Genotypic diversity, virulence, and molecular genetic tools in Histoplasma

Abstract

SUMMARYHistoplasmosis is arguably the most common fungal respiratory infection worldwide, with hundreds of thousands of new infections occurring annually in the United States alone. The infection can progress in the lung or disseminate to visceral organs and can be difficult to treat with antifungal drugs. Histoplasma, the causative agent of the disease, is a pathogenic fungus that causes life-threatening lung infections and is globally distributed. The fungus has the ability to germinate from conidia into either hyphal (mold) or yeast form, depending on the environmental temperature. This transition also regulates virulence. Histoplasma and histoplasmosis have been classified as being of emergent importance, and in 2022, the World Health Organization included Histoplasma as 1 of the 19 most concerning human fungal pathogens. In this review, we synthesize the current understanding of the ecological niche, evolutionary history, and virulence strategies of Histoplasma. We also describe general patterns of the symptomatology and epidemiology of histoplasmosis. We underscore areas where research is sorely needed and highlight research avenues that have been productive.

Keywords: Histoplasma; mycoses; virulence.

Fig 1

Spectrum of histoplasmosis. Left: Histoplasma is found in nitrogen-rich soil, which is usually provided by bird or bat guano. Middle: the spectrum of histoplasmosis ranges from asymptomatic infection to severe disseminated disease. Disease outcome is impacted by multiple factors, including the immune status of the host and the quantity of organisms inhaled. Right: strain background also impacts the type of disease. There are strains that cause cutaneous and subcutaneous bone lesions, and other ones that infect horses and mules and cause chronic ulcerative dermatitis, conjunctivitis, and pulmonary histoplasmosis. Modified from an original figure made by Grant S. Jones (with permission). Created with BioRender.com.

Fig 2

(A) Histoplasma species. Phylogenetic tree using whole genome data shows that Histoplasma is composed of at least five different species [tree modified from reference (228)]. Species names represent the nomenclature proposed by Sepúlveda et al. (228) as well as the nomenclature proposed by Kasuga et al. (227) (in parenthesis). (B) Extracellular proteolytic activity in Histoplasma. Secreted proteolytic activity is visible as transparent clearance halos around fungal colonies only in H. mississippiense (NAm 1) strains. Pictures show a reference strain for each species: WU24 (H. mississippiense), G217B (H. ohiense), 3/11 (H. suramericanum), G186A (H. capsulatum), and H88 (African clade). (C) α-(1, 3)-glucan. Smooth morphology occurs in the absence of α-(1, 3)-glucan in the cell walls. H. ohiense (NAm2) is the only species that shows a smooth colony morphology (pictures on panel B) due to the lack of α-(1, 3)-glucan. (D) Virulence. Differences in virulence among Histoplasma species. Conclusions should be drawn carefully when comparing relative virulence among isolates, and strain-level variation should be considered and evaluated before making species-level conclusions. References shown are as follows: (236, 237, 219).