Identifying the molecular determinants of thermoadaptation and parasitic growth of Histoplasma capsulatum

Project Summary
Histoplasma capsulatum causes pulmonary and systemic infections in both healthy and immunocompromised
individuals and is the most common cause of fungal respiratory infections in healthy hosts. Histoplasma is a
dimorphic fungal pathogen that can sense and respond to human body temperature by changing its growth
program from a hyphal (mold) form to a parasitic yeast form. 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. Histoplasma strains are classified into at
least eight geographically isolated clades: North American classes 1 and 2 (NAm 1 and NAm 2), Latin American
groups A and B (LAm A and LAm B), Eurasian, Netherlands, Australian and African, and an additional distinct
lineage (H81) comprised of Panamanian isolates.
Given the diversity in phenotypic traits, disease manifestation and geographic distribution, Histoplasma
species present a unique model, where variation in phenotypic traits can be studied in conjunction with the
phylogenetic markers. Our long-term research goal is to determine the genetic pathways that govern
thermoadaptation and virulence traits, which are both required for the parasitic lifestyle of Histoplasma species.
The goal of the proposed project is to identify genes or genomic regions in Histoplasma that control
thermoadaptation and intracellular growth. Previously published studies showed that Histoplasma species can
display differences in yeast-phase morphology and virulence. We recently published comparisons of the
chromosomal-level assemblies of five Histoplasma genomes (H143, H88, G186AR, WU24, and G217B), and
showed that these genomes are relatively invariant in terms of gene content. Instead, the primary differences
between the genomes are in the organization of genes and the abundance of repeats and transposable
elements. Thus, we hypothesize that the differences in gene order, repeat content and single nucleotide
variations (SNVs) can drive some of the observed variations in thermoadaptation and virulence traits.
In this project, we will sequence and fully assemble ~150 new clinical isolates of Histoplasma and make
associations with gene order, repeat content and SNVs to thermoadaptation (Aim 1) and intracellular growth
(Aim 2) of Histoplasma. We anticipate that these results will reveal new genes and genomic regions that are
critical in regulating parasitic lifestyle of Histoplasma. A better understanding of Histoplasma genome content
and identification of regulators of Histoplasma parasitic growth can also lead to development of better molecular
diagnostic screens for Histoplasma in clinical settings.

Grant Number: 1R21AI190982-01
NIH Institute/Center: NIH
Principal Investigator: Sinem Beyhan