Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
Biogen, Cambridge, Massachusetts, USA.
mBio. 2018 Apr 17;9(2):e00365-18. doi: 10.1128/mBio.00365-18.
A 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 disseminated Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with , 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 invasive appears 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, p67 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 to infection. IFN-β treatment promoted pathology and death from infection. We provide evidence that IFIT2 increases the pathological effects of invasive and that administration of IFN-β has deleterious effects during infection. The attributable mortality associated with systemic infections 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 systemic infection. This result infers a harmful effect of IFN during infection 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 to , and they suggest that IFN therapies present a risk factor for disseminated candidiasis.
对感染产生平衡的免疫反应对于防止不受调节或过度活跃的宿主防御引起的病理和组织损伤至关重要。干扰素（IFN）是感染固有防御的关键介质，在这项研究中，我们评估了由 I 型 IFN 诱导的特定基因编码的 IFIT2 在播散性侵袭性念珠菌病（一种频繁发生在免疫抑制或外科医疗干预期间的挑战，是导致高死亡率的常见罪魁祸首。当 IFIT2 敲除小鼠全身感染时，与野生型小鼠相比，它们的存活率提高，真菌负担减少。IFIT2 增加侵袭性的病理效应的机制之一似乎是抑制 NADPH 氧化酶的激活。IFIT2 的缺失增加了白细胞产生的活性氧，我们证明 IFIT2 是 NADPH 氧化酶关键调节亚基 p67 的结合伴侣。由于 IFN 的给药已被用于治疗病毒感染、癌症和多发性硬化症，我们在感染之前评估了 IFN-β 对小鼠的给药。IFN-β 治疗促进了感染的发病和死亡。我们提供的证据表明，IFIT2 增加了侵袭性的病理效应，并且 IFN-β 的给药在感染期间具有有害影响。在医疗保健环境中，系统性感染与相关的死亡率很高，估计超过 40%。这种危及生命的疾病在免疫系统较弱的患者中很常见，无论是由于疾病还是由于治疗引起的。I 型干扰素（IFN）是先天防御反应的细胞因子，用作特定癌症、病毒感染和多发性硬化症治疗中的免疫调节剂。在这项研究中，我们使用小鼠模型表明，缺失特定的 IFN 刺激基因编码的 IFIT2 可提高全身性感染后的存活率。这一结果推断出 IFN 在感染期间的有害作用，并得到我们的发现的支持，即侵袭性感染前给予 IFN-β 可促进致命的病理。这些发现有助于我们了解对的先天免疫反应，并表明 IFN 治疗为播散性念珠菌病带来了风险因素。
