期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 11, 页码 5163-5177出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI99411
关键词
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资金
- Shaw Foundation
- Providence Foundation Ltd.
- Respiratory Virus Research Foundation
- Hong Kong University Foundation
- Cheer Master Investments Ltd
- Hong Kong Health and Medical Research Fund [12110822]
- Health and Medical Research Fund Commissioned Research on Control of Infectious Diseases (Phase III) [HKM-15-M02, HKM-15-M04]
- Food and Health Bureau
- Government of the Hong Kong Special Administrative Region
- Collaborative Research Fund [C7011-15R]
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Ministry of Education of China)
- High Level Hospital - Summit Program in Guangdong at The University of Hong Kong-Shenzhen Hospital
Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-gamma-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-gamma-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-gamma for EV-A71 infection. Given that we detected high levels of IFN-gamma in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-gamma stimulation and the therapeutic options for treating severe EV-A71-associated complications.
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