Flying under the radar: Histoplasma capsulatum avoidance of innate immune recognition

Abstract

The dimorphic fungal pathogen Histoplasma capsulatum takes advantage of the innate immune system, utilizing host macrophages as a proliferative niche while largely avoiding stimulation of signaling host receptors. As a result, innate immune cells are unable to control H. capsulatum on their own. Not all host phagocytes respond to H. capsulatum in the same way, with neutrophils and dendritic cells playing important roles in impeding fungal growth and initiating a protective T1 response, respectively. Dendritic cells prime T-cell differentiation after internalization of yeasts via VLA-5 receptors and subsequent degradation of the yeasts. Dendritic cell-expressed TLR7 and TLR9 promote a type I interferon response for T1 polarization. In contrast to dendritic cells, macrophages provide a hospitable intracellular environment. H. capsulatum yeasts enter macrophages via binding to phagocytic receptors. Simultaneously, α-glucan masks immunostimulatory cell wall β-glucans and a secreted endoglucanase removes exposed β-glucans to minimize recognition of yeasts by Dectin-1. This review highlights how phagocytes interact with H. capsulatum yeasts and the mechanisms H. capsulatum uses to limit the innate immune response.

How Environmental Fungi Cause a Range of Clinical Outcomes in Susceptible Hosts

“…The majority of yeast will remain intracellular over the course of infection [336][337][338], and the fungus can disseminate within macrophages to reach tissues such as the liver, spleen, bone marrow, and CNS [94]. Compared to macrophages, dendritic cells display better fungicidal and inflammatory activity against H. capsulatum, so proliferation within macrophages also provides a niche to escape further immune detection [339].…”

Immunization Strategies for the Control of Histoplasmosis

“…Spores or active mycelia readily differentiate into budding yeast cells at physiological temperature and are phagocytosed by dendritic cells (DC), polymorphonuclear phagocytes (neutrophils), and alveolar macrophages [8]. Dendritic cells are able to rapidly phagocytose and kill yeast phase H. capsulatum in the lung; neutrophils also play a role in the acute response to H. capsulatum infection by inhibiting fungal growth through the release of azurophilic granule contents [9,10]. A few days after initial infection, phagocytosed H. capsulatum yeast cells are principally found within inflammatory macrophages, wherein they are able to survive and proliferate as facultative intracellular pathogens [8].…”

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

“…Differences in immune recognition among species are also given by specific surface components attached to these core layers, such as the pigment melanin in Fonsecaea pedrosoi , rodlets and galactomannans in Aspergillus fumigatus , glucuronoxylomannan (GXM) capsule in Cryptococcus sp. ( Gow et al., 2017 ) and α-1,3-glucans in thermally dimorphic fungi, among others ( Guimaraes et al., 2011 ; Gow et al., 2017 ; Ray and Rappleye, 2019 ). Despite mechanical protection for the fungal cells, all of these components are involved in the fungal escape of the immune response, since they all can shield cells from immune recognition ( Rappleye et al., 2007 ; Erwig and Gow, 2016 ; Gow et al., 2017 ).…”