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

Abstract

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. Author summaryLinked to advances in medical technology and the resulting increase in the number of intensive care patients, nosocomial infections with Candida albicans are on the rise. In patients suffering from invasive candidiasis the innate immune response is typically severely impaired. Strengthening the innate immune system has become a promising approach complementing the use of antifungal drugs. Our findings identify an unexpected and IL-17-independent role of IL-23 that prevents rapid death of myeloid cells during PLOS Pathogens | https://doi.

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“…Remarkably, this gene, which is highly expressed in Th17 cells, seems to play an important role in the proliferation and survival of these cells, which are critical for host defense against fungal infections [ 39 ]. In fact, genetic variants in the IL23R gene have been associated with different susceptibility to fungal infections [ 40 ] and IL-23R deficient mouse was susceptible to systemic infection with C. albicans [ 41 ]. Furthermore, IL-23R had been reported to be involved in the diversity of ileum microbiota in humans [ 42 ].…”

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“…As an alternative method to stimulate emergency granulopoiesis, we injected cohorts of mice in chemotherapy-induced remission with heat-killed Candida albicans ( 35 ). We found a comparable granulocytosis response in WT mice injected every 4 weeks with the two stimuli ( Fig.…”

“…As an alternative method to stimulate emergency granulopoiesis, we injected cohorts of mice in chemotherapy-induced remission with heat-killed Candida albicans (35). We found a Figure 4.…”

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