Abstract 1493 Investigating the Glutathione-Dependent Mechanism of Mosquito Infection by Malaria Parasite Plasmodium

Lysozyme is a b-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls.With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection.Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells.However, it remains unclear how a gain-or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection.We challenged Lyz1-/-and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression.We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella.We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids.Lyz1-/-mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation.The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions.The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory.Controlling lysozyme function may help alleviate the inflammatory progression.