ABSTRACTA balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminatedCandida albicans. Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, andC. albicansis a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically withC. albicans, they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasiveC. albicansappears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67phox. Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior toC. albicansinfection. IFN-β treatment promoted pathology and death fromC. albicansinfection. We provide evidence that IFIT2 increases the pathological effects of invasiveC. albicansand that administration of IFN-β has deleterious effects during infection.IMPORTANCEThe attributable mortality associated with systemicC. albicansinfections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemicC. albicansinfection. This result infers a harmful effect of IFN duringC. albicansinfection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response toC. albicans, and they suggest that IFN therapies present a risk factor for disseminated candidiasis.
Tolerization of a Type I Allergic Immune Response through Transplantation of Genetically Modified Hematopoietic Stem Cells