Regulatory Circuits that Link Cell Fate and Virulence in Histoplasma capsulatum

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Histoplasma capsulatum is one of several systemic dimorphic fungal pathogens that switch their growth program from an infectious mold form in the soil to a pathogenic yeast form in mammalian hosts. H. capsulatum causes up to 500,000 infections per year in the U.S. alone, making it the most common cause of fungal respiratory infections in healthy hosts. Infection occurs when the soil is disrupted, facilitating dispersion of hyphal fragments or spores that are inhaled by humans. Spores and hyphal fragments are the primary infectious agents; however, once introduced into the host, the pathogen converts to a budding-yeast form, which survives and replicates within host macrophages. In the laboratory, the switch between the infectious and parasitic states is modeled by changing the temperature: cells grow in the filamentous form at room temperature, whereas growth at 37ºC is sufficient to trigger growth in the yeast form and expression of virulence factors. Our long-term research goal is to understand how H. capsulatum cells sense host temperature and activate the expression of genes required for cell morphology and virulence.

Despite its importance to human health, very little is known about how H. capsulatum senses and responds to human body temperature. Our prior research findings significantly contributed to the understanding of the molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: she found that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting regulatory network. In this project, we aim to identify and characterize novel virulence factors of H. capsulatum. Specifically, downstream targets of the Ryp proteins will be tested for their role in pathogenesis. Additionally, we are investigating factors that regulate Ryp proteins in response to host temperature. These studies will provide fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host. Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum infections and help prevent other dimorphic fungal infections.

Funding for this project provided through NIH-NIAID R00 award (R00AI112691).