Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis

Abstract

ABSTRACTRecognition of pathogen-associated molecular patterns can trigger the IRE1α arm of the endoplasmic reticulum (ER) stress response in immune cells. IRE1α activation has been shown to maintain ER homeostasis while simultaneously coordinating diverse immunomodulatory programs in the setting of bacterial and viral infections. However, the role of IRE1α signaling in innate immune responses to fungal pathogens is unknown. Here we report that systemic infection with the fungusCandida albicanscauses severe renal immunopathology by triggering inflammatory IRE1α hyperactivation in host myeloid cells. Mechanistically, sensing of fungal β-glucans by the C-type lectin receptor Dectin-1 induced Src–Syk–NOX-dependent accumulation of intracellular reactive oxygen species and the ensuing generation of lipid peroxidation byproducts that sustained IRE1α activation. Selective deletion of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, reduced detrimental inflammatory responses in the kidney and extended survival in mice systemically infected withC. albicans. Hence, controlling IRE1α overactivation may be useful to impede the fatal immunopathogenic progression of disseminated candidiasis.One sentence summaryInnate IRE1α signaling in disseminated candidiasis