devine GJ, Suhrbier A. Generating prophylactic immunity against arboviruses in vertebrates and invertebrates. Nat Rev Immunol 2024; 24:621-636. [PMID: 38570719 DOI: 10.1038/s41577-024-01016-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/29/2024] [Indexed: 04/05/2024]
Abstract
The World Health Organization recently declared a global initiative to control arboviral diseases. These are mainly caused by pathogenic flaviviruses (such as dengue, yellow fever and Zika viruses) and alphaviruses (such as chikungunya and Venezuelan equine encephalitis viruses). Vaccines represent key interventions for these viruses, with licensed human and/or veterinary vaccines being available for several members of both genera. However, a hurdle for the licensing of new vaccines is the epidemic nature of many arboviruses, which presents logistical challenges for phase III efficacy trials. Furthermore, our ability to predict or measure the post-vaccination immune responses that are sufficient for subclinical outcomes post-infection is limited. Given that arboviruses are also subject to control by the immune system of their insect vectors, several approaches are now emerging that aim to augment antiviral immunity in mosquitoes, including Wolbachia infection, transgenic mosquitoes, insect-specific viruses and paratransgenesis. In this Review, we discuss recent advances, current challenges and future prospects in exploiting both vertebrate and invertebrate immune systems for the control of flaviviral and alphaviral diseases.
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Affiliation(s)
- Daniel J Rawle
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Leon E Hugo
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Abigail L Cox
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Gregor J Devine
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia.
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Brito RMDM, de Melo MF, Fernandes JV, Valverde JG, Matta Guedes PM, de Araújo JMG, Nascimento MSL. Acute Chikungunya Virus Infection Triggers a Diverse Range of T Helper Lymphocyte Profiles. Viruses 2024; 16:1387. [PMID: 39339863 PMCID: PMC11437511 DOI: 10.3390/v16091387] [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: 07/17/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Chikungunya virus (CHIKV) is an arbovirus causing acute febrile illness with severe joint pain, often leading to chronic arthralgia. This study investigated the adaptive immune responses during the early stages of symptomatic acute CHIKV infection, focusing on the transcription factors and cytokines linked to Th1, Th2, Th17, and Treg cells. Thirty-six individuals were enrolled: nine healthy controls and 27 CHIKV-positive patients confirmed by qRT-PCR. Blood samples were analyzed for the mRNA expression of transcription factors (Tbet, GATA3, FoxP3, STAT3, RORγt) and cytokines (IFN-γ, IL-4, IL-17, IL-22, TGF-β, IL-10). The results showed the significant upregulation of Tbet, GATA3, FoxP3, STAT3, and RORγt in CHIKV-positive patients, with RORγt displaying the highest increase. Correspondingly, cytokines IFN-γ, IL-4, IL-17, and IL-22 were upregulated, while TGF-β was downregulated. Principal component analysis (PCA) confirmed the distinct immune profiles between CHIKV-positive and healthy individuals. A correlation analysis indicated that higher Tbet expression correlated with a lower viral load, whereas FoxP3 and TGF-β were associated with higher viral loads. Our study sheds light on the intricate immune responses during acute CHIKV infection, characterized by a mixed Th1, Th2, Th17, and Treg response profile. These results emphasize the complex interplay between different adaptive immune responses and how they may contribute to the pathogenesis of Chikungunya fever.
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Affiliation(s)
| | - Marília Farias de Melo
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - José Veríssimo Fernandes
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Joanna Gardel Valverde
- Institute of Tropical Medicine of Rio Grande do Norte, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Paulo Marcos Matta Guedes
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Josélio Maria Galvão de Araújo
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
| | - Manuela Sales Lima Nascimento
- Department of Microbiology and Parasitology, Biosciences Center, Federal University of Rio Grande do Norte, Natal 59078-970, Brazil
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5
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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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6
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Ravindran S, Lahon A. Tropism and immune response of chikungunya and zika viruses: An overview. Cytokine 2023; 170:156327. [PMID: 37579710 DOI: 10.1016/j.cyto.2023.156327] [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: 10/10/2022] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/16/2023]
Abstract
Zika virus (ZIKV) and chikungunya virus (CHIKV) are two medically important vector-borne viruses responsible for causing significant disease burden in humans, including neurological sequelae/complications. Besides sharing some common clinical features, ZIKV has major shares in causing microcephaly and brain malformations in developing foetus, whereas CHIKV causes chronic joint pain/swelling in infected individuals. Both viruses have a common route of entry to the host body. i.e., dermal site of inoculation through the bite of an infected mosquito and later taken up by different immune cells for further dissemination to other areas of the host body that lead to a range of immune responses via different pathways. The immune responses generated by both viruses have similar characteristics with varying degrees of inflammation and activation of immune cells. However, the overall response of immune cells is not fully explored in the context of ZIKV and CHIKV infection. The knowledge of cellular tropism and the immune response is the key to understanding the mechanisms of viral immunity and pathogenesis, which may allow to develop novel therapeutic strategies for these viral infections. This review aims to discuss recent advancements and identify the knowledge gaps in understanding the mechanism of cellular tropism and immune response of CHIKV and ZIKV.
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Affiliation(s)
- Shilpa Ravindran
- Institute of Advanced Virology, Thiruvananthapuram, Kerala 695317, India
| | - Anismrita Lahon
- Institute of Advanced Virology, Thiruvananthapuram, Kerala 695317, India.
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7
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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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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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El Hajji M, Zaghdani A, Sayari S. Mathematical analysis and optimal control for Chikungunya virus with two routes of infection with nonlinear incidence rate. INT J BIOMATH 2021. [DOI: 10.1142/s1793524521500881] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Chikungunya fever, caused by Chikungunya virus (CHIKV) and transmitted to humans by infected Aedes mosquitoes, has posed a global threat in several countries. In this paper, we investigated a modified within-host Chikungunya virus (CHIKV) infection model with antibodies where two routes of infection are considered. In a first step, the basic reproduction number [Formula: see text] was calculated and the local and global stability analysis of the steady states is carried out using the local linearization and the Lyapunov method. It is proven that the CHIKV-free steady-state [Formula: see text] is globally asymptotically stable when [Formula: see text], and the infected steady-state [Formula: see text] is globally asymptotically stable when [Formula: see text]. In a second step, we applied an optimal strategy in order to optimize the infected compartment and to maximize the uninfected one. For this, we formulated a nonlinear optimal control problem. Existence of the optimal solution was discussed and characterized using some adjoint variables. Thus, an algorithm based on competitive Gauss–Seidel-like implicit difference method was applied in order to resolve the optimality system. The theoretical results are confirmed by some numerical simulations.
