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Protective Immune Responses Generated From Antigen-Containing Extracellular Vesicles

Emerson, LE;

Non Typhoidal Salmonella (NTS) is a gram-negative bacterial illness that causes over 95 million infections globally every year. While NTS normally causes self-limiting gastroenteritis, without prompt medical care, NTS can develop into severe blood-stream bacteremia, causing sepsis and death. During infection, bacteria travel through the gastrointestinal tract, passing through the stomach during the digestive process and into the small intestine. Within the small intestine Salmonella begin invasion by infected microfold cells, which are cells just above the gut-associated lymphoid tissue (GALT) that work to sense bacteria in the intestinal lumen. After infection of the microfold cells, Salmonella is detected by GALT immune cells, including macrophages, which are phagocytic cells important in the activation of innate and adaptive immune defenses. Salmonella invades macrophages using specialized virulence factors encoded on Salmonella pathogenicity island 2. Upon infection, Salmonella hijacks the host cytoskeleton system and alters the phagolysosome into a Salmonella-containing vacuole in which the bacteria will live and replicate. During Salmonella infection macrophages begin to excrete extracellular vesicles (EVs) that contain Salmonella antigens, and while extracellular vesicles are routinely secreted by host cells, the EVs 16 secreted after infection have immunomodulatory properties. However, how the EVs modulate the immune response is not well characterized. In this investigation the method by which antigens are packaged into EVs, changes in lipid composition, the potential of EVs to vaccinate a host, and the translational impact of the study are described. Results show that antigens are packaged to EVs partially in a ubiquitindependent manner, lipid composition is significantly altered following infection, EVs isolated following Salmonella infection protected mice against a lethal dose of Salmonella, and the vaccine is protective against additional serovars of Salmonella. Overall, results underscore the importance of EVs in the Salmonella immune response and the translational potential of an EV vaccine.