The Role of the Innate Immune System in Programmed Cell Death

Abstract

Infectious diseases are the leading cause of illness worldwide, leading to over 20 million hospitalizations each year in the United States alone. Although numerous diseases are treatable with vaccines and pharmacological agents, including antibiotics, a large fraction of infections remain poorly controlled, mainly due to lack of effective therapies and/or vaccines. Two such infectious agents are influenza A virus and the bacterium Salmonella enterica. Influenza A virus is transmitted through the aerosol route and infects lung epithelial cells, while Salmonella is transmitted via the fecal-oral route and infects the cells lining the intestine of the host. In each case, the first lines of defense against these infectious agents are non-phagocytic cells. How these pathogens are controlled in non-phagocytic cells dictates the overall outcome of infection; however there are significant gaps in our knowledge of how non-phagocytic cells respond to influenza A virus and Salmonella. Therefore, studying the fate of these cells during the course of infection is of crucial importance to disease outcome. In each case, the regulated (or programmed) death of the infected cell may represent an important pathogen clearance mechanism. Programmed cell death can be non-inflammatory (e.g., apoptosis) or pro-inflammatory (e.g., necroptosis and pyroptosis). In this dissertation, I outline experiments carried out to identify the pathways of programmed cell death activated by Salmonella and influenza A virus in their respective target non-phagocytic cells, both in vitro and in vivo. My work outlines new pathways of cell death activated by these pathogens and new mechanisms of both viral and bacterial clearance. This will have broad implications in the clearance of pathogens, and new therapeutic avenues to pursue upon treating infections.