Chad A. Rappleye rappleye.1@osu.edu B.S., Biology, University of Utah Ph.D., Biology, University of California, San Diego Postdoc, Molecular Microbiology, Washington University

Assistant Professor, Microbiology; Internal Medicine
Member: Center for Microbial Interface Biology (CMIB)
Member: Integrated Biomedical Science Graduate Program (IBGP)

Research interests

We are interested in the molecular mechanisms that underlie the virulence of the respiratory fungal pathogen Histoplasma capsulatum, the causative agent of histoplasmosis. In particular, we study the interaction between Histoplasma yeasts and their primary host cell, the mammalian macrophage. Unlike opportunistic pathogens, Histoplasma can cause disease in immunocompetent hosts, implying that Histoplasma has specific mechanisms designed to promote pathogenesis. One of these mechanisms is the elaboration of a cell wall polysaccharide, alpha-(1,3)-glucan, on the cell surface, which effectively masks the underlying immunostimulatory beta-glucans from detection by the host. The only other virulence factor identified to date is a secreted molecule of unknown function. With a genome harboring an estimated 10,000 genes, we have only scratched the surface in defining the genes important for Histoplasma virulence.

Our lab is employing genomics-based and molecular genetic approaches to identify additional factors contributing to the pathogenesis of Histoplasma. The completion of the Histoplasma genome sequence has enabled the construction of microarrays that are used to determine the transcriptional profile of Histoplasma under various conditions, including infection of macrophages. Once candidate genes have been identified, their importance in virulence is assessed through (i) the creation of loss of function mutants (i.e gene knock-outs) or gene depletion strains (via RNA interference) and (ii) the use of mutant strains in infection studies. Excellent animal models of disease exist for Histoplasma as well as in vitro culture systems which facilitate more detailed studies to dissect the effect of fungal proteins at the cellular level.

To provide a more complete description of the molecular basis of fungal pathogenesis, our research also investigates the host side of the host-pathogen equation. Using retroviral and lentiviral RNA interference systems to reduce host gene functions, we can now test the involvement of host molecules in the response to Histoplasma infection. This ability to perform loss of function experiments in both the host and pathogen combine into a powerful system to define fungal virulence factors and the cognate host pathways targeted.

Holbrook ED, Rappleye CA. 2008. Histoplasma capsulatum pathogenesis: making a lifestyle switch. Curr Opin Microbiol. Aug;11(4):318-24.

Rappleye CA, Goldman WE. 2008. Fungal stealth technology. Trends Immunol. Jan;29(1):18-24.

Rappleye CA, Eissenberg LG, Goldman WE. 2007. Histoplasma capsulatum alpha-(1,3)-glucan blocks innate immune recognition by the beta-glucan receptor. Proc Natl Acad Sci U S A. Jan 23;104(4):1366-1370.

Marion CL, Rappleye CA, Engle JT, Goldman WE. 2006. An alpha-(1,4)-amylase is essential for alpha-(1,3)-glucan production and virulence in Histoplasma capsulatum. Mol Microbiol. Nov;62(4):970-983.

Rappleye CA, Goldman WE. 2006. Defining Virulence Genes in the Dimorphic Fungi. Annu Rev Microbiol. Oct;60(1):281-303

Goldman, WE and Rappleye, CA. 2005. RNA interference as a tool for studying fungal pathogens. Nova Acta Leopoldina. 92(344):141-145.

Rappleye CA, Engle JT, Goldman WE. 2004. RNA interference in Histoplasma capsulatum demonstrates a role for alpha-(1,3)-glucan in virulence. Mol Microbiol. Jul;53(1):153-165.