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Affiliation(s)
- Miled El Hajji
- Department of Mathematics, Faculty of Sciences, University of Jeddah, Jeddah, Saudi Arabia
- ENIT-LAMSIN, 1002 Tunis-Belvédère, Tunis El Manar University, Tunis, Tunisia
| | - Abdelhamid Zaghdani
- University of Tunis, Boulevard du 9 Avril 1939 Tunis, Department of Mathematics, Ensit, Taha Hussein Avenue, Montfleury, Tunis, Tunisia
- Northern Border University, Faculty of Arts and Science, Rafha, P.O. 840, Saudi Arabia
| | - Sayed Sayari
- Carthage University, Isteub, 2 Rue de l’Artisanat Charguia 2, 2035 Tunis, Tunisia
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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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11
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Campos RK, Preciado-Llanes L, Azar SR, Kim YC, Brandon O, López-Camacho C, Reyes-Sandoval A, Rossi SL. Adenoviral-Vectored Mayaro and Chikungunya Virus Vaccine Candidates Afford Partial Cross-Protection From Lethal Challenge in A129 Mouse Model. Front Immunol 2020; 11:591885. [PMID: 33224148 PMCID: PMC7672187 DOI: 10.3389/fimmu.2020.591885] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/07/2020] [Indexed: 01/08/2023] Open
Abstract
Mayaro (MAYV) and chikungunya viruses (CHIKV) are vector-borne arthritogenic alphaviruses that cause acute febrile illnesses. CHIKV is widespread and has recently caused large urban outbreaks, whereas the distribution of MAYV is restricted to tropical areas in South America with small and sporadic outbreaks. Because MAYV and CHIKV are closely related and have high amino acid similarity, we investigated whether vaccination against one could provide cross-protection against the other. We vaccinated A129 mice (IFNAR -/-) with vaccines based on chimpanzee adenoviral vectors encoding the structural proteins of either MAYV or CHIKV. ChAdOx1 May is a novel vaccine against MAYV, whereas ChAdOx1 Chik is a vaccine against CHIKV already undergoing early phase I clinical trials. We demonstrate that ChAdOx1 May was able to afford full protection against MAYV challenge in mice, with most samples yielding neutralizing PRNT80 antibody titers of 1:258. ChAdOx1 May also provided partial cross-protection against CHIKV, with protection being assessed using the following parameters: survival, weight loss, foot swelling and viremia. Reciprocally, ChAdOx1 Chik vaccination reduced MAYV viral load, as well as morbidity and lethality caused by this virus, but did not protect against foot swelling. The cross-protection observed is likely to be, at least in part, secondary to cross-neutralizing antibodies induced by both vaccines. In summary, our findings suggest that ChAdOx1 Chik and ChAdOx1 May vaccines are not only efficacious against CHIKV and MAYV, respectively, but also afford partial heterologous cross-protection.
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Affiliation(s)
- Rafael Kroon Campos
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| | - Lorena Preciado-Llanes
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Sasha R. Azar
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Young Chan Kim
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Olivia Brandon
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - César López-Camacho
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Arturo Reyes-Sandoval
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Shannan L. Rossi
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
- Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, United States
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12
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El Hajji M. Modelling and optimal control for Chikungunya disease. Theory Biosci 2020; 140:27-44. [PMID: 33128733 DOI: 10.1007/s12064-020-00324-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/12/2020] [Indexed: 11/28/2022]
Abstract
A generalized model of intra-host CHIKV infection with two routes of infection has been proposed. In a first step, the basic reproduction number [Formula: see text] was calculated using the next-generation matrix method and the local and global stability analyses of the steady states are carried out using the Lyapunov method. It is proven that the CHIKV-free steady state [Formula: see text] is globally asymptotically stable when [Formula: see text] and the infected steady state [Formula: see text] is globally asymptotically stable when [Formula: see text]. In a second step, we applied an optimal strategy via the antibodies' flow rate in order to optimize infected compartment and to maximize the uninfected one. For this, we formulated a nonlinear optimal control problem. Existence of the optimal solution was discussed and characterized using an adjoint variables. Thus, an algorithm based on competitive Gauss-Seidel-like implicit difference method was applied in order to resolve the optimality system. The theoretical results are confirmed by some numerical simulations.
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Affiliation(s)
- Miled El Hajji
- Department of Mathematics, Faculty of Sciences, University of Jeddah, Jeddah, Saudi Arabia. .,ENIT-LAMSIN, Tunis El Manar university, BP. 37, Tunis-Belvédère, 1002, Tunis, Tunisia.
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13
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Guerrero D, Cantaert T, Missé D. Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses. Front Cell Infect Microbiol 2020; 10:407. [PMID: 32850501 PMCID: PMC7426362 DOI: 10.3389/fcimb.2020.00407] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 06/30/2020] [Indexed: 12/25/2022] Open
Abstract
Vector-borne diseases are responsible for over a billion infections each year and nearly one million deaths. Mosquito-borne dengue virus, West Nile, Japanese encephalitis, Zika, Chikungunya, and Rift Valley Fever viruses constitute major public health problems in regions with high densities of arthropod vectors. During the initial step of the transmission cycle, vector, host, and virus converge at the bite site, where local immune cells interact with the vector's saliva. Hematophagous mosquito saliva is a mixture of bioactive components known to modulate vertebrate hemostasis, immunity, and inflammation during the insect's feeding process. The capacity of mosquito saliva to modulate the host immune response has been well-studied over the last few decades and has led to the consensus that the presence of saliva is linked to the enhancement of virus transmission, host susceptibility, disease progression, viremia levels, and mortality. We review some of the major aspects of the interactions between mosquito saliva and the host immune response that may be useful for future studies on the control of arboviruses.
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Affiliation(s)
- David Guerrero
- Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia
| | - Tineke Cantaert
- Immunology Unit, Institut Pasteur du Cambodge, Institut Pasteur International Network, Phnom Penh, Cambodia
| | - Dorothée Missé
- MIVEGEC, IRD, University of Montpellier, CNRS, Montpellier, France
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14
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Srivastava P, Kumar A, Hasan A, Mehta D, Kumar R, Sharma C, Sunil S. Disease Resolution in Chikungunya-What Decides the Outcome? Front Immunol 2020; 11:695. [PMID: 32411133 PMCID: PMC7198842 DOI: 10.3389/fimmu.2020.00695] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 03/27/2020] [Indexed: 12/14/2022] Open
Abstract
Chikungunya disease (CHIKD) is a viral infection caused by an alphavirus, chikungunya virus (CHIKV), and triggers large outbreaks leading to epidemics. Despite the low mortality rate, it is a major public health concern owing to high morbidity in affected individuals. The complete spectrum of this disease can be divided into four phases based on its clinical presentation and immunopathology. When a susceptible individual is bitten by an infected mosquito, the bite triggers inflammatory responses attracting neutrophils and initiating a cascade of events, resulting in the entry of the virus into permissive cells. This phase is termed the pre-acute or the intrinsic incubation phase. The virus utilizes the cellular components of the innate immune system to enter into circulation and reach primary sites of infection such as the lymph nodes, spleen, and liver. Also, at this point, antigen-presenting cells (APCs) present the viral antigens to the T cells thereby activating and initiating adaptive immune responses. This phase is marked by the exhibition of clinical symptoms such as fever, rashes, arthralgia, and myalgia and is termed the acute phase of the disease. Viremia reaches its peak during this phase, thereby enhancing the antigen-specific host immune response. Simultaneously, T cell-mediated activation of B cells leads to the formation of CHIKV specific antibodies. Increase in titres of neutralizing IgG/IgM antibodies results in the clearance of virus from the bloodstream and marks the initiation of the post-acute phase. Immune responses mounted during this phase of the infection determine the degree of disease progression or its resolution. Some patients may progress to a chronic arthritic phase of the disease that may last from a few months to several years, owing to a compromised disease resolution. The present review discusses the immunopathology of CHIKD and the factors that dictate disease progression and its resolution.
