11/23/20 Building Community in the UCSF MSTP
We study the fungal pathogen Histoplasma capsulatum, which is a soil organism that can infect and colonize cells of the innate immune system after inhalation into mammals. Temperature is a major signal that triggers a developmental switch between the soil and host forms of the fungus. Our research is driven by two key questions. First, how do cells sense temperature and make a developmental switch from the soil to the host program? We focus on temperature because it is a sufficient signal to recapitulate the morphologic switch between Histoplasma filaments (the soil form) and yeast (the host form) in culture. This question is critical to understanding the basic biology of Histoplasma as well as a number of closely related fungi such as Blastomyces ,Coccidioides , and Paracoccidioides , each of which is a ubiquitous pathogen of immunocompetent hosts in endemic areas. In fact, one of the fascinating evolutionary questions about these environmental fungi is how regulatory circuits have evolved to link morphology and virulence programs with growth at host is be an entry point to broader studies of host-fungal interactions, since it will define critical developmental changes that promote the expression of virulence traits, as well as delineate molecular landmarks that will allow us to stage the interactions of the fungus with host cells.
Second, how does H. capsulatum defy the innate immune response to take up residence, often permanent, in immunocompetent hosts? The past ten years have witnessed an exponential increase in our understanding of the innate immune response to microbes, and yet, in the case of fungi, our insight is rudimentary at best. Our studies explore the molecular communication at the host-pathogen interface between H. capsulatum and the macrophage. H. capsulatum displays extremely robust macrophage colonization, so it is currently the best fungal candidate to probe the Achilles' heel of these powerful innate immune cells and determine novel mechanisms of virulence that have evolved in eukaryotic pathogens.