Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus‐specific neutralizing antibody response

• Published in: EMBO molecular medicine Vol. 7; no. 1; pp. 24 - 41
• Main Authors: Her, Zhisheng, Teng, Terk‐Shin, Tan, Jeslin JL, Teo, Teck‐Hui, Kam, Yiu‐Wing, Lum, Fok‐Moon, Lee, Wendy WL, Gabriel, Christelle, Melchiotti, Rossella, Andiappan, Anand K, Lulla, Valeria, Lulla, Aleksei, Win, Mar K, Chow, Angela, Biswas, Subhra K, Leo, Yee‐Sin, Lecuit, Marc, Merits, Andres, Rénia, Laurent, Ng, Lisa FP
• Format: Journal Article
• Language: English
• Published: England EMBO Press 01.01.2015; Wiley Open Access; BlackWell Publishing Ltd
• Subjects: Adult; Aged; Animals; Antibodies, Neutralizing; Antibodies, Neutralizing - immunology; Antibodies, Viral; Antibodies, Viral - immunology; Antibody response; Bone marrow; Chikungunya Fever; Chikungunya Fever - genetics; Chikungunya Fever - immunology; Chikungunya Fever - pathology; Chikungunya Fever - virology; Chikungunya virus; Chikungunya virus - immunology; Chikungunya virus - physiology; Emerging diseases; Encephalitis; Epitopes; Female; Fibroblasts; Genotyping; Human health and pathology; Humans; Immunology; Infections; Infectious diseases; Inflammation; Innate immunity; Investigations; joint inflammation; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology and Parasitology; Middle Aged; Myeloid cells; neutralizing antibodies; Pathology; Polymorphism, Single Nucleotide; Proteins; Replication; Ribonucleic acid; RNA; Species Specificity; TLR3; TLR3 protein; Toll-Like Receptor 3; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - immunology; Toll-like receptors; Vaccine development; Viral infections; Virology; Virus Replication; Viruses; West Nile virus; Young Adult; joint inflammation; neutralizing antibodies; innate immunity; TLR3; Chikungunya virus; Virology & Host Pathogen Interaction; TLR3 Subject Categories Immunology; Microbiology
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201404459

RNA‐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. Synopsis TLR3‐mediated innate response against CHIKV infection modulates the adaptive immune response and TLR3 deficiency results in enhanced viremia and more severe pathology in mice; in CHIKV‐infected patients, TLR3 expression is high and a TLR3 SNP associates with disease severity. TLR3 regulates host immunity in CHIKV infection and pathology in humans and mice. A loss of TLR3 was demonstrated to markedly increase virus replication and dissemination that led to more severe joint pathology. Bone marrow chimeric experiments indicated that TLR3‐expressing hematopoietic cells play a role CHIKV clearance. The loss of TLR3 impaired neutralizing capacity due to altered virus‐neutralizing epitope specificity. SNP genotyping analysis on TLR from patients identified SNP rs6552950 as associated with disease severity. TLR3‐mediated innate response against CHIKV infection modulates the adaptive immune response and TLR3 deficiency results in enhanced viremia and more severe pathology in mice; in CHIKV‐infected patients, TLR3 expression is high and a TLR3 SNP associates with disease severity.