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Affiliation(s)
- Priyanshu Srivastava
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Ankit Kumar
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Abdul Hasan
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Divya Mehta
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Ramesh Kumar
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Chetan Sharma
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Sujatha Sunil
- Vector-Borne Diseases Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
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15
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Chan YH, Teo TH, Utt A, Tan JJ, Amrun SN, Abu Bakar F, Yee WX, Becht E, Lee CYP, Lee B, Rajarethinam R, Newell E, Merits A, Carissimo G, Lum FM, Ng LF. Mutating chikungunya virus non-structural protein produces potent live-attenuated vaccine candidate. EMBO Mol Med 2020; 11:emmm.201810092. [PMID: 31015278 PMCID: PMC6554673 DOI: 10.15252/emmm.201810092] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Currently, there are no commercially available live-attenuated vaccines against chikungunya virus (CHIKV). Here, CHIKVs with mutations in non-structural proteins (nsPs) were investigated for their suitability as attenuated CHIKV vaccines. R532H mutation in nsP1 caused reduced infectivity in mouse tail fibroblasts but an enhanced type-I IFN response compared to WT-CHIKV Adult mice infected with this nsP-mutant exhibited a mild joint phenotype with low-level viremia that rapidly cleared. Mechanistically, ingenuity pathway analyses revealed a tilt in the anti-inflammatory IL-10 versus pro-inflammatory IL-1β and IL-18 balance during CHIKV nsP-mutant infection that modified acute antiviral and cell signaling canonical pathways. Challenging CHIKV nsP-mutant-infected mice with WT-CHIKV or the closely related O'nyong-nyong virus resulted in no detectable viremia, observable joint inflammation, or damage. Challenged mice showed high antibody titers with efficient neutralizing capacity, indicative of immunological memory. Manipulating molecular processes that govern CHIKV replication could lead to plausible vaccine candidates against alphavirus infection.
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Affiliation(s)
- Yi-Hao Chan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore City, Singapore
| | - Teck-Hui Teo
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.,Molecular Microbial Pathogenesis Unit, Department of Cell Biology and Infection, Institute Pasteur, Paris, France
| | - Age Utt
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Jeslin Jl Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
| | - Siti Naqiah Amrun
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
| | - Farhana Abu Bakar
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore City, Singapore
| | - Wearn-Xin Yee
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Etienne Becht
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Cheryl Yi-Pin Lee
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore.,NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore City, Singapore
| | - Bernett Lee
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
| | | | - Evan Newell
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Andres Merits
- Institute of Technology, University of Tartu, Tartu, Estonia
| | - Guillaume Carissimo
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
| | - Fok-Moon Lum
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore
| | - Lisa Fp Ng
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore City, Singapore .,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore.,Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
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16
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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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17
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Elaiw AM, Almalki SE, Hobiny A. Stability of delayed CHIKV dynamics model with cell-to-cell transmission. JOURNAL OF INTELLIGENT & FUZZY SYSTEMS 2020. [DOI: 10.3233/jifs-179531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Ahmed M. Elaiw
- Department of Mathematics, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sami E. Almalki
- Department of Mathematics, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Jeddah College of Technology, Technical and Vocational Training Corporation, Jeddah, Saudi Arabia
| | - A.D. Hobiny
- Department of Mathematics, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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18
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Prow NA, Hirata TDC, Tang B, Larcher T, Mukhopadhyay P, Alves TL, Le TT, Gardner J, Poo YS, Nakayama E, Lutzky VP, Nakaya HI, Suhrbier A. Exacerbation of Chikungunya Virus Rheumatic Immunopathology by a High Fiber Diet and Butyrate. Front Immunol 2019; 10:2736. [PMID: 31849947 PMCID: PMC6888101 DOI: 10.3389/fimmu.2019.02736] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 11/08/2019] [Indexed: 12/21/2022] Open
Abstract
Chikungunya virus (CHIKV) is a mosquito transmitted alphavirus associated with a robust systemic infection and an acute inflammatory rheumatic disease. A high fiber diet has been widely promoted for its ability to ameliorate inflammatory diseases. Fiber is fermented in the gut into short chain fatty acids such as acetate, propionate, and butyrate, which enter the circulation providing systemic anti-inflammatory activities. Herein we show that mice fed a high fiber diet show a clear exacerbation of CHIKV arthropathy, with increased edema and neutrophil infiltrates. RNA-Seq analyses illustrated that a high fiber diet, in this setting, promoted a range of pro-neutrophil responses including Th17/IL-17. Gene Set Enrichment Analyses demonstrated significant similarities with mouse models of inflammatory psoriasis and significant depression of macrophage resolution phase signatures in the CHIKV arthritic lesions from mice fed a high fiber diet. Supplementation of the drinking water with butyrate also increased edema after CHIKV infection. However, the mechanisms involved were different, with modulation of AP-1 and NF-κB responses identified, potentially implicating deoptimization of endothelial barrier repair. Thus, neither fiber nor short chain fatty acids provided benefits in this acute infectious disease setting, which is characterized by widespread viral cytopathic effects and a need for tissue repair.
