IFN 受体 2 在曲霉菌肺部感染过程中调控 TNF-α 介导的损伤性炎症。

IF 3.6 3区 医学 Q2 IMMUNOLOGY Journal of immunology Pub Date : 2024-10-15 DOI:10.4049/jimmunol.2200686
Agnieszka Rynda-Apple, Jazmin Reyes Servin, Julianna Lenz, Julia Roemer, Evelyn E Benson, Monica N Hall, Kelly M Shepardson
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引用次数: 0

摘要

在感染严重流感或 SARS-CoV-2 的患者中,由烟曲霉菌引起的侵袭性肺曲霉病的发病率增加,这表明抗病毒免疫反应创造了一个有利于真菌感染的环境。我们最近的证据表明,异源二聚体 IFNAR1/2 受体的 I 型 IFN 受体 2 亚基(IFNAR2)的缺失通过调节损伤反应使肺部的免疫环境变得宽松。由于损伤与侵袭性肺曲霉病的不良预后有关,这表明 IFNAR2 可能与烟曲霉的易感性有关。在这项研究中,我们确定 IFNAR2 的缺失会导致肺部炎症、发病率和对烟曲霉菌挑战的损伤增加,而 IFNAR1 的缺失则不会。虽然Ifnar2-/-小鼠的发病率增加,但我们发现,与野生型和Ifnar1-/-小鼠相比,Ifnar2-/-小鼠清除了更多的分生孢子。然而,随着感染的发展,这种早期清除并不能阻止 Ifnar2-/-小鼠发生侵袭性疾病。重要的是,通过中和 TNF-α,在烟曲霉感染早期改变 Ifnar2-/-小鼠的炎症环境,我们能够将这些小鼠的发病率和真菌清除率降低到野生型水平。总之,我们的研究结果确立了 IFNAR2 在调节宿主对烟曲霉的损伤反应以及通过调节炎症促成烟曲霉容许环境中的独特作用。具体来说,我们的数据揭示了 IFNAR2 在调节烟曲霉感染期间 TNF-α 介导的损伤和发病率中的作用。
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IFN Receptor 2 Regulates TNF-α-Mediated Damaging Inflammation during Aspergillus Pulmonary Infection.

The increased incidence of invasive pulmonary aspergillosis, caused by Aspergillus fumigatus, occurring in patients infected with severe influenza or SARS-CoV-2, suggests that antiviral immune responses create an environment permissive to fungal infection. Our recent evidence suggests that absence of the type I IFN receptor 2 subunit (IFNAR2) of the heterodimeric IFNAR1/2 receptor is allowing for this permissive immune environment of the lung through regulation of damage responses. Because damage is associated with poor outcome to invasive pulmonary aspergillosis, this suggested that IFNAR2 may be involved in A. fumigatus susceptibility. In this study, we determined that absence of IFNAR2 resulted in increased inflammation, morbidity, and damage in the lungs in response to A. fumigatus challenge, whereas absence of IFNAR1 did not. Although the Ifnar2-/- mice had increased morbidity, we found that the Ifnar2-/- mice cleared more conidia compared with both wild-type and Ifnar1-/- mice. However, this early clearance did not prevent invasive disease from developing in the Ifnar2-/- mice as infection progressed. Importantly, by altering the inflamed environment of the Ifnar2-/- mice early during A. fumigatus infection, by neutralizing TNF-α, we were able to reduce the morbidity and fungal clearance in these mice back to wild-type levels. Together, our results establish a distinct role for IFNAR2 in regulating host damage responses to A. fumigatus and contributing to an A. fumigatus-permissive environment through regulation of inflammation. Specifically, our data reveal a role for IFNAR2 in regulating TNF-α-mediated damage and morbidity during A. fumigatus infection.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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