| dc.description.abstract | With over 220,000 cases and 180,000 deaths annually, Cryptococcus neoformans is the most common cause of fungal meningitis and a leading cause of death in HIV/AIDS patients in Sub-Saharan Africa. C. neoformans can either be killed by innate airway phagocytes, or it can survive intracellularly. Pulmonary macrophage and dendritic cell (DC) subsets have been identified, and we hypothesize that each subset has different interactions with C. neoformans. For these studies, we purified murine pulmonary macrophage and DC subsets - alveolar macrophages, Ly6C- and Ly6C+ monocyte-like macrophages, interstitial macrophages, CD11b+ and CD103+ DCs. With each subset, we examined cryptococcal association, fungicidal activity, intracellular fungal morphology, cytokine secretion and transcriptional profiling. Results showed that all subsets associate with C. neoformans, but only monocyte-like macrophages inhibited growth. In addition, we observed sex differences in antifungal activity - the male Ly6C+ monocyte-like macrophages inhibited cryptococcal growth, while the female Ly6C- monocyte-like macrophages inhibited cryptococcal growth. In addition, cytokine analysis revealed that phagocyte polarization is not responsible for the differences in fungicidal activity observed. Imaging flow showed differing ratios of cryptococcal morphologies, c-shaped or budding, depending on phagocyte subset. RNA sequencing analysis revealed the up regulation and downregulation of many genes, including immunological pathways and pathways relating to relating to metabolic activity. Future studies gaining a more in-depth understanding on the functionality of individual genes and pathways specific to permissive and non-permissive pulmonary phagocytes will allow identification of key targets when developing therapeutic strategies to prevent cryptococcal meningitis. | |
