The avian influenza A virus (IAV) transmits zoonotically across species barriers infecting humans and other mammals.Novel viruses arise posing a threat to human health. H5N1 viruses, though presently  not capable of transmitting from human to human, causes severe respiratory problems leading to a high fatality rate. Macrophages are the first line of defense against influenza virus infection,its depletion increases the severity of the disease in animal models of influenza virus infection.  However, macrophages may also contribute to severity of the disease caused by H5N1 as some viruses may productively replicate in macrophages. Our previous data demonstrates that H5N1 viruses are unique in their ability to infect macrophages and that the HA protein is sufficient to confer this ability. However in a non-H5 virus infection, macrophages effectively block the transcription and viral replication.  Several cellular factors and cell-intrinsic innate immune pathways responsible for blocking virus replication in macrophages are being studied.H5N1 induce robust secretion of TNF-α by macrophages, a key regulator of virus-induced inflammation leading to pulmonary influx of inflammatory innate immune cells. Expression of TNF-α during influenza virus infection is regulated by the transcriptional activator NF-kB, a central regulator of inflammatory cytokine expression in macrophages. Additionally, nitric oxide mediates macrophage. Inducible nitric oxide combats viral infection.  Studies show that IAV infection depends on the activation of NF-kB.

 

The main objective of this project is to determine the impact of IAV replication on macrophage function. The hypothesis is that H5N1 viruses that are capable of replication in macrophages will alter cellular functions in ways that contribute to increased disease severity. The study will also invole testing for increased inflammatory responses of macrophages resulting from replication of H5N1 virus by measuring the levels of nitric oxide, TNF-α expression and NF-kB activation following infection with live or UV-inactivated H5N1 influenza virus. This study will help to address the potential risk posed by H5N1 by better understanding the replication of H5N1 and function of macrophage on infection with H5N1.