Investigating cytotoxic cell responses during Cryptococcal meningitis in patients with chronic advanced HIV co-infection

Abstract

Due to underlying immunosuppression, persons with chronic advanced HIV are susceptible to infections from opportunistic pathogens. Cryptococcus neoformans is an opportunistic fungal pathogen which causes localized pulmonary disease in immunocompetent persons; however, persons who are immunosuppressed can develop disseminated disease into the central nervous system called Cryptococcal meningitis (CM). Patients with CM present with constitutional symptoms such as fever, vomiting and weight loss, and central nervous system specific symptoms such as headache, photophobia, and nuchal rigidity due to high fungal burden in the brain impairing the recycling of cerebrospinal fluid. Treatment with a ~12-month course of combination antifungal therapy, as well as beginning antiretrovirals four-six weeks after antifungal treatment has been established, is essential for fungal clearance. However, despite prompt treatment mortality remains high, especially in low-resourced countries in sub-Saharan Africa. The immune response during CM is dysregulated due to low quantities of and dysfunctional CD4+ T-cells, which are principal players in orchestrating inflammatory immune responses in infected tissues. On one end of the spectrum, poor inflammatory responses allow for rampant C. neoformans fungal growth. While on the other end, hyper-inflammatory response, as in immune reconstitution inflammatory syndrome, can damage fragile tissues such as the brain parenchyma. While understanding CD4+ T-cells are essential to cryptococcal pathogenesis, little is known regarding cytotoxic cells, specifically CD8+ T-cells and Natural killer cells, during CM. Cytotoxic cells have the capability to target extracellular and intracellular pathogens, such as C. neoformans, for destruction as well as produce key inflammatory mediators that induce differentiation of naïve CD4+ T-cells and monocyte populations. Thus, the aims of this thesis are to 1) investigate the immune environment in the CNS to define the role of cytotoxic cells in patient outcome from CM and 2) characterize the cytotoxic cell populations in the CNS and periphery during infection to determine cellular function and contribution to the antifungal response.