Non-canonical activation of IRE1a during Candida albicans infection enhances macrophage fungicidal activity

Infection by intracellular pathogens can trigger activation of the IRE1a branch of the unfolded protein response (UPR), which then modulates innate immunity and infection outcomes during bacterial or viral infection. However, the mechanisms by which infection activates IRE1a have not been fully elucidated. While recognition of microbe-associated molecular patterns can activate IRE1a, it is unclear whether the canonical role of IRE1a in detecting misfolded proteins is required for its activation. Here, we report that Candida albicans infection of macrophages results in IRE1a activation through C-type lectin receptor signaling, reinforcing a role for IRE1a as a central regulator of host responses to infection by a broad range of pathogens. However, IRE1a activation was not preceded by protein misfolding in response to either C. albicans infection or lipopolysaccharide treatment, implicating a non-canonical mode of IRE1a activation after recognition of microbial patterns. Investigation of the phenotypic consequences of IRE1a activation in macrophage antimicrobial responses revealed that IRE1a activity enhances the fungicidal activity of macrophages. Macrophages lacking IRE1a activity displayed inefficient phagolysosomal fusion, enabling C. albicans to evade fungal killing and escape the phagosome. Together, these data provide mechanistic insight for the non-canonical activation of IRE1a during infection, and reveal central roles for IRE1a in macrophage antifungal responses. Overall design: To compare Ire1 dependent transcriptional responses to Candida albicans, we infected WT or IRE1?R macrophages for 4 hours before extracting RNA and sequencing via paired end Illumina reads