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The HIF-1?/LC3-II Axis Impacts Fungal Immunity in Human Macrophages.

ABSTRACT: The fungal pathogen Histoplasma capsulatum causes a spectrum of disease, ranging from local pulmonary infection to disseminated disease. The organism seeks residence in macrophages, which are permissive for its survival. Hypoxia-inducible factor 1? (HIF-1?), a principal regulator of innate immunity to pathogens, is necessary for macrophage-mediated immunity to H. capsulatum in mice. In the present study, we analyzed the effect of HIF-1? in human macrophages infected with this fungus. HIF-1? stabilization was detected in peripheral blood monocyte-derived macrophages at 2 to 24?h after infection with viable yeast cells. Further, host mitochondrial respiration and glycolysis were enhanced. In contrast, heat-killed yeasts induced early, but not later, stabilization of HIF-1?. Since the absence of HIF-1? is detrimental to host control of infection, we asked if large amounts of HIF-1? protein, exceeding those induced by H. capsulatum, altered macrophage responses to this pathogen. Exposure of infected macrophages to an HIF-1? stabilizer significantly reduced recovery of H. capsulatum from macrophages and produced a decrement in mitochondrial respiration and glycolysis compared to those of controls. We observed recruitment of the autophagy-related protein LC3-II to the phagosome, whereas enhancing HIF-1? reduced phagosomal decoration. This finding suggested that H. capsulatum exploited an autophagic process to survive. In support of this assertion, inhibition of autophagy activated macrophages to limit intracellular growth of H. capsulatum Thus, enhancement of HIF-1? creates a hostile environment for yeast cells in human macrophages by interrupting the ability of the pathogen to provoke host cell autophagy.

SUBMITTER: Friedrich D

PROVIDER: S-EPMC6589057 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The HIF-1α/LC3-II Axis Impacts Fungal Immunity in Human Macrophages.

Friedrich Dirk D Zapf Dorinja D Lohse Björn B Fecher Roger A RA Deepe George S GS Rupp Jan J

Infection and immunity 20190620 7

The fungal pathogen <i>Histoplasma capsulatum</i> causes a spectrum of disease, ranging from local pulmonary infection to disseminated disease. The organism seeks residence in macrophages, which are permissive for its survival. Hypoxia-inducible factor 1α (HIF-1α), a principal regulator of innate immunity to pathogens, is necessary for macrophage-mediated immunity to <i>H. capsulatum</i> in mice. In the present study, we analyzed the effect of HIF-1α in human macrophages infected with this fungu ...[more]

PMID: 31036602

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Dataset Information

The HIF-1?/LC3-II Axis Impacts Fungal Immunity in Human Macrophages.

Publications

The HIF-1α/LC3-II Axis Impacts Fungal Immunity in Human Macrophages.

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