Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus‐specific neutralizing antibody response
Copyright policy )Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus‐specific neutralizing antibody response
AbstractRNA‐sensing toll‐like receptors (TLRs) mediate innate immunity and regulate anti‐viral response. We show here that TLR3 regulates host immunity and the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human and mouse fibroblasts with defective TLR3 signaling. Up to 100‐fold increase in CHIKV load was observed in Tlr3−/− mice, alongside increased virus dissemination and pro‐inflammatory myeloid cells infiltration. Infection in bone marrow chimeric mice showed that TLR3‐expressing hematopoietic cells are required for effective CHIKV clearance. CHIKV‐specific antibodies from Tlr3−/− mice exhibited significantly lower in vitro neutralization capacity, due to altered virus‐neutralizing epitope specificity. Finally, SNP genotyping analysis of CHIKF patients on TLR3 identified SNP rs6552950 to be associated with disease severity and CHIKV‐specific neutralizing antibody response. These results demonstrate a key role for TLR3‐mediated antibody response to CHIKV infection, virus replication and pathology, providing a basis for future development of immunotherapeutics in vaccine development.
- Paris 13 University France
- University of Liverpool United Kingdom
- Sciences Po France
- University of Tartu Estonia
- National University of Singapore Singapore
Male, Medicine (General), chikungunya, cell infiltration, genotype, Chikungunya alphavirus, animal cell, QH426-470, Antibodies, Viral, Virus Replication, fibroblast, immunology, Mice, toll like receptor 3, single nucleotide polymorphism, TLR3 Subject Categories Immunology, animal, genetics, TLR3, innate immunity, virus replication, Research Articles, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C57BL mouse, adult, neutralizing antibody, Middle Aged, [SDV] Life Sciences [q-bio], aged, female, arthritis, priority journal, glycoprotein E2, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, disease severity, Female, Chikungunya virus, signal transduction, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, animal experiment, 610, Microbiology, Polymorphism, Single Nucleotide, Article, hematopoietic cell, virus antibody, Young Adult, R5-920, male, Species Specificity, Genetics, Animals, Humans, controlled study, neutralizing antibodies, human, infection sensitivity, protein expression, mouse, Aged, TLR3 protein, nonhuman, animal model, human cell, antibody response, virus load, major clinical study, Antibodies, Neutralizing, Toll-Like Receptor 3, Virology & Host Pathogen Interaction, Mice, Inbred C57BL, joint inflammation, Chikungunya Fever, knockout mouse, bone marrow cell, viral clearance
Male, Medicine (General), chikungunya, cell infiltration, genotype, Chikungunya alphavirus, animal cell, QH426-470, Antibodies, Viral, Virus Replication, fibroblast, immunology, Mice, toll like receptor 3, single nucleotide polymorphism, TLR3 Subject Categories Immunology, animal, genetics, TLR3, innate immunity, virus replication, Research Articles, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, C57BL mouse, adult, neutralizing antibody, Middle Aged, [SDV] Life Sciences [q-bio], aged, female, arthritis, priority journal, glycoprotein E2, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, disease severity, Female, Chikungunya virus, signal transduction, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, animal experiment, 610, Microbiology, Polymorphism, Single Nucleotide, Article, hematopoietic cell, virus antibody, Young Adult, R5-920, male, Species Specificity, Genetics, Animals, Humans, controlled study, neutralizing antibodies, human, infection sensitivity, protein expression, mouse, Aged, TLR3 protein, nonhuman, animal model, human cell, antibody response, virus load, major clinical study, Antibodies, Neutralizing, Toll-Like Receptor 3, Virology & Host Pathogen Interaction, Mice, Inbred C57BL, joint inflammation, Chikungunya Fever, knockout mouse, bone marrow cell, viral clearance
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