Genomic epidemiology of Histoplasma in Africa

Histoplasmosis, the disease caused by thermally dimorphic fungi in the genus Histoplasma, is usually associated with pulmonary involvement in healthy individuals and a disseminated syndrome in immunocompromised patients. Among African patients, lung disease is less commonly reported than skin, lymph node, or bone disease. Because different species or strains may be associated with different disease presentations and outcomes, understanding genetic and phenotypic variation in the genus Histoplasma is important for accurate diagnosis and treatment. We sequenced the genomes of 36 Histoplasma isolates from Africa and used population genomics to measure the genetic variation of the genus on the African continent and to compare the genetic diversity of these isolates to the previously described Indian and American phylogenetic species. We found that strains from Africa belong to genetic lineages that are differentiated enough to be considered a phylogenetic species. The first, the Africa lineage, is consistent with a previously described species (Histoplasma capsulatum duboisii) which includes clinical cases more frequently associated with extrapulmonary manifestations than cases caused by other lineages. While there is some evidence of gene flow between Histoplasma lineages, it has not precluded divergence. A second lineage corresponding to Histoplasma capsulatum farciminosum (Hcf) includes all the isolates from equine samples. We identified loci under selection in these two better-sampled lineages and found loci that have undergone parallel positive selection. A single African isolate resembles a South American lineage. Finally, we measured the potential range expansion of the disease using climatic projections, highlighting the need to implement surveillance to monitor phylogenetic species of Histoplasma across Africa. IMPORTANCE Histoplasma fungi, which cause histoplasmosis, are widespread and considered high-priority pathogens. While researchers have identified multiple genetically distinct lineages worldwide, little is known about Histoplasma diversity in Africa due to minimal sampling and inadequate diagnostics. Our study addresses this gap using population genomics to analyze stored African isolates. We identified three distinct groups: one of them is endemic to Africa and aligns with Histoplasma capsulatum duboisii, a lineage linked to skin-involved infections, while another lineage (Hcf) matches Histoplasma capsulatum farciminosum, associated with equine lymphangitis. Additionally, one African isolate closely resembles a South American lineage (mz5-like). These three lineages are genetically unique enough to be considered separate species. By integrating phylogenetics, clinical data, and environmental modeling, we provide the most comprehensive genetic assessment of African Histoplasma to date. This work not only enhances our understanding of an overlooked pathogen but also offers a model for studying other neglected fungi with global health implications.