Identifying Host and Pathogen Factors That Control Growth in Microsporidia

University Of Wisconsin-Madison, Madison WI

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Abstract

? DESCRIPTION (provided by applicant): Microsporidia comprise a phylum of fungal-like obligate intracellular pathogens that infect hosts ranging from invertebrates to humans. In immunocompromised humans, microsporidia can cause fatal wasting diarrhea. Latent infection by microsporidia is a common phenomenon, with up to 56% of the immune- competent population asymptomatically infected and transiently shedding spores. The full impact of these pathogens on human health is unknown. There is a critical lack of effective drugs to treat microsporidiosis. Only one drug is approved for treating humans, albendazole, which is ineffective against the leading cause of microsporidiosis, Enterocytozoon bieneusi. Determining the molecular mechanisms of microsporidian pathogenesis is critical for understanding how these pathogens cause disease and for developing new strategies for therapeutic intervention. Adaptation of microsporidia to this intracellular parasitic lifestyle has resulted in extreme gene loss and genome compaction, including the loss of conserved signaling components responsible for controlling proliferation and sporulation in other fungi. In addition, this obligat intracellular lifestyle of microsporidia has severely hampered the ability to propagate and study these organisms and is the primary reason for such a poor understanding of these pathogens. However, the discovery of Nematocida parisii, a natural pathogen of the model nematode Caenorhabditis elegans, provides a tractable system for understanding the molecular mechanisms of microsporidian pathogenesis in a whole animal model. I hypothesize that both microsporidian and host cell signaling pathways regulate microsporidia proliferation and differentiation into spores. I will take advantage of the N. parisii/C. elegans infection system to identify the host signals that control microsporidian proliferation and spore production. Then, I will analyze candidate developmental regulators of N. parisii sporulation to determine their stage-specific expression, and characterize the direct targets of these transcription factors. Ultimately, these studies will shed light on host factors critical for microsporidian pathogenesis, and developmentally regulated genes in microsporidia; genes important for the formation of infectious spores. Genes expressed during microsporidian differentiation are likely to include many genes responsible for coordinating egress from host cells, forming specialized spore- structures, including those responsible for invading host cells. Host genes that are required for microsporidian proliferation and differentiation into spores are key targets for novel strategies t combat these ubiquitous pathogens.