INVESTIGATING INFLAMMASOME RESPONSES TO SALMONELLA IN HUMAN MACROPHAGES

As an enteric bacterial pathogen, Salmonella enterica serovar Typhimurium causes diarrheal disease, leading to morbidity and mortality worldwide. Once inside the host, Salmonella uses specialized machinery known as type III secretion systems (T3SSs) to inject effectors into the host cell cytosol. Subsequently, these effectors remodel host cellular processes to facilitate bacterial colonization. Salmonella infects a variety of cell types, including innate immune cells such as macrophages. It is important to characterize how innate immune cells sense and respond to Salmonella infection, as these cells represent the critical first line of host defense against invading pathogens. While immune responses to infection are often studied in mice, innate immune genes differ between mice and humans. Thus, it is imperative to define human-specific innate immune responses to Salmonella. Host cells harbor multiprotein signaling complexes known as inflammasomes, which become activated upon detecting the cytosolic presence of pathogens, like Salmonella. Inflammasome activation leads to pro-inflammatory cytokine release, which recruits immune cells to the site of infection, and a lytic form of cell death, known as pyroptosis, which eliminates the pathogen’s intracellular replicative niche. In mice, Salmonella triggers inflammasome activation, which controls the infection and protects the host. In this dissertation, we studied inflammasome responses to Salmonella in human macrophages. We found that human macrophages undergo a multifaceted inflammasome response to Salmonella, as the NAIP/NLRC4, NLRP3, and caspase-4/5 inflammasomes are all activated during infection. Importantly, we also discovered that inflammasome activation restricts Salmonella’s intracellular replication in human macrophages. Upon investigating how inflammasomes restrict Salmonella replication, we found that caspase activation and cell death factors are critical for controlling Salmonella in human macrophages. While Salmonella is considered a vacuolar pathogen, we surprisingly observed both vacuolar and cytosolic populations of Salmonella in human macrophages. Moreover, inflammasome responses appear to primarily restrict cytosolic Salmonella replication. Altogether, our findings highlight how Salmonella infection is detected and subsequently controlled by inflammasome responses in human macrophages. Importantly, these studies offer insight into human innate immune responses to bacterial infections.