Rina Matsuda

“Inflammatory monocytes enhance control of Yersinia pseudotuberculosis by intestinal pyogranulomas”

Rina Matsuda, Daniel Sorobetea, Igor Brodsky

In various infectious contexts, chronic immune stimulation induces the formation of granulomas: immune cell aggregates that are thought to sequester pathogens. Despite being a prominent feature of numerous infections, key gaps in our knowledge remain about the functional role of granulomas and their mechanisms of formation. Yersinia are bacterial pathogens that block immune cell function and induce granuloma formation in lymphoid tissues. Yersinia pseudotuberculosis (Yptb), closely related to plague-causing Yersinia pestis, causes self-limiting gastroenteritis and lymphadenitis. Following fecal-oral transmission, Yptb invades the intestinal mucosa and infects local lymphoid tissue including the Peyer’s patches and mesenteric lymph nodes, then disseminates to distal organs. While granuloma formation is a hallmark of Yersinia infection of lymphatic organs, mechanisms of enteric control of Yersinia are relatively poorly understood. We observe, for the first time, granulomatous lesions throughout the small intestine during acute murine Yptb infection. Live bacteria are abundant within granulomas but largely absent from non-granuloma intestinal tissue, suggesting that intestinal granulomas play a previously unappreciated role in mucosal control of Yptb. Paradoxically, bacterial virulence is necessary for granuloma formation, as avirulent Yptb lacking its type III secretion system and injected effector proteins does not induce intestinal granuloma formation. By histological and flow cytometric analyses, intestinal granulomas are highly enriched in neutrophils and inflammatory monocytes. Importantly, monocytes play a key role in bacterial restriction by intestinal granulomas, as monocyte-deficient Ccr2-/- mice exhibit a defect in granuloma-mediated control of Yptb, increased dissemination of bacteria to non-granuloma intestinal tissue and peripheral organs, and acute mortality following oral infection. Overall, this work will mechanistically define a previously unappreciated facet of the host immune response to Yersinia infection. Findings will provide new insight into poorly studied granulomatous disorders and potential therapeutic targets for the treatment of chronic disease.