Type I interferons during host–fungus interactions: Is antifungal immunity going viral?

Abstract

Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly: I interferons (IFN-I): Beyond the viral control Type I interferons (IFN-I) are crucial in antiviral host defense.However, increasing evidence suggests that IFN-I also play important roles during infections with nonviral pathogens.IFN-I, a family of multiple cytokines that all activate the IFN-α/β receptor (IFNAR), induce expression of interferon-stimulated genes (ISGs) via JAK-STAT1/2 signaling (Fig 1A).ISG-encoded proteins are involved in different processes, many going beyond antiviral defense.In contrast to their well-understood role during viral infections, IFN-I exert both beneficial and detrimental effects to the host.IFN-I orchestrate host defense through antimicrobial and immunomodulatory properties, but also instigate tissue damage and strong proinflammatory responses [1].While this contrasting role is incompletely understood, a growing number of studies implicated IFN-I responses during fungal infections caused by Candida species and Aspergillus fumigatus (Fig 1B). IFN-I during invasive fungal infections: A controversial role?Multiple systemic candidiasis models show activation of IFN-I responses, but whether this mediates protection remains unclear.Mice lacking IFNAR showed increased susceptibility to candidiasis [2], suggesting a protective role of IFN-I.This attenuation of Ifnar1 -/-mice correlated with reduced neutrophil recruitment [1].Contrastingly, reduced neutrophil recruitment resulting from Ifnar1 deficiency was also observed to improve survival by limiting immunopathology [3].Indirect detrimental effects of IFN-I were observed during Candida parapsilosis infection through IL-27 induced by IFNAR signaling [4].IL-27R-deficient mice showed a progressive reduction in C. parapsilosis burden, suggesting that IL-27 compromises fungal clearance.Yet, no changes in survival were observed [4].Finally, Ifnar1 -/-mice showed lower Candida glabrata burdens 7 days postinfection [5], proposing that IFN-I promotes its persistence, although these differences were no longer observed at later stages [5].Several studies hint toward an explanation for the detrimental effect of IFN-I through interference with specific antifungal defense processes.IFN-β, for example, promoted pathology and death from candidiasis by inducing an ISG with tetratricopeptide repeats 2 (IFIT2), which suppressed production of NADPH-oxidase-dependent reactive oxygen species [6].During C. glabrata infection, IFN-I were reported to dysregulate macrophage metal homeostasis, which exemplary favored fungal iron acquisition [7].While these studies partially solve the puzzle of IFN-I during systemic candidiasis, we have to be mindful that effects of IFN-I may differ between murine models and humans.Polymorphisms in IFN-I-related genes associate with an increased susceptibility to candidemia [8],