title: Deciphering the pathways of death of Histoplasma capsulatum-infected macrophages: implications for the immunopathogenesis of early infection.
abstract: Apoptosis of leukocytes is known to strongly influence the immunopathogenesis of infection. In this study, we dissected the death pathways of murine macrophages (MΦs) infected with the intracellular pathogen Histoplasma capsulatum. Yeast cells caused apoptosis of MΦs 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; however, 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 MΦs 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 postinfection, and the latter was not detected until 8 h postinfection. In vivo, the lungs of TNFR1(-/-) mice infected for 1 d contained fewer apoptotic MΦs than wild-type mice, whereas the lungs of IL-10(-/-) mice exhibited more. Blockade of apoptosis by a pan-caspase inhibitor or by simvastatin sharply reduced the 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 MΦs engenders apoptosis, triggered in part in an autocrine TNF-α-dependent manner, followed by release of IL-10 that likely prevents apoptosis of newly infected neighboring phagocytes.
authors.affiliation: Medical Service, Veterans Affairs Hospital, Cincinnati, OH 45220, USA. george.deepe@uc.edu
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
authors.forename: William R
authors.initials: WR
authors.lastname: Buesing
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D061945:Caspase Inhibitors; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006658:Histoplasma / Q000276:immunology*; D006660:Histoplasmosis / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology; D019821:Simvastatin / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000924:Anticholesteremic Agents; D061945:Caspase Inhibitors; C556062:IL10 protein, mouse; D011480:Protease Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D019821:Simvastatin; C505409:Casp3 protein, mouse; D053148:Caspase 3
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