Murine iNOS expression is essential for antifungal defenses in kidneys during disseminated cryptococcosis

Autor: Kristie D Goughenour, Jessica Zhao, Jintao Xu, Peter Zhao, Christine Freeman, Anutosh Ganguly, Michal A Olszewski
Rok vydání: 2021
Předmět:
Zdroj: The Journal of Immunology. 206:16.30-16.30
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.206.supp.16.30
Popis: C. neoformans, is one of the top 3 fungal pathogens, causing disseminated disease with high mortality in the absence of immunoprotecion. The protective Th1 immune response leads to M1 macrophage polarization that upregulates inducible nitric oxide synthase (iNOS) generating microbicidal nitric oxide. The role of iNOS has been studied in pulmonary defenses to C. neoformans, while its role in disseminated infection remains unknown. Here we study the effect of iNOS deletion in mouse model of disseminated cryptococcosis. The iNOS−/− and the WT, C57BL/6 mice were infected with 106 CFU of C. neoformans 52D via retro-orbital intravenous inoculation. Infected iNOS−/− mice showed significantly reduced survival times, however, they lacked significant increases in fungal burdens in the common infection sites (lung, spleen and CNS). Interestingly, iNOS deletion resulted in nearly 100-fold increase of the kidney fungal burden. Kidney histology revealed extensive lesions resulting in almost complete destruction of the kidney cortical area in iNOS−/− mice and a corresponding loss of kidney function was observed. The lack of fungal control was not due to a failure to recruit immune cells as iNOS−/− mice had increased kidney leukocyte recruitment as well as increases in monocytes and neutrophils. BMDMs from iNOS−/− mice were able to kill Cryptococcus despite a slight M2 bias seen in vivo. iNOS−/− mice had no defect in T-cell polarization, but a slight decrease in surface markers of activation. We conclude that iNOS expression is particularly important for local fungal control in kidneys, although its deletion does not induce a shift in a systemic immunophenotype in the iNOS−/− mice; rather it serves as an effector molecule in a local kidney environment.
Databáze: OpenAIRE
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