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

The National Institute of Allergy and Infectious Diseases (NIAID) awarded the J. Craig Venter Institute, Inc. a Project Grant of $556,375 under the Allergy and Infectious Diseases Research program (CFDA 93.855) on July 23, 2025, with a completion date of June 30, 2027. The research focuses on identifying the molecular determinants governing thermoadaptation and parasitic growth in Histoplasma capsulatum, a dimorphic fungal pathogen responsible for pulmonary and systemic infections in both immunocompromised and healthy individuals. The project involves comparative genomic analysis of multiple Histoplasma strains across eight geographically isolated clades to identify genes and genomic regions controlling the pathogen's ability to sense and respond to human body temperature by converting from hyphal to yeast form—a critical adaptation for intracellular survival and replication within host macrophages.

The deliverables under this award include research outputs and scientific findings related to the genetic pathways governing thermoadaptation and virulence traits in Histoplasma species, leveraging previously published chromosomal-level genome assemblies and comparative genomic methodologies. As a specialized research organization with demonstrated expertise in genomics, bioinformatics, and infectious disease research, JCVI will conduct investigator-initiated basic science research advancing understanding of fungal pathogen mechanisms, contributing to potential therapeutic and diagnostic development strategies for histoplasmosis.

Abstract

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.