Maia Lintner
Research Mentor(s): Michal Olszewski
Mentor Department: Internal Medicine, Pulmonary and Critical Care Medicine
Authors: Maia Lintner, Jintao Xu, Michal Olszewski, Rylan Hissong, Kristie Goughenour
Session: Session 4 (1:00pm – 1:50pm)
Presentation Type: Oral
Abstract
Cryptococcus neoformans (C. neo), is a fungal pathogen causing a life-threatening meningitis (CM), predominantly in immunocompromised individuals. Inducible nitric oxide synthase (Nos2) produces nitric oxide, a molecule that shows antifungal properties. However, little is known about the role of Nos2/NO in CM. Comparing the outcomes of CM in the wild-type (WT) and Nos2 knockout (Nos2-/-) mice, we observed that Nos2 deficiency surprisingly does not affect fungal clearance, but instead it leads to increased neuroinflammation documented by increased recruitment of inflammatory monocytes and neutrophils, disruption of blood-brain barrier (BBB) demonstrated by Evan’s blue dye extravascular leak, and accelerated mouse mortality. Furthermore, Nos2-deficient mice exhibit elevated inflammatory cytokine, IL-1a/ß levels, which could explain the excessive neutrophil brain infiltration. Neutrophil depletion in iNos2-/- mice improves survival, highlighting their role in exacerbating CNS damage in the absence of Nos2. Selective deletion of Nos2 from inflammatory monocytes, using CCR2creNos2fl/fl mice established that IM-derived Nos2 is a key protective factor against neuroinflammation. By defining the neuroprotective functions of Nos2, this study supports the development of future targeted immunomodulatory therapies to enhance IM function while preserving antifungal immunity. Understanding Nos2 regulation in CM may inform broader strategies for treating neuroinflammatory diseases.