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Affiliation(s)
- Natalie A Prow
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia
| | - Thiago D C Hirata
- Computational Systems Biology Laboratory, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Bing Tang
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Thibaut Larcher
- Institut National de Recherche Agronomique, Unité Mixte de Recherche 703, Oniris, Nantes, France
| | - Pamela Mukhopadhyay
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Tiago Lubiana Alves
- Computational Systems Biology Laboratory, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Thuy T Le
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Joy Gardner
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Yee Suan Poo
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Eri Nakayama
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Viviana P Lutzky
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Helder I Nakaya
- Computational Systems Biology Laboratory, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Andreas Suhrbier
- Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Australian Infectious Disease Research Centre, University of Queensland, Brisbane, QLD, Australia
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19
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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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20
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Vertically transmitted chikungunya, Zika and dengue virus infections: The pathogenesis from mother to fetus and the implications of co-infections and vaccine development. Int J Pediatr Adolesc Med 2019; 7:107-111. [PMID: 33094137 PMCID: PMC7567994 DOI: 10.1016/j.ijpam.2019.05.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 04/01/2019] [Accepted: 05/26/2019] [Indexed: 01/23/2023]
Abstract
Chikungunya (CHIKV), Zika (ZIKV), and Dengue viruses (DENV) exhibit similar epidemiological and clinical patterns but have different pathophysiological mechanisms of disease manifestations. Differences occur in the severity of clinical presentations with the highest mortality in the general population attributed to DENV and neurological morbidity due to ZIKV. ZIKV and DENV infections can cause fetal loss with ZIKV exhibiting teratogenesis. CHIKV is associated with severe complications in the newborn. Co-circulation of the three viruses and the cross-reactive immune response between ZIKV and DENV viruses has implications for an attenuated clinical response and future vaccine development. Co-infections could increase due to the epidemiologic synergy, but there is limited evidence about the clinical effects, especially for the vulnerable newborn. The purpose of this paper is to review the pathophysiological basis for vertically transmission manifestations due to CHIKV, DENV, and ZIKV, to determine the potential effects of co-circulation on newborn outcomes and the potential for vaccine protection. Inflammatory cytokines are responsible for placental breaches in DENV and ZIKV; Hofbauer cells facilitate the transfer of ZIKV from the placenta to the fetal brain, and high viral loads and mechanical placental disruption facilitate the transmission of CHIKV. Co-infection of these viruses can present with severe manifestations, but the clinical and serologic evidence suggests that one virus predominates which may influence fetal transmission. All three viruses are in different stages of vaccine development with DENV vaccine being fully licensed. Antibody-enhanced infections in seronegative vaccinated candidates who develop natural infection to dengue limit its use and have implications for ZIKV vaccine development. Targeting transmission capacity in the vector could prevent transmission to all three viruses, and breast milk immunity could provide further clues for vaccine development.
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21
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Abstract
Chikungunya virus (CHIKV) is an alphavirus that is primarily transmitted by Aedes species mosquitoes. Though reports of an illness consistent with chikungunya date back over 200 years, CHIKV only gained worldwide attention during a massive pandemic that began in East Africa in 2004. Chikungunya, the clinical illness caused by CHIKV, is characterized by a rapid onset of high fever and debilitating joint pain, though in practice, etiologic confirmation of CHIKV requires the availability and use of specific laboratory diagnostics. Similar to infections caused by other arboviruses, CHIKV infections are most commonly detected with a combination of molecular and serological methods, though cell culture and antigen detection are reported. This review provides an overview of available CHIKV diagnostics and highlights aspects of basic virology and epidemiology that pertain to viral detection. Although the number of chikungunya cases has decreased since 2014, CHIKV has become endemic in countries across the tropics and will continue to cause sporadic outbreaks in naive individuals. Consistent access to accurate diagnostics is needed to detect individual cases and initiate timely responses to new outbreaks.
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22
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Bhat SM, Mudgal PP, N S, Arunkumar G. Spectrum of candidate molecules against Chikungunya virus - an insight into the antiviral screening platforms. Expert Rev Anti Infect Ther 2019; 17:243-264. [PMID: 30889372 DOI: 10.1080/14787210.2019.1595591] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
INTRODUCTION Chikungunya disease has undergone a phenomenal transition in its status from being recognized as a sporadic infection to acquiring a global prominence over the last couple of decades. The causative agent behind the explosive epidemics worldwide is the re-emerging pathogen, Chikungunya virus (CHIKV). Areas covered: The current review discusses all the possible avenues of antiviral research towards combating CHIKV infection. Aspects of antiviral drug discovery such as antiviral targets, candidate molecules screened, and the various criteria to be a potential inhibitor are all discussed at length. Existing antiviral drug screening tools for CHIKV and their applications are thoroughly described. Clinical trial status of agents with therapeutic potential has been updated with special mention of candidate molecules under patent approval. Databases such as PubMed, Google Scholar, ScienceDirect, Google Patent, and Clinical Trial Registry platforms were referred. Expert opinion: The massive outbreaks of Chikungunya viral disease in the recent past and the serious health concerns imposed thereby, have driven the search for effective therapeutics. The greatest challenge being the non-availability of robust, reproducible, cost-effective and biologically accurate assay models. Nevertheless, there is a need to identify good models mimicking the appropriate microenvironment of an infectious setting.
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Affiliation(s)
- Shree Madhu Bhat
- a Manipal Centre for Virus Research , Manipal Academy of Higher Education (Deemed to be University) , Manipal , Karnataka , India
| | - Piya Paul Mudgal
- a Manipal Centre for Virus Research , Manipal Academy of Higher Education (Deemed to be University) , Manipal , Karnataka , India
| | - Sudheesh N
- a Manipal Centre for Virus Research , Manipal Academy of Higher Education (Deemed to be University) , Manipal , Karnataka , India
| | - Govindakarnavar Arunkumar
- a Manipal Centre for Virus Research , Manipal Academy of Higher Education (Deemed to be University) , Manipal , Karnataka , India
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23
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Goyal M, Chauhan A, Goyal V, Jaiswal N, Singh S, Singh M. Recent development in the strategies projected for chikungunya vaccine in humans. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:4195-4206. [PMID: 30573950 PMCID: PMC6292406 DOI: 10.2147/dddt.s181574] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The unprecedented epidemic spread of chikungunya worldwide illustrates the critical need for potent vaccines and therapeutic interventions. The morbidity and mortality associated with this arboviral infection has become a major public health problem in many countries across different continents. Increasing public–private partnerships have opened new avenues in research and development of vaccines. This review mainly focuses on the recent advances in patented approaches for chikungunya vaccine development and the forthcoming challenges.
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Affiliation(s)
- Manu Goyal
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India,
| | - Anil Chauhan
- Indian Council of Medical Research Advanced Centre for Evidence Based Child Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India,
| | | | - Nishant Jaiswal
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India, .,Indian Council of Medical Research Advanced Centre for Evidence Based Child Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India,
| | - Shreya Singh
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Meenu Singh
- Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India, .,Indian Council of Medical Research Advanced Centre for Evidence Based Child Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India,
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24
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Elaiw AM, Alade TO, Alsulami SM. Analysis of latent CHIKV dynamics models with general incidence rate and time delays. JOURNAL OF BIOLOGICAL DYNAMICS 2018; 12:700-730. [PMID: 30067144 DOI: 10.1080/17513758.2018.1503349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 07/17/2018] [Indexed: 06/08/2023]
Abstract
In this paper, we study the stability analysis of latent Chikungunya virus (CHIKV) dynamics models. The incidence rate between the CHIKV and the uninfected monocytes is modelled by a general nonlinear function which satisfies a set of conditions. The model is incorporated by intracellular discrete or distributed time delays. Using the method of Lyapunov function, we established the global stability of the steady states of the models. The theoretical results are confirmed by numerical simulations.
