Agranulocytosis leads to intestinal Echinococcus multilocularis oncosphere invasion and hepatic metacestode development in naturally resistant Wistar rats.

Susceptibility to Echinococcus multilocularis infection considerably varies among intermediate (mostly rodents) and dead-end host species (e.g. humans and pig), in particular regarding intestinal oncosphere invasion and subsequent hepatic metacestode development. Wistar rats are highly resistant to infection and subsequent diseases upon oral inoculation with E. multilocularis eggs, however, after immunosuppressive treatment with dexamethasone, rats become susceptible. To address the role of the cellular innate immunity, Wistar rats were individually or combined depleted of natural killer (NK) cells, macrophages (MΦ) and granulocytes (polymorphonuclear cells, PMN) prior to E. multilocularis egg inoculation. Although NK cell and MΦ depletion did not alter the resistance status of rats, the majority of PMN-depleted animals developed liver metacestodes within 10 weeks, indicating that PMN are key players in preventing oncosphere migration and/or development in Wistar rats. In vitro studies indicated that resistance is not caused by neutrophil reactive oxygen species or NETosis. Also, light microscopical examinations of the small intestine showed that oral inoculation of E. multilocularis eggs does not elicit a mucosal neutrophil response, suggesting that the interaction of oncospheres and neutrophils may occur after the former have entered the peripheral blood. We suggest to consider granulocytes as mediators of resistance in more resistant species, such as humans.

IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival.

The opportunistic fungal pathogen Candida albicans can cause invasive infections in susceptible hosts and the innate immune system, in particular myeloid cell-mediated immunity, is critical for rapid immune protection and host survival during systemic candidiasis. Using a mouse model of the human disease, we identified a novel role of IL-23 in antifungal defense. IL-23-deficient mice are highly susceptible to systemic infection with C. albicans. We found that this results from a drastic reduction in all subsets of myeloid cells in the infected kidney, which in turn leads to rapid fungal overgrowth and renal tissue injury. The loss in myeloid cells is not due to a defect in emergency myelopoiesis or the recruitment of newly generated cells to the site of infection but, rather, is a consequence of impaired survival of myeloid cells at the site of infection. In fact, the absence of a functional IL-23 pathway causes massive myeloid cell apoptosis upon C. albicans infection. Importantly, IL-23 protects myeloid cells from apoptosis independently of the IL-23-IL-17 immune axis and independently of lymphocytes and innate lymphoid cells. Instead, our results suggest that IL-23 acts in a partially autocrine but not cell-intrinsic manner within the myeloid compartment to promote host protection from systemic candidiasis. Collectively, our data highlight an unprecedented and non-canonical role of IL-23 in securing survival of myeloid cells, which is key for maintaining sufficient numbers of cells at the site of infection to ensure efficient host protection.