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 o hyphal fragments or spores that are inhaled by humans. The morphologic switch between the hyphal and yeast forms is critical to the establishment and maintenance of disease. 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 37?C is sufficient to trigger growth in the yeast form and expression of virulence factors. The long-term research goal of Dr. Beyhan-Pelvan 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. Dr. Beyhan-Pelvan's 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 the mentored phase of this project, Dr. Beyhan-Pelvan aims to use findings from her previous work 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. These studies will also serve as a training opportunity for Dr. Beyhan-Pelvan to learn macrophage and mouse infection techniques. During the independent phase of this award, Dr. Beyhan-Pelvan aims to investigate 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. Findings from this work can be used to investigate how other thermally dimorphic fungi can transition into a pathogenic form in response to host temperature. Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum infections and help prevent other dimorphic fungal infections. Dr. Beyhan-Pelvan has a longstanding interest in studying the molecular mechanisms used by microorganisms to sense and respond to environmental cues to regulate important biological processes (i.e. regulation of cell morphology, biofilm formation, motility or virulence). This project is proposed to complement her research interests and provide her with the required training in virulence studies. Dr. Sil's laboratory provides a unique opportunity to learn experimental techniques required to study both H. capsulatum's pathogenesis and physiology. Dr. Sil offers both funds and support staff to train Dr. Beyhan-Pelvan in macrophage and mouse infections with H. capsulatum. Additionally, as a mentor, Dr. Sil will work closely with Dr. Beyhan-Pelvan to prepare her for academic job searches. Furthermore, co-mentor Dr. Johnson and advisory committee members Drs. Engel, Madhani and Cox, who have facilitated transition of numerous post-doctoral trainees into independent investigators, will provide additional mentoring with emphasis on preparation for job searches and securing a tenure-track assistant professor position in a top-tier research university.
Histoplasma capsulatum, a dimorphic fungal pathogen, is the most common cause of fungal respiratory infections in immunocompetent hosts, and a significant source of morbidity and mortality in immunocompromised patients. H. capsulatum's ability to cause disease is linked to its ability to sense mammalian body temperature and change its cell morphology from an environmental mold form to a parasitic yeast form. The identification and characterization of (1) novel virulence factors of H. capsulatum and (2) regulatory proteins that influence cell shape and pathogenesis will significantly advance our understanding of how this organism responds to host temperature to cause disease.