Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response (EMBO Molecular Medicine 2015, 7(1):24-41)

報告日期: 2015/03/24
報告時間: 16:00/16:50
報告學生: 許翊輝
講評老師: 葉才明
附件下載: 下載[1457-1425857104-1.pdf] 

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

Her, Z., et al. (2015).EMBO Mol Med 7(1): 24-41.

Speaker: Alan Yi-Hui Hsu (許翊輝)                       Time: 16:00~16:50, March 24, 2015

Commentator: Prof. Trai-Ming Yeh (葉才明 教授)   Place: Room 602

Abstract :

        The role of toll-like receptors (TLRs) has been well depicted in the host innate immune response against viral infections, which it serves as a pattern recognition receptor (PRR) to identify halmark structural regions from pathogens termed pathogen associated molecular patterens (PAMPs). Once these PRRs are activated they will stimulate anti-viral inflammatory cytokines such as type I interferons and trigger the adaptive immune response. Chikungunya virus (CHIKV) is a rapidly emerging old world pathogen which is wrecking havoc throughout tropical and subtropical regions in recent years and is mainly spread by the bite of the Aedes species of mosquitos. In this study the authors show that TLR3 is crucial for viral clearance and pathology in CHIKV infection and loss of TLR3 would aggravate clinical symptoms, viral replication and viral dissemination to multiple organs. It was shown that without TLR3 there was massive amounts of myeloid cells infiltrating into the joint regions, causing edema and inflammation. However the pathology effect in the joint regions was directly mediated by CD4+ T cells and when removed lowered the disease score and reduced the number of infiltrating neutrophils but had no effect on viral replication. Further analysis showed that hematopoietic TLR3 expressing cells were the cells charged with CHIKV clearance, and while the TLR3-/- bone marrow was present the viral titer was significantly higher. The mechanism behind the higher viremia and pathogenesis during TLR3 deficiency was due to the lack of ability to recognize the highly antigenic CHIKV epitope namely the E2 glycoprotein, thus leading to lower neutralization valances, all while the levels of anti-CHIKV IgM and IgG did not differ when compared with wild type mice. Lastly, the report showed that some TLR3 polymorphism SNPs among humans could lead to CHIKV infection disease severity and also correlated to the recognition of the epitopes on the E2 glycoprotein where the copy number of the rare allele correlated to the severity of CHIKV infection.


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