Interferon‐γ and Granulocyte‐Macrophage Colony‐Stimulating Factor Augment the Activity of Polymorphonuclear Leukocytes against Medically Important Zygomycetes

Abstract

Zygomycetes cause serious invasive infections, predominantly in immunocompromised and diabetic patients with poor prognoses and limited therapeutic options. We compared the antifungal function of human polymorphonuclear leukocytes (PMNLs) against hyphae of Rhizopus oryzae and R. microsporus, the most frequently isolated zygomycetes, with that against the less frequently isolated Absidia corymbifera. We then evaluated the effects of interferon (IFN)- gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF), alone or combined, on PMNL antifungal function against these zygomycetes. Both PMNL oxidative burst in response to hyphae and PMNL-induced hyphal damage were significantly lower in response to Rhizopus species than in response to A. corymbifera. Incubation of PMNLs with IFN- gamma and GM-CSF alone or combined for 22 h increased the PMNL-induced hyphal damage of all 3 species. The treatment of PMNLs with the combination of IFN- gamma and GM-CSF significantly increased the release of tumor necrosis factor- alpha in response to R. microsporus and A. corymbifera hyphae. IFN- gamma significantly reduced interleukin-8 release in response to all zygomycetes. Although Rhizopus species demonstrate a decreased susceptibility to the antifungal activity of human PMNLs, in comparison with A. corymbifera, IFN- gamma and GM-CSF augment the hyphal damage of all 3 zygomycetes, suggesting a role for IFN- gamma and GM-CSF in the management of invasive zygomycosis.

Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis

“…Finally, elevated free iron is known to have a profound and detrimental effect on immune cells necessary for combating mucormycosis. Specifically, elevated concentrations of iron were found to be toxic to phagocytes (19)(20)(21), and spleen cells from mice fed excess levels of iron secrete less IFN-γ (22), a cytokine that upregulates killing of several Mucorales family members (including R. oryzae) by human neutrophils (23). Additionally, BHB, which has been reported to abrogate the formation of bovine neutrophil extracellular traps and their bactericidal activity against pathogen E. coli (9), attenuated the ability of human neutrophils to kill R. oryzae ex vivo by reducing ROS production.…”

Mucorales-specific T cells emerge in the course of invasive mucormycosis and may be used as a surrogate diagnostic marker in high-risk patients

“…The contribution of T cells to host defenses against these moulds could only be suspected on the basis of the enhanced fungicidal activity against Mucorales of polymorphonuclear leukocytes exposed to IFN-␥, 16 but this has not yet been demonstrated formally.…”

Novel Perspectives on Mucormycosis: Pathophysiology, Presentation, and Management

“…Cytokines that activated phagocytic activity, such as gamma interferon and granulocyte-macrophage colony-stimulating factor, increase the ability of phagocytes to kill agents of mucormycosis in vitro (44). A recent case report suggested a favorable outcome in a leukemic child with rhinocerebral mucormycosis following the addition of gamma interferon and granulocyte-macrophage colony-stimulating factor to the regimen (3).…”