Author: Zachary Taylor Morrow

Publisher:

Published: 2023

Total Pages: 0

ISBN-13:

Listeria monocytogenes is a gram-positive facultative intracellular pathogen that stimulates a robust CD8+ T-cell response and has been utilized for decades to understand various aspects of innate and adaptive immunity. Due to its ability to stimulate CD8+ T-cells, L. monocytogenes has been developed as a safe anti-tumor vaccine platform. Efforts to understand how L. monocytogenes primes CD8+ T-cell responses led to the observation that L. monocytogenes that fail to access the host cytosol do not prime robust CD8+ T-cell responses. This led us to hypothesize that activation of a cytosol-specific innate immune pathway was necessary for the optimal T-cell response toward L. monocytogenes. Counterintuitively, I show that two cytosol-specific innate immune pathways activated by L. monocytogenes, the production of type I interferon, and inflammasome activation are actively detrimental to, or are dispensable for the T-cell response, respectively. Type I interferon impairs the formation of memory precursor effector cells, leading to deficits in protective immunity, and is likely acting on antigen presenting cells. I aided in identifying that macrophages and dendritic cells produce PGE2 during L. monocytogenes infection. The production of PGE2 is the first cytosol-specific innate immune pathway identified that is necessary for the optimal T-cell response toward L. monocytogenes. I show that PGE2 production is dependent on the calcium-dependent cytosolic phospholipase A2 (cPLA2) and that calcium fluxes necessary for PGE2 production are likely emanating from inositol-triphosphate-signaling dependent endoplasmic reticulum receptors. Finally, in an altogether different approach, I show that L. monocytogenes can be engineered to express and secrete mammalian cytokines as an in-situ vaccine platform. Taken together, my work demonstrates how innate immune signaling informs adaptive T-cell responses during L. monocytogenes vaccination, and that L. monocytogenes can be engineered to modulate innate immune pathways resulting in a better vaccine platform. This thesis begins to unravel how the first cytosol-specific innate immune pathway necessary for T-cell priming is triggered and highlights new avenues for the therapeutic application of L. monocytogenes to combat cancer.