The fatal H5N1 infection has a high mortality rate among infected patients. The pathogenesis of H5N1 viral infection is associated with the ability of the virus to induce apoptotic cell death. However, the molecular mechanism of apoptosis induced by H5N1 remains unclear. In the present study we demonstrate that H5N1 virus is able to up-regulate the expression of gene associated with retinoid and interferon induced mortality-19 (GRIM-19) in human monocyte-derived macrophages (hMDMs). GRIM-19 has been identified as a novel gene with apoptotic effects in virus-infected cells. The percentage of apoptotic cells is significantly decreased in H5N1-infected GRIM-19 depleted hMDMs, which is also associated with a decrease of BH3-interacting domain death agonist cleavage and apoptosis-inducing factor (AIF) release to the cytosol. These results suggested the involvement of GRIM-19 in apoptosis induced by H5N1 virus. Furthermore, neutralizing-IFN-β Ab is able to suppress GRIM-19 expression in H5N1-infected cells resulting in a decrease in apoptotic cell number, indicating that IFN-β secreted by H5N1-infected hMDMs regulates GRIM-19 expression leading to apoptosis. Altogether, the results presented here provide additional insight on the regulatory mechanism of H5N1 viral-induced apoptotic cell death in hMDMs.
Keywords: Apoptosis; GRIM-19; H5N1; IFN-β; influenza.