A277 THE FIRST LINE OF DEFENSE: THE ROLE OF EPITHELIAL CELL INFLAMMASOMES IN CONTROLLING CAMPYLOBACTER JEJUNI INFECTION

Campylobacter jejuni is the most common cause of bacterial gastroenteritis in the developed world, often rivaling the total number of E.coli and Salmonella infections combined. Furthermore, even after the initial infection has been cleared, C. jejuni infection has been strongly linked to the development of Guillain Barre syndrome. Despite this, many aspects of its colonization and infection of the gut remain poorly defined. One cryptic aspect of its pathogenesis is C. jejuni’s’s ability to invade intestinal epithelial cells as it colonizes and infects the host intestine. Our previous work has illustrated that C. jejuni has the capacity to invade intestinal epithelial cells in the mammalian gut near the apical ends of intestinal crypts, where it resides within LAMP-1 positive vesicles. The aim of this study is the characterize the role of the epithelial cell inflammasome in defending against cell invasion by C. jejuni in vivo and to describe the impact of inflammasome activation and cell invasion on the immune response to C. jejuni infection. Using a combination of knockout mouse models and an in vitro primary epithelial cell model, we can now illustrate the role of epithelial cell intrinsic inflammasomes in controlling Campylobacter cell invasion during the course of infection. We infected mice lacking key inflammasome components, including Asc, Caspase 1, and relevant nod-like receptors, along with knockout mice in relevant inflammasome-linked cytokines, including IL18. We also used primary epithelial cells, derived from human and murine sources, and cultivated as organoid cultures, do create monolayer cultures we could infect with C. jejuni. This allowed us to model C. jejuni cell invasion of the intestinal epithelium in vitro. Mice lacking key inflammasome components lose much of their ability to limit C. jejuni invasion and replication inside of intestinal epithelial cells. This allows C. jejuni to replicate to large numbers inside of these LAMP1 positive vesicles, from where they can be released back into the intestinal lumen and infect additional epithelial cells. The consequences of impaired inflammasome function include increased pathogen burdens, a prolonged course of infection and significantly increased pathology in infected mice. Conversely, mice with functional epithelial cell inflammasomes effectively control the number of intracellular bacteria and exhibit only moderate infection induced pathology and pathophysiology. Although much remains to be discovered regarding the role of epithelial cell invasion in C. jejuni pathogenesis, these findings highlight the importance of epithelial cells as an active player in combating this important enteric pathogen. CAG, CCC, CIHR

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