Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis

Abstract

The fungal pathogen Histoplasma capsulatum causes respiratory and disseminated disease, even in immunocompetent hosts. In contrast to opportunistic pathogens, which are readily controlled by phagocytic cells, H. capsulatum yeasts are able to infect macrophages, survive antimicrobial defenses, and proliferate as an intracellular pathogen. In this review, we discuss some of the molecular mechanisms that enable H. capsulatum yeasts to overcome obstacles to intracellular pathogenesis. H. capsulatum yeasts gain refuge from extracellular obstacles such as antimicrobial lung surfactant proteins by engaging the β-integrin family of phagocytic receptors to promote entry into macrophages. In addition, H. capsulatum yeasts conceal immunostimulatory β-glucans to avoid triggering signaling receptors such as the β-glucan receptor Dectin-1. H. capsulatum yeasts counteract phagocyte-produced reactive oxygen species by expression of oxidative stress defense enzymes including an extracellular superoxide dismutase and an extracellular catalase. Within the phagosome, H. capsulatum yeasts block phagosome acidification, acquire essential metals such as iron and zinc, and utilize de novo biosynthesis pathways to overcome nutritional limitations. These mechanisms explain how H. capsulatum yeasts avoid and negate macrophage defense strategies and establish a hospitable intracellular niche, making H. capsulatum a successful intracellular pathogen of macrophages.

Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens

“…Why C. albicans encodes three different extracellular Cu-SOD enzymes is currently not understood, but each SOD may function in distinct host niches. In addition to C. albicans, the pulmonary fungal pathogen Histoplasma capsulatum expresses a single Cu-only SOD3 that has been shown to be important for fungal survival against the O 2 ·− attack of macrophages and for virulence in a mouse model of lung infection 122, 140 . Cu-only SODs are also important for virulence of the pulmonary fungal pathogen Paracocidiodes brasiliensis 141 and of the arthropod fungal pathogen Beauveria bassiana 142 that can cause keratitis in humans 143–144 .…”

Eng1 and Exg8 Are the Major α-Glucanases Secreted by the Fungal Pathogen Histoplasma capsulatum

“…Central to the pathobiology of Histoplasma is the ability of pathogenic yeasts to infect and parasitize host phagocytes (1). The cell wall is the first fungal structure encountered by host phagocytes, and thus features of the cell wall contribute to the outcome of the interaction between pathogen and host.…”

Intracellular pathogens convert macrophages from death traps into hospitable homes

“…Together with other monocyte cells such as the dendritic cells, the macrophage presents protein peptides from the pathogen to helper T lymphocytes to stimulate the ones capable of responding to the infection by activating the B lymphocytes displaying the proper anti-pathogen antibodies. The macrophage can also cooperate with cytotoxic T lymphocytes for the destruction of cells infected with pathogens.This Minireview series on Intracellular Pathogens describes the intra-macrophagic escape and survival mechanisms developed by very different intracellular pathogens: the bacteria of the Chlamydiales order [1], the parasite Leishmania [2] and the fungus Histoplasma capsulatum [3]. All three pathogens are internalized into macrophages by receptor-mediated endocytosis, involving specific receptors for each microorganism [4][5][6].…”

“…This Minireview series on Intracellular Pathogens describes the intra-macrophagic escape and survival mechanisms developed by very different intracellular pathogens: the bacteria of the Chlamydiales order [1], the parasite Leishmania [2] and the fungus Histoplasma capsulatum [3]. All three pathogens are internalized into macrophages by receptor-mediated endocytosis, involving specific receptors for each microorganism [4][5][6].…”

“…The Minireviews in this series discuss the recent advances in understanding the complex dance between microorganism and macrophage [1][2][3]. Importantly, they highlight the common strategies employed by each pathogen to circumvent host defense, and as such will be useful in considering future therapeutic angles.…”