The role of ISG15 in macrophages during influenza virus infection

Abstract

Influenza virus is a pathogen causing severe infection in millions of people annually. Innate immunity, the first line of defense against influenza, is an important determinant of host pathogenesis. The major effectors in innate immunity are hundreds of interferon-stimulated genes (ISGs) having diverse functions against pathogens. Recently, the functions of ISGs in influenza virus infection has started to be deciphered. ISG15 is one of the ISGs known to protect host against influenza pathogenesis. It can either function as a free protein, or covalent modifier through an ubiquitination-like enzyme cascade (ISGylation). Previously, free- and ISGylated-form of ISG15 have been found to protect mice against influenza virus challenge. However, the precise role of free and ISGylation are still largely unknown. Epithelial cells are the major cell types infected by influenza viruses. However, other innate immune cell types such as macrophages are also susceptible and contribute greatly in host defense. Recently, there are more evidences suggesting that ISG15 is playing different roles depending on cellular contexts. In this thesis, the roles of free- and ISGylated-form of ISG15 in influenza-infected macrophages were analyzed. Rather than acting as a viral replication inhibitor in epithelial cells, ISG15 is essential for phagocytic function of macrophages, and it is also acting as an immunomodulator in macrophages suppressing secretion of a chemoattractant MCP-1 (CCL2). Through a yet undiscovered unconventional secretion pathway, influenza virus infected macrophage secretes a much higher amount of ISG15 comparing to epithelial cells into the extracellular space. In this thesis, different possible pathways were evaluated, and autophagy was demonstrated to have role(s) in controlling ISG15 secretion.