Effects of Helicobacter pylori infection and pan-caspase inhibition on human neutrophil fate and function
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Neutrophils (polymorphonuclear leukocytes, PMN) are the first responders of the immune system and comprise up to 70 percent of circulating leukocytes in humans. Helicobacter pylori is a gastric pathogen infecting over 50 percent of people globally that causes gastritis, peptic ulcers, and gastric cancer. Uniquely, H. pylori is capable of infecting PMN, and we have shown infection induces an N1-like subtype differentiation in PMN notable for profound nuclear hypersegmentation and an extended cell lifespan. This dissertation aimed to elucidate the fate of H. pylori infected PMN. We found a stark disappearance of RIP kinases, indicating that in addition to apoptosis, infected PMN subvert necroptosis and PANoptosis death pathways. Herein, we show that H. pylori infected PMN die by an atypical pyroptosis, characterized by activated pro-inflammatory caspase-4 but not caspase-1 or caspase-5. Distinctly, Gasdermin D is not activated and accordingly, infected cells do not secrete IL-1[beta] or IL-18. Moreover, infection robustly upregulates and activates the pore forming protein ninjurin-1. Given the role of caspases in cell death, we also sought to determine the extent to which neutrophil function and lifespan are affected by treatment with the pan-caspase inhibitor Q-VD-OPh (QVD). We found that QVD-treated PMN lived five times longer than untreated cells while sustaining critical effector functions. Combined, this work advances our understanding of human neutrophil plasticity and neutrophil biology.
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Ph. D.