, 2006); the Wor1 homologue, Ryp1 (Nguyen & Sil, 2008); and two velvet-family regulators, Ryp2 and Ryp3 (Webster & Sil, 2008). As this transition to the yeast form is essential

for pathogenesis, and highly homologous proteins are encoded in multiple sequenced isolates, these signaling mechanisms are likely conserved among Histoplasma strains. The H. capsulatum species is not monophyletic and has been subdivided Protein Tyrosine Kinase inhibitor into geographically distinct phylogenetic lineages. Based on concordance of multiple gene sequence geneologies, Histoplasma strains separate into at least six major clades: North American class 1 (NAm1), North American class 2 (NAm2), a Panamanian clade, Latin American group A, Latin American group B, and an African clade (which includes the Histoplasma capsulatum variety dubosii) (Kasuga et al., 1999, 2003). Interestingly, clinical differences in histoplasmosis disease manifestation exist among the groups. For example, some African clade strains cause primarily cutaneous and subcutaneous lesions rather than pulmonary

involvement, and these have historically been classified as H. capsulatum var dubosii. Whether this manifestation is determined by genetic differences in Histoplasma strains is unclear since pulmonary disease-causing strains are also part of the African clade (Kasuga et al., 2003). In North America, a correlation between NAm1 infections and hosts with AIDS has been suggested, whereas NAm2 strains are isolated from histoplasmosis patients regardless of HIV-status (Spitzer et al., selleck chemical 1990). However, another study identified a NAm1-class strain from an HIV-negative individual (Jiang et al., 2000). As all these findings are isothipendyl based on relatively small sample sizes, better epidemiological data are necessary to establish the link between NAm1 Histoplasma strain infection potential and the immune status of the host. In mouse studies, Latin American and NAm2 isolates differ in acute and chronic disease

potential (Durkin et al., 2004) as well as the extent of cutaneous disease presentation (Karimi et al., 2002). Differences in surfactant-sensitivity have also been reported between NAm2 and Panamanian strains (McCormack et al., 2003). Together these findings suggest important diversity in virulence, infectivity, and pathogenesis among strains and indicate that sequence variations between phylogenetic groups are not inconsequential. In this review, we discuss important genetic and functional differences in virulence determinants of Histoplasma. As establishment of functional roles relies on molecular genetic manipulation, we focus on two Histoplasma clinical isolates with sequenced genomes and in which genes have been disrupted or gene products depleted: a NAm2 strain, G217B, and an isolate from Panama, G186A.