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Published on: October 22, 2012
Murine Inducible Nitric Oxide Synthase Expression Is Essential for Antifungal Defenses in Kidneys during Disseminated
Kristie D Goughenour1,2, Jessica Zhao1,2, Jintao Xu1,2
1Research Service, VA Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI.
Abstract:
Disseminated cryptococcosis has a nearly 70% mortality, mostly attributed to CNS infection, with lesser-known effects on other organs. Immune protection against Cryptococcus relies on Th1 immunity with M1 polarization, rendering macrophages fungicidal. The importance of M1-upregulated inducible NO synthase (iNOS) has been documented in pulmonary anticryptococcal defenses, whereas its role in disseminated cryptococcosis remains controversial. Here we examined the effect of iNOS deletion in disseminated (i.v.) C. deneoformans 52D infection, comparing wild-type (C57BL/6J) and iNOS-/- mice. iNOS-/- mice had significantly reduced survival and nearly 100-fold increase of the kidney fungal burden, without increases in the lungs, spleen, or brain. Histology revealed extensive lesions and almost complete destruction of the kidney cortical area with a loss of kidney function. The lack of fungal control was not due to a failure to recruit immune cells because iNOS-/- mice had increased kidney leukocytes. iNOS-/- mice also showed no defect in T cell polarization. We conclude that iNOS is critically required for local anticryptococcal defenses in the kidneys, whereas it appears to be dispensable in other organs during disseminated infection. This study exemplifies a unique phenotype of local immune defenses in the kidneys and the organ-specific importance of a single fungicidal pathway.
Insights
Inducible nitric oxide synthase (iNOS) is crucial for controlling fungal infections in the kidneys during disseminated cryptococcosis. Its absence severely impairs survival and kidney function, highlighting organ-specific immune defense mechanisms.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Disseminated cryptococcosis has high mortality, primarily due to central nervous system (CNS) infections.
- Immune responses involving Th1 immunity and M1 macrophage polarization are vital for controlling Cryptococcus, with inducible nitric oxide synthase (iNOS) playing a key role.
Purpose of the Study:
- To investigate the role of iNOS in disseminated Cryptococcus deneoformans infection.
- To determine the organ-specific importance of iNOS in controlling fungal burden and host survival.
Main Methods:
- Comparison of wild-type and iNOS knockout (iNOS-/-) mice infected intravenously with C. deneoformans.
- Assessment of survival rates, fungal burden in various organs (kidneys, lungs, spleen, brain), kidney histology, and immune cell infiltration.
Main Results:
- iNOS-/- mice exhibited significantly reduced survival and a 100-fold increase in kidney fungal burden compared to wild-type mice.
- Histological analysis of iNOS-/- kidneys showed extensive lesions, cortical destruction, and loss of function, despite increased leukocyte infiltration.
- Fungal burden did not increase in other organs (lungs, spleen, brain) of iNOS-/- mice, and T cell polarization remained intact.
Conclusions:
- iNOS is essential for local antifungal defense in the kidneys during disseminated cryptococcosis.
- The findings highlight the organ-specific requirement for iNOS in controlling Cryptococcus, demonstrating a unique kidney immune defense phenotype.
