Host-pathogen interactions are a cornerstone of microbiology and medicinal research. Many incredible cellular mechanisms evolved from arms races between pathogens and host defenses. Studying these mechanisms leads to significant advances in molecular biology (ex. CRISPR/Cas) and medicine (ex. Penicillin). By understanding the delicate balance of the damage-response framework of microbial disease and studying how microbes and host cells outmaneuver each other, we can better understand pathogenesis to develop therapeutic strategies against debilitating disease. I study the host-pathogen interactions of Cryptococcus neoformans and macrophages, sites of various cellular phenomena with far reaching implications in fields ranging from immunology to bioremediation.
I begin by describing phagolysosome acidification dynamics as a bet hedging strategy which macrophages employ to maximize fitness considering the variety of encounterable pathogens. Understanding this initial, broadly effective defense gives a frame of reference for downstream host-pathogen interactions. Phagolysosomal pH is an important aspect of this initial defense but is largely overlooked and undervalued.
Next, I focus on the mechanism of C. neoformans macrophage-to-macrophage transfer. The existence of this phenomenon has been previously reported, but its mechanism is undiscovered. Using fluorescent microscopy with reporters specific to cellular compartments, antibody blockades for surface receptors, and live cell microscopy to follow infection outcomes I focus on understanding the circumstances of this phenomenon and place its mechanism within known cellular processes.
Finally, I present work in progress toward understanding the interplay of C. neoformans and macrophages in the context of Dragotcytosis. Using transcriptomics, fluorescence microscopy, and simulations I outline how phagolysosome acidification and Dragotcytosis are linked and provide evidence suggesting Dragotcytosis is a survival mechanism to escape hostile phagolysosomes.
These data bring new understanding to several facets of C. neoformans pathogenesis and suggest mechanisms which may be common to other human pathogens.
Written under the advisory of Arturo Casadevall, Monica Mugnier, Dennis Wirtz, and Valeria Culotta
