Saturday, May 31, 2025
5/31/2025
Dissecting innate immune control of intestinal and systemic Yersinia infection - Project Summary Infection by many pathogens leads to the formation of structures termed granulomas, organized clusters of macrophages, neutrophils, and lymphocytes, that contain and control the infection, but can also serve as sites for pathogen replication and dissemination. Infection by enteric Yersinia leads to the formation of pyogranulomas (PGs, granulomas enriched in neutrophils) in infected intestinal and systemic tissues. We recently reported that CCR2-dependent inflammatory monocytes are essential for acute control of Yp within infected sites, were required for formation of organized PGs, and were necessary for the activation of neutrophils and production of IL-1 cytokines within the granuloma. We also recently demonstrated for the first time, the existence of intestinal pyogranulomas (PGs), following oral Yersinia pseudotuberculosis (Yp) infection. PGs contain high numbers of viable bacteria relative to adjacent non-PG intestinal tissue, and are enriched in neutrophils and inflammatory monocytes. Intestinal PGs contain similar bacterial burdens as Peyer’s patches, suggesting that PGs represent a previously undescribed site for Yp interaction with the mucosal immune system. Critically, whole-body TNFR1 deficiency, as well as loss of TNFR1 expression on monocytes phenocopied susceptibility of Ccr2-/- mice to Yp infection, and also resulted in failure to form organized PGs or activate neutrophils. Notably, loss of TNFR1 signaling, or loss of monocytes, led to reduced levels of IL-1 production in intestinal PG, and TNFR1 deficiency led to cell-intrinsic loss of IL-1 production. Furthermore, non-hematopoietic IL-1R signaling was needed to mediate control of Yp infection. These findings provoke the hypothesis that a monocyte-driven TNF-IL-1 signaling circuit mediates control of Yp infection. Based on these findings we propose the following specific Aims: First we will define how monocyte-specific TNFR1 signaling contributes to expression of IL-1 in innate immune cells. Second, we will dissect the requirement and sufficiency of IL-1R signaling on intestinal epithelial cells in control of Yp infection. Finally, in collaboration with the Waldor laboratory, we will utilize a newly-developed next- generation chromosomal barcode library together with deep sequencing and a powerful computational toolkit to define the replication and dissemination dynamics of Yp in wild-type and immune-compromised settings.
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