Deciphering the Pathways of Death ofHistoplasma capsulatum-Infected Macrophages: Implications for the Immunopathogenesis of Early Infection

Abstract

Apoptosis of leukocytes is known to strongly influence the immunopathogenesis of infection. Herein, we dissected the death pathways of murine Mφ infected with the intracellular pathogen, Histoplasma capsulatum. Yeast cells caused apoptosis of Mφ at a wide range of multiplicity of infection, but smaller inocula resulted in delayed detection of apoptosis. Upon infection, caspases 3 and 1 were activated, and both contributed to cell death but only the former was involved in apoptosis. The principal driving force for apoptosis involved the extrinsic pathway via engagement of TNFR1 by TNF-α. Infected Mφ produced IL-10 that dampened apoptosis. The chronology of TNF-α and IL-10 release differed in vitro. The former was detected by 2 h post-infection and the latter not until 8 h post-infection. In vivo, the lungs of TNFR1−/− mice infected for one day contained fewer apoptotic Mφ than WT whereas lungs of IL-10−/− mice exhibited more. Blockade of apoptosis by a pan-caspase inhibitor or by simvastatin sharply reduced release of TNF-α but enhanced IL-10. However, these treatments did not modify the fungal burden in vitro over 72 h. Thus, suppressing cell death modulated cytokine release but did not alter the fungal burden. These findings provide a framework for the early pathogenesis of histoplasmosis in which yeast cell invasion of lung Mφ engenders apoptosis triggered in part an autocrine TNF-α-dependent manner followed by release of IL-10 that likely prevents apoptosis of newly infected neighboring phagocytes.

Cryptococcus neoformans–Induced Macrophage Lysosome Damage Crucially Contributes to Fungal Virulence

“…These combined data sets open the possibility that Cn -induced phagolysosome damage may enhance programmed cell death in macrophages. Intriguingly, lysosome damage induced by ground silica has been shown to induce inflammasome activation and pyroptosis in activated macrophages (35, 52) consistent with the observed activation of caspase-1 in cells infected with fungal pathogens (53–56). Lysosome damage can also have a role in apoptosis as released lysosomal cathepsins can cleave apoptosis proteins to initiate programed cell death in cultured fibroblasts (57–65).…”

Antifungal Activity of the Lipophilic Antioxidant Ferrostatin‐1

“…Fer‐1 prevents non‐apoptotic death of macrophages infected with H. capsulatum: Previous studies examining macrophage death driven by H. capsulatum described apoptosis as the predominate death mechanism . Here, we found that death of infected bone‐marrow‐derived macrophages (BMDMs) in vitro was non‐apoptotic.…”

“…Death of infected macrophages is an important part of the interaction between pathogen and host. Previous studies have focused on the classic caspase‐dependent cell death process: apoptosis . Although the exact biochemical sequence in infected macrophage apoptosis is unknown, it is dependent on the fungal gene cbp1 and involves endoplasmic reticulum stress and release of the pro‐inflammatory cytokine tumor necrosis factor‐α (TNF‐α).…”

The occurrence of histoplasmosis in Brazil: A systematic review

“…The clinical spectrum of this illness ranges from an asymptomatic, self-limited illness to a progressive disseminated disease. The primary focus of this fungal infection is the lung, and the disease prognosis depends on the host immune response, the fungal inoculum size inhaled, and the fungal virulence (Deepe and Buesing, 2012). Immunocompromised subjects, especially individuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), patients undergoing corticosteroid or other forms of immunosuppressive therapy, and those undergoing cytotoxic chemotherapy, can develop more severe forms of the disease, due to fungal dissemination to several organs (Damasceno et al, 2013;Kauffman, 2007).…”