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EMBO Mol Med. 2015 Jan;7(1):24-41. doi: 10.15252/emmm.201404459.

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

Author information

1
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.
2
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore, Singapore.
3
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.
4
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.
5
Institute of Technology, University of Tartu, Tartu, Estonia.
6
Institute of Infectious Disease and Epidemiology (IIDE), Tan Tock Seng Hospital, Singapore, Singapore.
7
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.
8
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.

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.

KEYWORDS:

Chikungunya virus; TLR3; innate immunity; joint inflammation; neutralizing antibodies

PMID:
25452586
PMCID:
PMC4309666
DOI:
10.15252/emmm.201404459
[Indexed for MEDLINE]
Free PMC Article

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