Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis
Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz
Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz
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Research Article Immunology Infectious disease

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis

Abstract

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase–driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.

Authors

Deepika Awasthi, Sahil Chopra, Byuri A. Cho, Alexander Emmanuelli, Tito A. Sandoval, Sung-Min Hwang, Chang-Suk Chae, Camilla Salvagno, Chen Tan, Liliana Vasquez-Urbina, Jose J. Fernandez Rodriguez, Sara F. Santagostino, Takao Iwawaki, E. Alfonso Romero-Sandoval, Mariano Sanchez Crespo, Diana K. Morales, Iliyan D. Iliev, Tobias M. Hohl, Juan R. Cubillos-Ruiz

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Figure 5

Gene expression profiles controlled by IRE1α in kidney-infiltrating neutrophils and monocytes from mice with systemic candidiasis.

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Gene expression profiles controlled by IRE1α in kidney-infiltrating neut...
(A–G) Ern1fl/fl or Ern1fl/fl Vav1Cre mice were infected with 105 C. albicans cells, and 36 hours later, kidney-infiltrating neutrophils (Ly6G+Ly6Clo) and monocytes (Ly6Chi) were sorted (n = 4 per genotype) for RNA-Seq analyses. (A) Experimental scheme. (B) PCA showing distinct clustering of each genotype. (C) Volcano plot highlighting the top 10 upregulated (Up) and downregulated (Dn) DEGs. The 2 vertical dashed lines on each side correspond to –1.0 and 1.0 cut points, which are log2 fold-change cutoffs used for determining DEGs. The horizontal dashed line corresponds to P-adjusted (P.adj) values of 0.05, which was another cutoff used for determining DEGs. (D) Heatmap displaying the 81 upregulated and 109 downregulated DEGs in Ern1fl/fl Vav1Cre compared with Ern1fl/fl cells. (E and F) Pathway score analyses showing significant downregulation of global UPR gene markers in (E) Ern1fl/fl Vav1Cre neutrophils and monocytes compared with their Ern1fl/fl counterparts, (F) whereas no significant difference was observed for RIDD target genes. *P = 0.029, by Wilcoxon test. (G) Pathway enrichment analysis depicting significant downregulation of multiple inflammatory gene programs. (H–K) Ern1WT (gray bars) or Ern1KO (blue bars) neutrophils isolated from the bone marrow (n = 4–5 per genotype) were stimulated with HKCA (MOI = 10) for 6 hours, and expression of the indicated transcripts was determined by RT-qPCR. *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001, by 2-way ANOVA with Šídák’s multiple-comparison test (H, I, and K) and 2-way ANOVA with Tukey’s multiple-comparison test (J).