Chikungunya Virus Neutralization Antigens and Direct Cell-to-Cell Transmission Are Revealed by Human Antibody-Escape Mutants

PLoS Pathogens

Laurent Renia¹  Cui Lin²  Raymond T. P. Lin²  Jan Fric³  Wen Huang³  Yiu-Wing Kam³  Chia Yin Lee³  Benoit Malleret³  Lisa F. P. Ng³  Celine Prakash³  Esther G. L. Koh³  Lucile Warter³  Cheng-I Wang³  Wendy W. L. Lee³ 

[1] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;National Public Health Laboratory, Ministry of Health, Singapore;Singapore Immunology Network, BMSI, A*STAR, Singapore

关键词: Chikungunya virus;    Chikungunya infection;    Antibodies;    Cell binding assay;    Substitution mutation;    Sindbis virus;    Microbial mutation;    Mouse models;   

DOI  :  10.1371/journal.ppat.1002390

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop “groove” as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis.

【 授权许可】

CC BY