Tumor necrosis factor-α coordinates the macrophage innate immune response to Histoplasma capsulatum.

Authors

Bradford L Crowther, William Buesing, Ty Troutman, George S Deepe

Published in

Infection and immunity. Pages e0030226. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Histoplasma capsulatum is a fungal pathogen that thrives in macrophages until activated by interferon-gamma (IFN-γ). Tumor necrosis factor-α (TNF-α) is required for control of infection during adaptive immunity but does not directly activate macrophages to eliminate fungal elements. Collapse of immunity associated with TNF-α blockade is not accompanied by depression of IFN-γ. To determine if TNF-α antagonism impairs fungal clearance prior to adaptive immunity, we infected mice given anti-TNF-α and quantified lung H. capsulatum up to day 3 of infection. Anti-TNF-α elevated the number of organisms in the lungs by day 3. Neutralization of IFN-γ manifested a similar effect. Since neutralization of both cytokines impaired innate immunity, we hypothesized that the action of IFN-γ required TNF-α. IFN-γ-stimulated macrophages expressed fungicidal activity in vitro, and TNF-α neutralization or its congenital deficiency in macrophages reversed this effect. Blockade of TNF-α slightly dampened M1 response but did not promote M2. TNF-α was not required for IFN-γ to shift the metabolic capacity of macrophages. We investigated the production of nitric oxide, which is a mediator of anti-H. capsulatum activity by macrophages. In the absence of TNF-α, there was no difference when compared to IFN-γ stimulation alone. Lung macrophages harbored the highest infection burden in anti-TNF-α recipients. Though IFN-γ receptor 1 was modestly downregulated by anti-TNF-α blockade, this treatment downregulated pSTAT1 at day 2 of infection. TNF-α is required for optimal IFN-γ signaling and effector function of cytokine-stimulated macrophages. When TNF-α is absent, macrophages are insufficiently activated and fail to halt intracellular growth of yeast cells.

PMID:
42809420
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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