The immunomodulatory effects of focal adhesion kinase in human macrophages and pneumocytes during influenza A virus infection

Abstract

Highly pathogenic avian influenza (HPAI) H5N1 viruses have a mortality rate of about 60%, continue to transmit zoonotically, and poses a pandemic threat. Dysregulation of cytokine induction is believed to contribute, at least in part, to the pathogenesis of severe H5N1 disease in humans. Focal adhesion kinase (FAK) is a tyrosine receptor kinase that has been extensively studied in cancers. FAK has also been linked to herpes simplex for regulating virus entry and host response, and more recently, in other viruses such as influenza. Primary human macrophages and human alveolar epithelial cells are targets for highly pathogenic avian influenza (HPAI) H5N1 virus. The binding of influenza virus to the host cell is able to activate several intracellular pathways including the phosphatidylinositol-3-kinase (PI3K) pathway which is linked to FAK. However, there is a lack of information on the role of FAK in cytokine induction after HPAI H5N1 virus infection. Through quantitative polymerase chain reaction (qPCR) analysis, the mRNA levels of cytokines e.g. IFN-β, TNF-α, IP-10, in human macrophages and human alveolar epithelial cells infected with HPAI H5N1 virus were significantly reduced by the treatment with FAK inhibitor compared to vehicle-treated infected cells. In our previous publication, we showed by Western blot analysis that H5N1-infected primary cells strongly activated IFN regulatory factor 3 (IRF3) protein and p38 protein kinase; both of which are linked to the induction of proinflammatory cytokines and chemokines in virus-infected primary cells. The treatment of FAK inhibitor reduced the activation of IRF3 and p38 in H5N1-infected cells. Our results demonstrate the immunomodulatory activities of FAK during H5N1 infection and this suggests targeting FAK may be a novel therapeutic option for severe influenza disease. Further study on the downstream signalling molecules of FAK will disclose more host-targeted therapeutic options for future development to confront severe influenza disease.