Biology subjects

Eislmayr, K. D.

Publications and source records attributed to Eislmayr, K. D..

3 recordsLinked to original sources

bioRxiv2026

Mechanisms of mucosal immunity to oral Shigella infection in a physiological mouse model

Shigella flexneri causes bacillary dysentery, a diarrheal disease responsible for significant global morbidity and mortality. Despite extensive efforts, there is no licensed Shigella vaccine, and due to the lack of tractable and physiological models, mechanisms of adaptive immunity to Shigella are poorly understood. Here, we establish a mouse model that permits mechanistic dissection of adaptive immunity to a physiological oral challenge with Shigella. We find primary Shigella infection confers robust cross-serotype protection against secondary challenge, in a manner strictly dependent on the adaptive immune compartment. Shigella infection induces Shigella-specific CD4+ and CD8+ T cells, but only CD4+ T cells are required for protection. CD4+ T cells produce IFN{gamma} upon secondary challenge, and help B cells produce Shigella-specific IgA. Neither anti-Shigella antibodies nor IFN{gamma} are individually required for immunity to Shigella, but loss of both eliminates protective immunity. Collectively, our results demonstrate that CD4+ T cells orchestrate antibody and cytokine defense against shigellosis.

immunology↗

bioRxiv2025

Shigella OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome

The NAIP-NLRC4 inflammasome senses pathogenic bacteria by recognizing the cytosolic presence of bacterial proteins such as flagellin and type III secretion system (T3SS) subunits. In mice, the NAIP-NLRC4 inflammasome provides robust protection against bacterial pathogens that infect intestinal epithelial cells, including the gastrointestinal pathogen Shigella flexneri. By contrast, humans are highly susceptible to Shigella, despite the ability of human NAIP-NLRC4 to robustly detect Shigella T3SS proteins. Why the NAIP-NLRC4 inflammasome protects mice but not humans against Shigella infection remains unclear. We previously found that human THP-1 cells infected with Shigella lose responsiveness to NAIP-NLRC4 stimuli, while retaining sensitivity to other inflammasome agonists. Using mT3Sf, a "minimal Shigella" system, to express individual secreted Shigella effector proteins, we found that the OspF effector specifically suppresses NAIP-NLRC4-dependent cell death during infection. OspF was previously characterized as a phosphothreonine lyase that inactivates p38 and ERK MAP kinases. We found that p38 was critical for rapid priming of NAIP-NLRC4 activity, particularly in cells with low NAIP-NLRC4 expression. Overall, our results provide a mechanism by which Shigella evades inflammasome activation in humans, and describe a new mechanism for rapid priming of the NAIP-NLRC4 inflammasome.

immunology↗

bioRxiv2025

Macrophages orchestrate elimination of Shigella from the intestinal epithelial cell niche via TLR-induced IL-12 and IFN-γ

Bacteria of the genus Shigella replicate in intestinal epithelial cells and cause shigellosis, a severe diarrheal disease that resolves spontaneously in most healthy individuals. During shigellosis, neutrophils are abundantly recruited to the gut, and have long been thought to be central to Shigella control and pathogenesis. However, how shigellosis resolves remains poorly understood due to the longstanding lack of a tractable and physiological animal model. Here, using our newly developed Nlrc4-/-Casp11-/- mouse model of shigellosis, we unexpectedly find no major role for neutrophils in limiting Shigella or in disease pathogenesis. Instead, we uncover an essential role for macrophages in the host control of Shigella. Macrophages respond to Shigella via TLRs to produce IL-12, which then induces IFN-{gamma}, a cytokine that is essential to control Shigella replication in intestinal epithelial cells. Collectively, our findings reshape our understanding of the innate immune response to Shigella.

immunology↗