Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis

Awasthi, D.; Chopra, S.; Cho, B. A.; Emmanuelli, A.; Sandoval, T. A.; Hwang, S.-M.; Chae, C.-S.; Salvagno, C.; Tan, C.; Vasquez-Urbina, L.; Fernandez Rodriguez, J. J.; Santagostino, S. F.; Iwawaki, T. R.; Romero-Sandoval, E. A.; Sanchez Crespo, M.; Morales, D. K.; Iliev, I. D.; Hohl, T. M.; Cubillos-Ruiz, J. R.

doi:10.1101/2022.11.17.513879

bioRxiv · 10.1101/2022.11.17.513879

Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis

Awasthi, D.·Chopra, S.·Cho, B. A.·Emmanuelli, A.·Sandoval, T. A.·Hwang, S.-M.·Chae, C.-S.·Salvagno, C.·Tan, C.·Vasquez-Urbina, L.·Fernandez Rodriguez, J. J.·Santagostino, S. F.·Iwawaki, T. R.·Romero-Sandoval, E. A.·Sanchez Crespo, M.·Morales, D. K.·Iliev, I. D.·Hohl, T. M.·Cubillos-Ruiz, J. R.

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Abstract

Recognition of pathogen-associated molecular patterns can trigger the IRE1 arm of the endoplasmic reticulum (ER) stress response in immune cells. IRE1 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 IRE1 signaling in innate immune responses to fungal pathogens is unknown. Here we report that systemic infection with the fungus Candida albicans causes severe renal immunopathology by triggering inflammatory IRE1 hyperactivation in host myeloid cells. Mechanistically, sensing of fungal {beta}-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 IRE1 activation. Selective deletion of IRE1 in leukocytes, or treatment with an IRE1 pharmacological inhibitor, reduced detrimental inflammatory responses in the kidney and extended survival in mice systemically infected with C. albicans. Hence, controlling IRE1 overactivation may be useful to impede the fatal immunopathogenic progression of disseminated candidiasis. One sentence summaryInnate IRE1 signaling in disseminated candidiasis

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Awasthi, D., Chopra, S., Cho, B. A., Emmanuelli, A., Sandoval, T. A., Hwang, S.-M., Chae, C.-S., Salvagno, C., Tan, C., Vasquez-Urbina, L., Fernandez Rodriguez, J. J., Santagostino, S. F., Iwawaki, T. R., Romero-Sandoval, E. A., Sanchez Crespo, M., Morales, D. K., Iliev, I. D., Hohl, T. M., Cubillos-Ruiz, J. R.. 2022-11-17. Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis. https://doi.org/10.1101/2022.11.17.513879

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