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Affiliation(s)
- Ahmed M Elaiw
- a Department of Mathematics, Faculty of Science , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Taofeek O Alade
- a Department of Mathematics, Faculty of Science , King Abdulaziz University , Jeddah , Saudi Arabia
| | - Saud M Alsulami
- a Department of Mathematics, Faculty of Science , King Abdulaziz University , Jeddah , Saudi Arabia
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25
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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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26
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Paniz-Mondolfi AE, Blohm GM, Hernandez-Perez M, Larrazabal A, Moya D, Marquez M, Talamo A, Carrillo A, Rothe de Arocha J, Lednicky J, Morris JG. Cutaneous features of Zika virus infection: a clinicopathological overview. Clin Exp Dermatol 2018; 44:13-19. [PMID: 30267436 DOI: 10.1111/ced.13793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/13/2018] [Indexed: 12/19/2022]
Abstract
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus transmitted mainly by Aedes species of mosquitos. Although the infection is usually mild and self-limiting, it is emerging as a public health challenge in tropical and subtropical countries owing to its unprecedented pathogenicity and increased risk for fetal malformations and neurological symptoms. Cutaneous manifestations as for other mosquito-borne viruses remain a hallmark of the disease. This article provides a detailed overview on ZIKV infection, including its varied cutaneous clinical manifestations and diagnostic aspects, and also provides detailed insights into its pathogenesis in human skin.
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Affiliation(s)
- A E Paniz-Mondolfi
- Department of Infectious Diseases and Tropical Medicine, Clínica IDB Cabudare, Instituto de Investigaciones Biomédicas IDB, Barquisimeto, Lara, Venezuela.,Instituto Venezolano de los Seguros Sociales (IVSS), Department of Health, Caracas, Venezuela
| | - G M Blohm
- Department of Biology, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL, USA
| | - M Hernandez-Perez
- Department of Dermatopathology, Miraca Life Sciences Research Institute/Tufts Medical Center, Boston, MA, USA
| | - A Larrazabal
- Department of Infectious Diseases and Tropical Medicine, Clínica IDB Cabudare, Instituto de Investigaciones Biomédicas IDB, Barquisimeto, Lara, Venezuela.,Infectious Diseases Research Branch-Venezuelan Science and the Zoonosis and Emerging Pathogens Regional Collaborative Network, Arboviral Diseases Branch, Barquisimeto, Lara, Venezuela
| | - D Moya
- Department of Infectious Diseases and Tropical Medicine, Clínica IDB Cabudare, Instituto de Investigaciones Biomédicas IDB, Barquisimeto, Lara, Venezuela.,Infectious Diseases Research Branch-Venezuelan Science and the Zoonosis and Emerging Pathogens Regional Collaborative Network, Arboviral Diseases Branch, Barquisimeto, Lara, Venezuela
| | - M Marquez
- Infectious Diseases Research Branch-Venezuelan Science and the Zoonosis and Emerging Pathogens Regional Collaborative Network, Arboviral Diseases Branch, Barquisimeto, Lara, Venezuela.,Health Sciences Department, College of Medicine, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Lara, Venezuela
| | - A Talamo
- Infectious Diseases Research Branch-Venezuelan Science and the Zoonosis and Emerging Pathogens Regional Collaborative Network, Arboviral Diseases Branch, Barquisimeto, Lara, Venezuela.,Health Sciences Department, College of Medicine, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Lara, Venezuela
| | - A Carrillo
- Department of Infectious Diseases and Tropical Medicine, Clínica IDB Cabudare, Instituto de Investigaciones Biomédicas IDB, Barquisimeto, Lara, Venezuela.,Infectious Diseases Research Branch-Venezuelan Science and the Zoonosis and Emerging Pathogens Regional Collaborative Network, Arboviral Diseases Branch, Barquisimeto, Lara, Venezuela.,Health Sciences Department, College of Medicine, Universidad Nacional Experimental 'Francisco de Miranda', Punto Fijo, Falcon, Venezuela
| | - J Rothe de Arocha
- Sociedad Anticancerosa del Estado Lara, Barquisimeto, Lara, Venezuela.,Psoriasis Unit, Hospital Central Antonio Maria Pineda, Barquisimeto, Lara, Venezuela
| | - J Lednicky
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.,Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA
| | - J G Morris
- Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.,Division of Infectious Diseases and Global Health, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
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27
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Danillo Lucas Alves E, Benedito Antonio Lopes da F. Characterization of the immune response following in vitro mayaro and chikungunya viruses (Alphavirus, Togaviridae) infection of mononuclear cells. Virus Res 2018; 256:166-173. [PMID: 30145137 DOI: 10.1016/j.virusres.2018.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 08/09/2018] [Accepted: 08/14/2018] [Indexed: 02/07/2023]
Abstract
Two Alphaviruses stand out for their clinical importance in Brazil: chikungunya (CHIKV) and mayaro (MAYV) viruses. Few studies exist on the mechanisms of the immune response after infection by these viruses and neither a treatment nor a vaccine for these pathogens are available. Although their infection does not have a high mortality rate, they can lead to a joint involvement that can persist for months. The aims of this work were the study of the mechanisms of antiviral immune response following in vitro (U937 cells) infection with these viruses; to investigate the characteristics of the infection by these viruses; and to determine possible molecular targets that could serve as antiviral therapies against these pathogens. Several genes were modulated after infection by these viruses, and the three antiviral detection and response pathways were activated (Toll-like, RIG-I and NOD-like). Eotaxin and IL-6 were induced in all experiments. The cellular immune response profile found for each virus was different, with CHIKV activating primarily an inflammatory response (Th1 and Th17) and MAYV inducing a regulatory/suppressive response, an important feature to contain the inflammation resulting from infection. The data acquired by this study could provide an explanation why CHIKV infections, due to activation of the inflammatory response, are more clinically relevant than MAYV infections, which generates mostly an anti-inflammatory response after infection.
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Affiliation(s)
- Esposito Danillo Lucas Alves
- Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo State, Brazil.
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28
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Elaiw AM, Alade TO, Alsulami SM. Analysis of within-host CHIKV dynamics models with general incidence rate. INT J BIOMATH 2018. [DOI: 10.1142/s1793524518500626] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
In this paper we study the stability analysis of two within-host Chikungunya virus (CHIKV) dynamics models. The incidence rate between the CHIKV and the uninfected monocytes is modeled by a general nonlinear function. The second model considers two types of infected monocytes (i) latently infected monocytes which do not generate CHIKV and (ii) actively infected monocytes which produce the CHIKV particles. Sufficient conditions are found which guarantee the global stability of the positive steady states. Using the Lyapunov function, we established the global stability of the steady states of the models. The theoretical results are confirmed by numerical simulations.
