Immunomodulatory Effect of Azithromycin in Influenza a Infection

Influenza A(fluA) is the major pathogen of humans and has the potential to cause world- wide pandemics. Studies in humans have implicated adaptive immunity including antibody response and T cell responses in protective immunity against fluA infection. However, the role of the innate immune response players like natural killer(NK) cells and dendritic cells in protective immunity against fluA infection is poorly understood. NK (CD3-/CD56+) cells may fight against flu-A infection by non-MHC-restricted cytotoxicity to kill virus infected cells or by production of IFN-gamma, TNF-alpha, GM-CSF, and chemokine to suppress viral replication. NKp46 on NK cells binds hemagglutinin of influenza virus, while NKG2A and NKp30 are involved in interaction with dendritic cells that shape subsequent T cell response. Dendritic cells (DC) are also pivotal in protection against Flu-A infection. DC-derived IL-15 may enhance NK function and flu-A specific CD8 T cell response. Our previous work has shown the role of IL-15 in modulating flu-A infected NK cells (Journal of Infectious Disease, in press) Azithromycin (AZM), a macrolide antibiotic widely used in respiratory tract infections, possesses an intrinsic anti-inflammatory effect which may provide therapeutic benefit in fighting severe flu-A infection characterized by hypercytokinemia. Our project, therefore, aims to examine the immunomodulative effect of AZM on flu-A infected NK cells and dendritic cells. During the first year, we will examine the immunomodulatory effect of AZM on flu-A infected NK cells. We will also seek to determine its effect on cytotoxic function and cytokine production; Our second year effort will focus on investigating the molecular mechanism of AZM-induced apoptosis of flu-A infected NK cells ; Finally, in the third year, we will explore the effect of AZM on the function of recombinat hamaagglutinin(HA) stimulated dendritic cells, with special emphasis on cytokine production and ability to modulate subsequent T cell activation. Our work will provide important clue as to whether AZM will provide therapeutic benefit in the defense of flu-A infection.

Project ID:PC10107-0374
External Project ID:NSC101-2314-B182A-116