Non-canonical activation of IRE1α during Candida albicans infection enhances macrophage fungicidal activity

While the canonical function of IRE1 is to detect misfolded proteins and activate the unfolded protein response (UPR) to maintain cellular homeostasis, microbial pathogens can also activate IRE1, which modulates innate immunity and infection outcomes. However, how infection activates IRE1 and its associated inflammatory functions have not been fully elucidated. Recognition of microbe-associated molecular patterns can activate IRE1, but it is unclear whether this depends on protein misfolding. Here, we report that a common and deadly fungal pathogen, Candida albicans, activates macrophage IRE1 through C-type lectin receptor signaling, reinforcing a role for IRE1 as a central regulator of host responses to infection by a broad range of pathogens. This activation did not depend on protein misfolding in response to C. albicans infection. Moreover, lipopolysaccharide treatment was also able to activate IRE1 prior to protein misfolding, suggesting that pathogen-mediated activation of IRE1 occurs through non-canonical mechanisms. During C. albicans infection, we observed that IRE1 activity promotes phagolysosomal fusion that supports the fungicidal activity of macrophages. Consequently, macrophages lacking IRE1 activity displayed inefficient phagosome maturation, enabling C. albicans to lyse the phagosome, evade fungal killing, and drive aberrant inflammatory cytokine production. Mechanistically, we show that IRE1 activity supports phagosomal calcium flux after phagocytosis of C. albicans, which is crucial for phagosome maturation. Importantly, deletion of IRE1 activity decreased the fungicidal activity of phagocytes in vivo during systemic C. albicans infection. Together, these data provide mechanistic insight for the non-canonical activation of IRE1 during infection, and reveal central roles for IRE1 in macrophage antifungal responses.