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Affiliation(s)
- Ahmed M. Elaiw
- Department of Mathematics, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
| | - Taofeek O. Alade
- Department of Mathematics, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
| | - Saud M. Alsulami
- Department of Mathematics, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia
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29
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Banerjee N, Mukhopadhyay S. Oxidative damage markers and inflammatory cytokines are altered in patients suffering with post-chikungunya persisting polyarthralgia. Free Radic Res 2018; 52:887-895. [PMID: 29898618 DOI: 10.1080/10715762.2018.1489131] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Redox homoeostasis is necessary for the maintenance of living systems. Chikungunya viral infection manifests into joint inflammation and debilitating polyarthralgia affecting the life style of the patient badly. The disease pathophysiology is poorly understood and there is a lack of targeted therapeutics. The pathogenic role of free radicals in arthritis is well established. This study aims for the first time to evaluate the status of several standard oxidative stress markers and their correlation in chikungunya patients suffering with polyarthralgia. Expression of Siglec-9 on monocytes; which can modulate oxidative stress is studied along with intracellular reactive oxygen species (ROS), cellular lipid and protein damage markers in chikungunya patients with/without persisting polyarthralgia along with healthy controls. Furthermore, plasma NO level, antioxidant status was investigated along with some inflammatory cytokines namely IL-6, IFN-γ, CXCL-9, IL-10 and TGFβ1. Interestingly, all oxidative damage markers are altered significantly in groups but their alteration levels vary in patients with/without persisting polyarthralgia. Siglec-9 expression level is increased in patients revealing cellular response to manage oxidative stress with respect to controls. Correlation studies reveal that intracellular ROS correlates well with most of the studied parameters but the correlation coefficient (Pearson r) differs with disease manifestation demonstrating strong role of these factors in a pro-oxidant milieu. The presence of free radicals increases the availability of neoantigens continuously, which possibly further cascades oxidative damage and development of persisting polyarthralgia.
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Affiliation(s)
- Nilotpal Banerjee
- a Department of Laboratory Medicine , School of Tropical Medicine , Kolkata , India
| | - Sumi Mukhopadhyay
- a Department of Laboratory Medicine , School of Tropical Medicine , Kolkata , India
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30
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Prow NA, Tang B, Gardner J, Le TT, Taylor A, Poo YS, Nakayama E, Hirata TDC, Nakaya HI, Slonchak A, Mukhopadhyay P, Mahalingam S, Schroder WA, Klimstra W, Suhrbier A. Lower temperatures reduce type I interferon activity and promote alphaviral arthritis. PLoS Pathog 2017; 13:e1006788. [PMID: 29281739 PMCID: PMC5770078 DOI: 10.1371/journal.ppat.1006788] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 01/16/2018] [Accepted: 12/04/2017] [Indexed: 12/28/2022] Open
Abstract
Chikungunya virus (CHIKV) belongs to a group of mosquito-borne alphaviruses associated with acute and chronic arthropathy, with peripheral and limb joints most commonly affected. Using a mouse model of CHIKV infection and arthritic disease, we show that CHIKV replication and the ensuing foot arthropathy were dramatically reduced when mice were housed at 30°C, rather than the conventional 22°C. The effect was not associated with a detectable fever, but was dependent on type I interferon responses. Bioinformatics analyses of RNA-Seq data after injection of poly(I:C)/jetPEI suggested the unfolded protein response and certain type I interferon responses are promoted when feet are slightly warmer. The ambient temperature thus appears able profoundly to effect anti-viral activity in the periphery, with clear consequences for alphaviral replication and the ensuing arthropathy. These observations may provide an explanation for why alphaviral arthropathies are largely restricted to joints of the limbs and the extremities.
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Affiliation(s)
- Natalie A. Prow
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
| | - Bing Tang
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Joy Gardner
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Thuy T. Le
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Adam Taylor
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
| | - Yee S. Poo
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Eri Nakayama
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Thiago D. C. Hirata
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Helder I. Nakaya
- School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Andrii Slonchak
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
| | | | - Suresh Mahalingam
- Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
| | - Wayne A. Schroder
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - William Klimstra
- Department of Microbiology and Molecular Genetics Center for Vaccine Research University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Australian Infectious Disease Research Centre, Brisbane, Queensland, Australia
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31
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Thanapati S, Sudeep AB, Kulkarni SP, Tripathy AS. Regulation of the chikungunya-virus-induced innate inflammatory response by protein tyrosine phosphatase non-receptor 6 in muscle cells. Arch Virol 2017; 163:243-248. [PMID: 29058147 DOI: 10.1007/s00705-017-3615-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 09/29/2017] [Indexed: 01/03/2023]
Abstract
Chikungunya virus (CHIKV)-induced myositis is an emerging affliction with high incidence globally. Given the essential regulatory role of protein tyrosine phosphatase non-receptor 6 (PTPN6) in virus-induced myositis, the expression of the PTPN6 and TNF-α genes in a CHIKV-infected muscle cell line was examined by quantitative PCR, and the expression of PTPN6 and STAT 3 was examined by immunoblotting. In addition, the effect of PTPN6 siRNA treatment on TNF-α gene expression was assessed. Increased higher expression of PTPN6 and TNF-α, and significant upregulation of TNF-α upon PTPN6 siRNA treatment were observed, suggesting that CHIKV has the ability to induce host PTPN6 gene expression, which may lead to a decreased pro-inflammatory immune response in the host.
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Affiliation(s)
- Subrat Thanapati
- Hepatitis Group, National Institute of Virology, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - A B Sudeep
- Entomology group, National Institute of Virology, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - Shruti P Kulkarni
- Hepatitis Group, National Institute of Virology, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - Anuradha S Tripathy
- Hepatitis Group, National Institute of Virology, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India.
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32
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Godaert L, Najioullah F, Bartholet S, Colas S, Yactayo S, Cabié A, Fanon JL, Césaire R, Dramé M. Atypical Clinical Presentations of Acute Phase Chikungunya Virus Infection in Older Adults. J Am Geriatr Soc 2017; 65:2510-2515. [PMID: 28940357 DOI: 10.1111/jgs.15004] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES We aimed to determine whether the presentation of Chikungunya virus (CHIKV) infection differs between older and younger adults with regard to clinical form during the acute phase defined by the World Health Organization: acute clinical, atypical, and severe acute. DESIGN Cross-sectional, retrospective. SETTING University Hospital of Martinique. PARTICIPANTS Individuals aged 65 and older (n = 267, mean age 80.4 ± 87.9) who attended the emergency department with a positive biological diagnosis of CHIKV (reverse transcriptase polymerase chain reaction) between January and December 2014 and a randomly selected sample of individuals younger than 65 (n = 109, mean age 46.2 ± 12.7). RESULTS Typical presentation was present in 8.2% of older adults and 59.6% of younger individuals (P < .001), atypical presentation in 29.6% of older adults and 5.6% of younger individuals (P < .001), and severe presentation in 19.5% of older adults and 17.4% of younger individuals (P = .65). One hundred fourteen (42.7%) of the older group and 19 (17.4%) of the younger group could not be classified in any category (absence of fever, absence of joint pain, or both) (P < .001). CONCLUSION Only 8.2% of the older adults presenting in the acute phase of CHIKV have typical forms, suggesting that the most-frequent clinical presentation of CHIKV in older adults differs from that in younger individuals.
