Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1α (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 IRE1a-dependent overexpression of key inflammatory mediators such as IL-1Β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE), and TNF-α. Selective ablation of IRE1a in leukocytes, or treatment with an IRE1a 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.This work was supported by NIH T32 5T32AI134632-02 and F31CA257631 training grants (to AE); the Cancer Research Institute–Irvington Institute Postdoctoral Fellowship Award (to CSC and CS); NIH/NCI Cancer Center Support Grant P30 CA008748 (to SFS); and NIH R01 NS114653 and R21 CA248106 (to EARS). This work was also supported by a Junta de Castilla y León/Fondo Social Europeo Fellowship (to JJF); the CSIC’s Global Health Platform (PTI Salud Global, to MSC); Plan Nacional de Salud y Farmacia Grant PID2020-113751RB-I00, funded by MCIN/AEI/ 10.13039/501100011033 (to MSC); Junta de Castilla y León/Fondo Social Europeo Grant VA175P20 (to MSC); NIH grant R01 DK121977 and the Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases Award (to IDI); NIH R37 093808, NIH R01 139632, NIH R21 142639, and the Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Diseases (to TMH); NIH R01 NS114653, NIH R01 CA271619, NIH R21 CA248106, US Department of Defense OC150431, OC200166, and OC200224, the Mark Foundation for Cancer Research ASPIRE Award, and The Pershing Square Sohn Foundation (to JRCR)

Primary angiocentric/angioinvasive T-cell lymphoma of the tympanic bulla in a feline leukaemia virus-positive cat

Case summary A 5-year-old neutered female feline leukaemia virus (FeLV)-positive domestic shorthair cat with a 5 month history of otitis media was referred for head tilt, stertor and dyspnoea. Computed tomography scan revealed soft tissue opacities inside the right tympanic bulla, with bone remodelling, and concurrent nasopharyngeal and intracranial invasion. Endoscopically guided bioptic samples were collected from the nasopharynx and middle ear. Histology revealed dense sheets of round, large, neoplastic cells, often surrounding or invading vascular walls. Neoplastic cells expressed CD3, FeLV p27 and gp70 antigens. A middle ear angiocentric/angioinvasive T-cell lymphoma was diagnosed. After improvement of clinical conditions following radiation therapy, the cat died unexpectedly. At necropsy, hepatic and splenic spread was detected. Relevance and novel information Primary middle ear tumours are rare and their diagnosis is often delayed as clinical signs mimic more common otological conditions. Multiple bioptic specimens are pivotal for a definitive diagnosis. The young age of the cat, serology and immunohistochemistry revealed a possible transforming role of FeLV