Mechanisms underlying Cryptococcus neoformans-induced meningoencephalitis and neurotoxicity in a CD4 T cell-deficient mouse

Abstract Cryptococcus neoformans (Cn) is an encapsulated fungus and the causative agent of cryptococcosis. HIV/AIDS patients are significantly susceptible to develop and die of cryptococcal meningoencephalitis (CME) despite of optimal antifungal treatment. The polysaccharide capsule of Cn is abundantly released during infection, causing formidable effects to the host immunity. Its main component, glucuronoxylomannan (GXM), has been implicated in fungal brain invasion and consequent neuropathology. However, there are important knowledge gaps regarding the involved fungal factor(s), regulatory mechanisms, and interaction between Cn and cells of the central nervous system (CNS) that are implicated in CME progression. Therefore, our long-term goal is to fully dissect cellular pathways involved in the neuropathology associated with Cn brain infection. Post-mortem pathological studies in human CME brain tissue samples have demonstrated that there is an intimate relationship between neurons and cryptococcomas. However, the role of GXM on neuronal and cognitive dysfunction observed in CME patients is not well understood. Our preliminary data show that Cn GXM binds to the surface of neurons and causes several cellular changes including morphological alterations, increases in intracellular calcium activity, and altered synaptic transmission. GXM release also leads to an increase in reactive astrocytes and hinders microglial migration, both findings that directly link immune response factors to Cn neuropathology. Hence, the goal of this application is to elucidate the mechanisms by which Cn GXM interfere with neuronal physiology in the basal ganglia, one of the main brain regions associated with cognitive and motor function and significantly colonized by Cn, especially in the setting of CD4 T cell deficiency. Our central hypothesis is that Cn GXM accumulation results in neuroimmune dysregulation and neurotoxicity, contributing to CME pathogenesis and cognitive impairment. To address our hypothesis, we propose the following aims: (1) To determine how Cn GXM affects basal ganglia function in CD4 T cell-deficient mice; (2) To test the hypothesis that exposure to Cn GXM leads to basal ganglia principal neurons death in CD4 T cell- deficient mice; and (3) To investigate how Cn exposure leads to altered synaptic transmission in the basal ganglia and lead to neurobehavioral deficits. Identifying novel mechanisms by which Cn alters neuronal function and behavior in immunocompromised individuals will provide new insights into this neuropathology. In addition, results from our proposal will potentially facilitate future development of new therapeutics and preventive measures for combating CNS cryptococcosis (a disease that kills ~20% of people with AIDS worldwide) and effective management of its potential neuro- sequelae in survivors.