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Affiliation(s)
- Lidvine Godaert
- Department of Geriatrics, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Fatiha Najioullah
- Department of Virology, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Seendy Bartholet
- Department of Geriatrics, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Sébastien Colas
- Department of Geriatrics, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Sergio Yactayo
- Department of Pandemic and Epidemic Diseases, World Health Organization, Geneva, Switzerland
| | - André Cabié
- Department of Infectious Diseases, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Jean-Luc Fanon
- Department of Geriatrics, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Raymond Césaire
- Department of Virology, University Hospitals of Martinique, Fort-de-France, Martinique
| | - Moustapha Dramé
- Faculty of Medicine, University of Reims Champagne-Ardenne, Reims, France.,Department of Research and Public Health, University Hospital of Reims, Robert Debré Hospital, Reims, France
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33
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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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34
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Kulkarni SP, Ganu M, Jayawant P, Thanapati S, Ganu A, Tripathy AS. Regulatory T cells and IL-10 as modulators of chikungunya disease outcome: a preliminary study. Eur J Clin Microbiol Infect Dis 2017; 36:2475-2481. [PMID: 28840350 DOI: 10.1007/s10096-017-3087-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 07/31/2017] [Indexed: 12/26/2022]
Abstract
Regulatory T (Treg) cells hold centre stage in regulating the immune responses in most viral infections. However, their involvement in chikungunya infection is unexplored. In the current study, the frequencies and functionality of peripheral Treg and T effector (Teff) cells were assessed during different phases of chikungunya by flow cytometry and in-vitro cytokine assays. Treg cells were also studied in rheumatoid arthritis (RA) patients, whose symptoms closely mimic chronic chikungunya arthritis patients. Frequency of Treg cells was lower in acute and chronic chikungunya arthritis patients than in recovered individuals and controls, and comparable among recovered individuals and controls. Treg/Teff ratio was lower in acute than in chronic chikungunya arthritis patients, recovered individuals and controls. Higher secretion of CHIKV specific IL-10 was observed in recovered individuals than in acute, chronic chikungunya arthritis patients and controls. Frequencies of Treg and Teff cells were higher and Treg/Teff ratio was lower in RA patients than in chronic chikungunya arthritis patients. The results indicate that reduction of Treg cells was associated with ongoing CHIKV infection and normalization of Treg cells with resolution of disease. Contrasting phenotypic data in RA and chronic chikungunya arthritis suggest an altogether different mechanism of Treg-mediated pathology in both arthritis conditions. Overall, our preliminary study, suggesting an association of peripheral Treg cells and IL-10 with recovery from chikungunya, may provide insight into chikungunya disease prognosis and warrants further study.
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Affiliation(s)
- S P Kulkarni
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - M Ganu
- Sanjeevan Hospital, Latur, Maharashtra, India
| | - P Jayawant
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - S Thanapati
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India
| | - A Ganu
- Sanjeevan Hospital, Latur, Maharashtra, India
| | - A S Tripathy
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune, Maharashtra, 411021, India.
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35
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Olajiga OM, Adesoye OE, Emilolorun AP, Adeyemi AJ, Adeyefa EO, Aderibigbe IA, Adejumo SA, Adebimpe WO, Opaleye OO, Sule WF, Oluwayelu DO. Chikungunya Virus Seroprevalence and Associated Factors among Hospital Attendees in Two States of Southwest Nigeria: A Preliminary Assessment. Immunol Invest 2017; 46:552-565. [PMID: 28742401 DOI: 10.1080/08820139.2017.1319383] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Chikungunya virus (CHIKV) is a re-emerging pathogen causing long-term polyarthritis and encephalitis. In conducting a preliminary investigation, we hypothesized that there is no serologic evidence of CHIKV infection among attendees of selected hospitals in Lagos and Osun States, Nigeria. Sera from 304 consecutively selected participants were screened for CHIKV IgG and IgM using ELISA. Findings were analyzed vis-à-vis participants' demographic and clinical data. Over 90.0% of the participants had never heard of CHIKV despite the fact that a large proportion of them (88.8%) had secondary/tertiary education. Overall, 41.8% were positive for, at least, one antibody type (IgG or IgM), while about 16.0% of the participants had dual seropositivity (CHIKV IgG and IgM) with gender as associated factor (odds ratio [OR]: 2.8, p = 0.03). Prevalence rates were 31.8% and 38.4% for CHIKV IgG and IgM, respectively. Only hospital location (Osogbo) was associated with CHIKV IgG (OR: 2.2, p = 0.009), while gender alone was associated with CHIKV IgM (OR: 3.0, p = 0.001). Participants seropositive for CHIKV antibodies were mostly adults (18-59 yrs) belonging to the active work-force; five (22.7%) and three (20.0%) of the pregnant participants had CHIKV IgG and IgM, respectively. Detection of CHIKV IgM in some participants might make them potentially infectious to the newborn and mosquito vectors. Importantly, participants positive for either IgG or IgM had fever (72.8%, 67.2%) and general body pains (61.7%, 57.6%), respectively. This ELISA-based study revealed serologic evidence of CHIKV infection among hospital attendees in Lagos and Osun states with the group-specific prevalence rates being considerably high. ABBREVIATIONS Chikungunya virus (CHIKV); Chikungunya (CHIK); enzyme-linked immunosorbent assay (ELISA); immunoglobulin G or M (IgG/IgM); odds ratio (OR); non-structural proteins (nsP); hemagglutination inhibiting (HI); complement fixing (CF); neutralization test (NT); immunofluorescence assay (IFA); plaque reduction neutralization test (PRNT); confidence interval (CI); analysis of variance (ANOVA); body temperature (BT); Building Nigeria's Response to Climate Change (BNRCC).
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Affiliation(s)
- Olayinka M Olajiga
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Olajumoke E Adesoye
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Adewale P Emilolorun
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Abiodun J Adeyemi
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Emmanuel O Adeyefa
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Ismail A Aderibigbe
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Salmot A Adejumo
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Wasiu O Adebimpe
- b Department of Community Medicine, College of Health Sciences , Osun State University , Osogbo , Nigeria
| | - Oluyinka O Opaleye
- c Department of Medical Microbiology and Parasitology, College of Health Sciences , Ladoke Akintola University of Technology , Osogbo , Nigeria
| | - Waidi F Sule
- a Department of Biological Sciences, Faculty of Basic and Applied Sciences , Osun State University , Osogbo , Nigeria
| | - Daniel O Oluwayelu
- d Department of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine , University of Ibadan , Ibadan , Nigeria
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Complete Genome Sequences of 15 Chikungunya Virus Isolates from Puerto Rico. GENOME ANNOUNCEMENTS 2017; 5:5/27/e00561-17. [PMID: 28684571 PMCID: PMC5502852 DOI: 10.1128/genomea.00561-17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Here, we report the complete genome sequences of 15 chikungunya virus strains isolated from human plasma from infected patients in Puerto Rico. The results show that currently circulating chikungunya strains in Puerto Rico are closely related.
