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The cell wall is a ubiquitous structure in the fungal kingdom, with some features varying depending on the species. Additional external structures can be present, such as the capsule of  Cryptococcus neoformans  ( Cn ), its major virulence factor, mainly composed of glucuronoxylomannan (GXM), with anti-phagocytic and anti-inflammatory properties. The literature shows that other cryptococcal species and even more evolutionarily distant species, such as the  Trichosporon asahii, T. mucoides , and  Paracoccidioides brasiliensis  can produce GXM-like polysaccharides displaying serological reactivity to GXM-specific monoclonal antibodies (mAbs), and these complex polysaccharides have similar composition and anti-phagocytic properties to cryptococcal GXM. Previously, we demonstrated that the fungus  Histoplasma capsulatum (Hc)  incorporates, surface/secreted GXM of  Cn  and the surface accumulation of the polysaccharide enhances  Hc  virulence  in vitro  and  in vivo . In this work, we characterized the ability of  Hc  to produce cellular-attached (C-gly- Hc ) and secreted (E-gly) glycans with reactivity to GXM mAbs. These C-gly- Hc  are readily incorporated on the surface of acapsular  Cn  cap59; however, in contrast to  Cn  GXM, C-gly- Hc  had no xylose and glucuronic acid in its composition. Mapping of recognized  Cn  GXM synthesis/export proteins confirmed the presence of orthologs in the  Hc  database. Evaluation of C-gly and E-gly of  Hc  from strains of distinct monophyletic clades showed serological reactivity to GXM mAbs, despite slight differences in their molecular dimensions. These C-gly- Hc  and E-gly- Hc  also reacted with sera of cryptococcosis patients. In turn, sera from histoplasmosis patients recognized  Cn  glycans, suggesting immunogenicity and the presence of cross-reacting antibodies. Additionally, C-gly- Hc  and E-gly- Hc  coated  Cn  cap59 were more resistant to phagocytosis and macrophage killing. C-gly- Hc  and E-gly- Hc  coated  Cn  cap59 were also able to kill larvae of  Galleria mellonella . These GXM-like  Hc  glycans, as well as those produced by other pathogenic fungi, may also be important during host-pathogen interactions, and factors associated with their regulation are potentially important targets for the management of histoplasmosis.

Histoplasma capsulatum Glycans From Distinct Genotypes Share Structural and Serological Similarities to Cryptococcus neoformans Glucuronoxylomannan