title: Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response.
abstract: 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.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Her
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Terk-Shin
authors.initials: TS
authors.lastname: Teng
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Jeslin J L
authors.initials: JJ
authors.lastname: Tan
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
authors.forename: Teck-Hui
authors.initials: TH
authors.lastname: Teo
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Yiu-Wing
authors.initials: YW
authors.lastname: Kam
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Fok-Moon
authors.initials: FM
authors.lastname: Lum
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
authors.forename: Wendy W L
authors.initials: WW
authors.lastname: Lee
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Christelle
authors.initials: C
authors.lastname: Gabriel
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore Doctoral School in Translational and Molecular Medicine (DIMET), University of Milano-Bicocca, Milan, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Melchiotti
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Anand K
authors.initials: AK
authors.lastname: Andiappan
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lulla
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Aleksei
authors.initials: A
authors.lastname: Lulla
authors.affiliation: Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Mar K
authors.initials: MK
authors.lastname: Win
authors.affiliation: Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Angela
authors.initials: A
authors.lastname: Chow
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Subhra K
authors.initials: SK
authors.lastname: Biswas
authors.affiliation: Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore.
authors.forename: Yee-Sin
authors.initials: YS
authors.lastname: Leo
authors.affiliation: Institut Pasteur, Biology of Infection Unit, Paris, France Inserm U1117, Paris, France Paris Descartes University Sorbonne Paris Cité, Necker-Enfants Malades University Hospital, Institut Imagine, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lecuit
authors.affiliation: Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Institute of Infection and Global Health, University of Liverpool, Liverpool, UK lisa_ng@immunol.a-star.edu.sg.
authors.forename: Lisa F P
authors.initials: LF
authors.lastname: Ng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D065632:Chikungunya Fever / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002646:Chikungunya virus / Q000276:immunology / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013045:Species Specificity; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3
keywords: Chikungunya virus; TLR3; innate immunity; joint inflammation; neutralizing antibodies