Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response
Autor(es): Her Zhisheng, Teng Terk-Shin, Tan Jeslin J L, Teo Teck-Hui, Kam Yiu-Wing, Lum Fok-Moon, Lee Wendy W L, 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 F P
Resumo: RNA-sensing toll-like receptors (TLRs) mediate innate immunity - regulate anti-viral response. We show here that TLR3 regulates host immunity - the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human - mouse fibroblasts with defective TLR3 signaling. Up to 100-fold increase in CHIKV load was observed in Tlr3-/- mice, alongside increased virus dissemination - 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 - CHIKV-specific neutralizing antibody response. These results demonstrate a key role for TLR3-mediated antibody response to CHIKV infection, virus replication - pathology, providing a basis for future development of immunotherapeutics in vaccine development.
Palavras-Chave: Chikungunya virus; TLR3; Innate immunity; Joint inflammation; Neutralizing antibodies
Imprenta: EMBO Molecular Medicine, v. 7, n. 1, p. 24-41, 2015
Identificador do objeto digital: 10.15252/emmm.201404459
Descritores: Chikungunya virus - Biochemistry ; Chikungunya virus - Cell ; Chikungunya virus - Cytopathology ; Chikungunya virus - Pathogenesis ; Chikungunya virus - Proteins ; Chikungunya virus - RNA ; Chikungunya virus - Antibodies ; Chikungunya virus - Inflammation ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Molecular screening ; Chikungunya virus - Vaccine ; Chikungunya virus - Chikungunya fever ; Chikungunya virus - Epidemiology ; Chikungunya virus - Immunology
Data de publicação: 2015
