Mechanisms of iNOS-mediated protection against CNS damage in cryptococcal meningitis 3992

Abstract Description Inducible nitric oxide synthase (iNOS) is a pivotal yet controversial factor in infectious and inflammatory diseases. By producing nitric oxide (NO), iNOS controls microbial growth but can also cause inflammatory damage. In cryptococcal meningitis (CM), a leading global cause of mortality, inflammation drives disease progression, but iNOS’s role in balancing fungal clearance and tissue damage is unclear. Using a murine CM model, we found that iNOS-deficient mice infected with Cryptococcus neoformans strain H99 experienced worsened neurological symptoms, rapid weight loss, and early mortality. While fungal burdens remained unchanged, iNOS deficiency increased CNS inflammation, marked by elevated neutrophil infiltration and severe brain damage. Monocyte-specific iNOS deletion (CCR2creNos2flox) mirrored whole-body knockouts, identifying monocyte-derived cells as the primary iNOS source. Neutrophil depletion rescued iNOS-deficient mice from early mortality, implicating iNOS in mitigating neutrophil-driven injury. Mechanistically, iNOS deficiency increased IL-1α/IL-1β production by monocyte-derived cells, which contributes to neutrophil recruitment. Human CM data align, showing reduced iNOS expression correlates with poor neurological outcomes despite antifungal treatment. Our findings establish iNOS as a critical regulator that prevents neutrophil-mediated neuronal damage by suppressing IL-1 production, suggesting therapies targeting this pathway could reduce CM neuropathology. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)