Targeting the proviral host kinase, FAK, limits influenza a virus pathogenesis and NFkB-regulated pro-inflammatory responses

被引:17
作者
Bergmann, Silke [1 ]
Elbahesh, Husni [1 ,2 ]
机构
[1] Univ Tennessee, Hlth Sci Ctr, Dept Microbiol Immunol & Biochem, Memphis, TN 38163 USA
[2] Univ Vet Med Hannover, Res Ctr Emerging Infect & Zoonosis RIZ, Bunteweg 17, D-30559 Hannover, Germany
关键词
FOCAL ADHESION KINASE; SMALL-MOLECULE INHIBITOR; NS1; PROTEIN; KAPPA-B; GENE-EXPRESSION; Y397; SITE; PHOSPHORYLATION; REPLICATION; ACTIVATION; CANCER;
D O I
10.1016/j.virol.2019.05.020
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Influenza A virus (IAV) infections result in similar to 500,000 global deaths annually. Host kinases link multiple signaling pathways at various stages of infection and are attractive therapeutic target. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, regulates several cellular processes including NFkB and antiviral responses. We investigated how FAK kinase activity regulates IAV pathogenesis. Using a severe infection model, we infected IAV-susceptible DBA/2 J mice with a lethal dose of H1N1 IAV. We observed reduced viral load and pro-inflammatory cytokines, delayed mortality, and increased survival in FAK inhibitor (Y15) treated mice. In vitro IAV-induced NFkB-promoter activity was reduced by Y15 or a dominant negative kinase-dead FAK mutant (FAK-KD) independently of the viral immune modulator, NS1. Finally, we observed reduced IAV-induced nuclear localization of NFkB in FAK-KD expressing cells. Our data suggest a novel mechanism where IAV hijacks FAK to promote viral replication and limit its ability to contribute to innate immune responses.
引用
收藏
页码:54 / 63
页数:10
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