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.
Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Chikungunya Fever/immunology , Chikungunya virus/physiology , Toll-Like Receptor 3/genetics , Virus Replication , Adult , Aged , Animals , Chikungunya Fever/genetics , Chikungunya Fever/pathology , Chikungunya Fever/virology , Chikungunya virus/immunology , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Polymorphism, Single Nucleotide , Species Specificity , Toll-Like Receptor 3/immunology , Young AdultABSTRACT
Peaks of influenza activity in July 2009 and January 2010 were >90% pandemic H1N1 (pH1N1), but by May 2010, H3N2 predominated in hospital attendances (46·5%, versus 38·9% pH1N1); H3N2 hospital attendances were older (72·9% aged ≥60 years versus 13·5% for pH1N1), but the age-stratified proportions admitted for pneumonia ]were similar. As at the end of the third epidemic wave in Singapore, pH1N1 cases in hospital attendances were still markedly younger than cases of H3N2 or influenza B, with little evidence for any changes in severity.
