Affiliation:
1. Departments of Microbiology and Microbial Infection and Immunity, Ohio State University, Columbus, Ohio, USA
2. Department of Pediatrics, University of Wisconsin—Madison, Madison, Wisconsin, USA
3. Departments of Medicine and Medical Microbiology and Immunology, University of Wisconsin—Madison, Madison, Wisconsin, USA
Abstract
ABSTRACT
The fungal pathogen
Histoplasma capsulatum
parasitizes host phagocytes. To avoid antimicrobial immune responses,
Histoplasma
yeasts must minimize their detection by host receptors while simultaneously interacting with the phagocyte. Pathogenic
Histoplasma
yeast cells, but not avirulent mycelial cells, secrete the Eng1 protein, which is a member of the glycosylhydrolase 81 (GH81) family. We show that
Histoplasma
Eng1 is a glucanase that hydrolyzes β-(1,3)-glycosyl linkages but is not required for
Histoplasma
growth
in vitro
or for cell separation. However,
Histoplasma
yeasts lacking Eng1 function have attenuated virulence
in vivo
, particularly during the cell-mediated immunity stage.
Histoplasma
yeasts deficient for Eng1 show increased exposure of cell wall β-glucans, which results in enhanced binding to the Dectin-1 β-glucan receptor. Consistent with this, Eng1-deficient yeasts trigger increased tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) cytokine production from macrophages and dendritic cells. While not responsible for large-scale cell wall structure and function, the secreted Eng1 reduces levels of exposed β-glucans at the yeast cell wall, thereby diminishing potential recognition by Dectin-1 and proinflammatory cytokine production by phagocytes. In α-glucan-producing
Histoplasma
strains, Eng1 acts in concert with α-glucan to minimize β-glucan exposure: α-glucan provides a masking function by covering the β-glucan-rich cell wall, while Eng1 removes any remaining exposed β-glucans. Thus,
Histoplasma
Eng1 has evolved a specialized pathogenesis function to remove exposed β-glucans, thereby enhancing the ability of yeasts to escape detection by host phagocytes.
IMPORTANCE
The success of
Histoplasma capsulatum
as an intracellular pathogen results, in part, from an ability to minimize its detection by receptors on phagocytic cells of the immune system. In this study, we showed that
Histoplasma
pathogenic yeast cells, but not avirulent mycelia, secrete a β-glucanase, Eng1, which reduces recognition of fungal cell wall β-glucans. We demonstrated that the Eng1 β-glucanase promotes
Histoplasma
virulence by reducing levels of surface-exposed β-glucans on yeast cells, thereby enabling
Histoplasma
yeasts to escape detection by the host β-glucan receptor, Dectin-1. As a consequence, phagocyte recognition of
Histoplasma
yeasts is reduced, leading to less proinflammatory cytokine production by phagocytes and less control of
Histoplasma
infection
in vivo
. Thus,
Histoplasma
yeasts express two mechanisms to avoid phagocyte detection: masking of cell wall β-glucans by α-glucan and enzymatic removal of exposed β-glucans by the Eng1 β-glucanase.
Funder
HHS | NIH | National Institute of Allergy and Infectious Diseases
Publisher
American Society for Microbiology
Cited by
69 articles.
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