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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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Jain J, Nayak K, Tanwar N, Gaind R, Gupta B, Shastri JS, Bhatnagar RK, Kaja MK, Chandele A, Sunil S. Clinical, Serological, and Virological Analysis of 572 Chikungunya Patients From 2010 to 2013 in India. Clin Infect Dis 2017; 65:133-140. [DOI: 10.1093/cid/cix283] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 03/28/2017] [Indexed: 01/06/2023] Open
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Thanapati S, Ganu M, Giri P, Kulkarni S, Sharma M, Babar P, Ganu A, Tripathy AS. Impaired NK cell functionality and increased TNF-α production as biomarkers of chronic chikungunya arthritis and rheumatoid arthritis. Hum Immunol 2017; 78:370-374. [DOI: 10.1016/j.humimm.2017.02.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/06/2017] [Accepted: 02/11/2017] [Indexed: 01/16/2023]
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Silva LA, Dermody TS. Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 2017; 127:737-749. [PMID: 28248203 PMCID: PMC5330729 DOI: 10.1172/jci84417] [Citation(s) in RCA: 240] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Chikungunya virus (CHIKV), a reemerging arbovirus, causes a crippling musculoskeletal inflammatory disease in humans characterized by fever, polyarthralgia, myalgia, rash, and headache. CHIKV is transmitted by Aedes species of mosquitoes and is capable of an epidemic, urban transmission cycle with high rates of infection. Since 2004, CHIKV has spread to new areas, causing disease on a global scale, and the potential for CHIKV epidemics remains high. Although CHIKV has caused millions of cases of disease and significant economic burden in affected areas, no licensed vaccines or antiviral therapies are available. In this Review, we describe CHIKV epidemiology, replication cycle, pathogenesis and host immune responses, and prospects for effective vaccines and highlight important questions for future research.
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RNA-Seq analysis of chikungunya virus infection and identification of granzyme A as a major promoter of arthritic inflammation. PLoS Pathog 2017; 13:e1006155. [PMID: 28207896 PMCID: PMC5312928 DOI: 10.1371/journal.ppat.1006155] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 12/28/2016] [Indexed: 02/07/2023] Open
Abstract
Chikungunya virus (CHIKV) is an arthritogenic alphavirus causing epidemics of acute and chronic arthritic disease. Herein we describe a comprehensive RNA-Seq analysis of feet and lymph nodes at peak viraemia (day 2 post infection), acute arthritis (day 7) and chronic disease (day 30) in the CHIKV adult wild-type mouse model. Genes previously shown to be up-regulated in CHIKV patients were also up-regulated in the mouse model. CHIKV sequence information was also obtained with up to ≈8% of the reads mapping to the viral genome; however, no adaptive viral genome changes were apparent. Although day 2, 7 and 30 represent distinct stages of infection and disease, there was a pronounced overlap in up-regulated host genes and pathways. Type I interferon response genes (IRGs) represented up to ≈50% of up-regulated genes, even after loss of type I interferon induction on days 7 and 30. Bioinformatic analyses suggested a number of interferon response factors were primarily responsible for maintaining type I IRG induction. A group of genes prominent in the RNA-Seq analysis and hitherto unexplored in viral arthropathies were granzymes A, B and K. Granzyme A-/- and to a lesser extent granzyme K-/-, but not granzyme B-/-, mice showed a pronounced reduction in foot swelling and arthritis, with analysis of granzyme A-/- mice showing no reductions in viral loads but reduced NK and T cell infiltrates post CHIKV infection. Treatment with Serpinb6b, a granzyme A inhibitor, also reduced arthritic inflammation in wild-type mice. In non-human primates circulating granzyme A levels were elevated after CHIKV infection, with the increase correlating with viral load. Elevated granzyme A levels were also seen in a small cohort of human CHIKV patients. Taken together these results suggest granzyme A is an important driver of arthritic inflammation and a potential target for therapy. Trial Registration: ClinicalTrials.gov NCT00281294 The largest chikungunya virus (CHIKV) epidemic ever recorded began in 2004 in Africa and spread across Asia reaching Europe and recently the Americas, with millions of cases reported. We undertook a detailed analysis of the mRNA expression profile during acute and chronic arthritis in an adult wild-type mouse model of CHIKV infection and disease. Gene induction profiles showed a high concordance with published human data, providing some validation of the mouse model. The host response was overwhelmingly dominated by type I interferon response genes, even after type I interferon induction was lost. The analysis also provided information on CHIKV RNA, with no adaptive viral genome changes identified. An important goal of the analysis was to identify new players in arthritic inflammation. Granzyme A was prominent in the RNA-Seq data and granzyme A deficient mice showed reduced arthritis, with no effects on viral loads. Arthritic disease could also be ameliorated in wild-type mice with a granzyme A inhibitor. Elevated circulating granzyme A levels were seen in non-human primates infected with CHIKV and in human CHIKV patients. Granzyme A thus emerges to be a major driver of CHIKV-mediated arthritic inflammation and a potential target for anti-inflammatory interventions.
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Next generation sequencing of DNA-launched Chikungunya vaccine virus. Virology 2016; 490:83-90. [PMID: 26855330 DOI: 10.1016/j.virol.2016.01.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 01/11/2016] [Accepted: 01/13/2016] [Indexed: 11/22/2022]
Abstract
Chikungunya virus (CHIKV) represents a pandemic threat with no approved vaccine available. Recently, we described a novel vaccination strategy based on iDNA® infectious clone designed to launch a live-attenuated CHIKV vaccine from plasmid DNA in vitro or in vivo. As a proof of concept, we prepared iDNA plasmid pCHIKV-7 encoding the full-length cDNA of the 181/25 vaccine. The DNA-launched CHIKV-7 virus was prepared and compared to the 181/25 virus. Illumina HiSeq2000 sequencing revealed that with the exception of the 3' untranslated region, CHIKV-7 viral RNA consistently showed a lower frequency of single-nucleotide polymorphisms than the 181/25 RNA including at the E2-12 and E2-82 residues previously identified as attenuating mutations. In the CHIKV-7, frequencies of reversions at E2-12 and E2-82 were 0.064% and 0.086%, while in the 181/25, frequencies were 0.179% and 0.133%, respectively. We conclude that the DNA-launched virus has a reduced probability of reversion mutations, thereby enhancing vaccine safety.
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Lum FM, Ng LF. Cellular and molecular mechanisms of chikungunya pathogenesis. Antiviral Res 2015; 120:165-74. [DOI: 10.1016/j.antiviral.2015.06.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 05/27/2015] [Accepted: 06/16/2015] [Indexed: 12/15/2022]
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