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Innate Immunity: Mechanisms and Modulation | EK39


EK39-EPOSTER-WINSOR-NATHANIEL - The NOD-like receptor protein NLRP6 regulates the colonic mucus layer during Tritrichomonas infection


Apr 12, 2021 12:00am ‐ Apr 12, 2021 12:00am

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The NOD-like receptor protein NLRP6 regulates the colonic mucus layer during Tritrichomonas infection Nathaniel Winsor[1], Paul Lemire[2], Samuel Killackey[2], Ziqi Liu[2], Susan Robertson[1], Heather Maughan[3], Cathy Streutker[4], Dana Philpott[1], Stephen Girardin[1,2]. [1]University of Toronto, Department of Immunology [2]University of Toronto, Department of Laboratory Medicine and Pathobiology [3]Ronin Institute, Montclair NJ [4]Saint Michael's Hospital, Toronto ON. Introduction: Enteric parasitic infection represents a major health burden in the developing world. Pathogen detection often involves members of the NOD-like receptor (NLR) family of proteins, however, the role of these proteins in parasitic infection is poorly characterized. A key step in the intestinal anti-parasitic response is the growth of the mucus layer. NLRP6 is the most common NLR protein in intestinal epithelial cells and it has been suggested that NLRP6 regulates both goblet cell abundance and mucus secretion. Methods: We developed a novel parasitic infection model utilizing protist species of the family Tritrichomonas (Tm). Protists were harvested and FACS-purified from the cecum of infected mice and delivered by oral gavage into recipient animals. Results: Upon infection, Nlrp6-/- mice possess a thinner mucus layer when compared to Nlrp6+/+ littermates. We excluded a role for the microbiome, as regardless of Tm infection, 16S rDNA sequencing in Nlrp6-/- and Nlrp6+/+ littermates did not reveal significant differences. In the colon, infected Nlrp6-/- mice have increased levels of tuft, goblet and proliferating cells. IL-18 is matured downstream of NLRP6 activation. However, littermate-controlled Tm infections in Il18-/- mice did not phenocopy the effects of NLRP6 deficiency, suggesting an IL-18 independent role for NLRP6 in the colon. Defects in the mucus layer result in chronic inflammation and can contribute to the development of colorectal cancer (CRC). To assess the functional impact of the thinner mucus layer in Tm+ Nlrp6-/- mice, we crossed infected animals onto the Apcmin/+ background, a genetic model for CRC, and determined that chronically infected Nlrp6-/-Apcmin/+ mice have a greater intestinal tumour burden than Apcmin/+ littermates. Conclusion: NLRP6 regulates mucus secretion in response to parasitic infection. Future work aims to determine whether the NLRP6-mucus axis is dependent on Caspase-1/11 activation.

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