Host-Pathogen Dynamics in Microglia during C. neoformans and HIV Co-infection

Cryptococcus neoformans (CN) is a significant human pathogen causing chronic meningoencephalitis (CME), a major contributor to mortality in AIDS patients, accounting for approximately 19% of deaths. This research project aims to explore the phenomenon of replicative aging in CN, particularly its impact during infection in AIDS patients. Replicative lifespan analysis reveals an accumulation of older CN cells in AIDS patients' cerebrospinal fluid (CSF), highlighting a potential selection mechanism in the host environment. These aged CN cells demonstrate a resilient phenotype, exhibiting enhanced resistance to macrophage-mediated killing. Microglia, the predominant tissue-residing macrophages in the brain, are key players in CN infection in the central nervous system (CNS). Microglia can be co-infected with HIV-1. These cells also contribute to the pathogenesis of HIV- 1-associated neurocognitive disorders (HAND) and create a niche that facilitates CN's intracellular growth. Extracellular growth of CN is associated with the upregulation of a copper transporter (CTR4), which is crucial for CN's survival in the brain. The overarching hypothesis of this research is that aged CN cells accumulate in the CSF of AIDS patients due to their altered host-pathogen interaction with microglial cells. Ultimately, this leads to heterogeneity of the in vivo expanding CN population, characterized by a generational distribution shift. Our preliminary data suggest that old CNs’ resistance to phagocytic attack may be due to various physiological changes during replicative aging, including cell wall remodeling, altered mitochondrial function, and the expression of an efflux pump, which modulates the phagolysosomal pH. The proposed study is structured around three specific aims: Aim 1: To investigate the host-pathogen dynamics in microglia co-infected with CN and HIV, focusing on the survival strategies employed by aged CN cells. Aim 2: To determine if selective microglia depletion changes the generational distribution of CN populations in both immunocompetent and CD4+ depleted mice. Aim 3: To explore if serial isolates with altered RLS emerge in AIDS patients with CME. This research will provide crucial insights into the survival mechanisms of CN in the brain of AIDS patients, with potential implications for developing targeted therapies against CN infections in immunocompromised populations.