Huckestein Brydie R, Antos Danielle, Manni Michelle L, Zeng Kelly, Miller Leigh M, Parenteau Kristen L, Gelhaus Stacy L, Mullett Steven J, Shoemaker Jason E, Alcorn John F
Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Aug 1;327(2):L189-L202. doi: 10.1152/ajplung.00407.2023. Epub 2024 May 29.
Children are susceptible to influenza infections and can experience severe disease presentation due to a lack of or limited pre-existing immunity. Despite the disproportionate impact influenza has on this population, there is a lack of focus on pediatric influenza research, particularly when it comes to identifying the pathogenesis of long-term outcomes that persist beyond the point of viral clearance. In this study, juvenile outbred male and female mice were infected with influenza and analyzed following viral clearance to determine how sex impacts the persistent inflammatory responses to influenza. It was found that females maintained a broader cytokine response in the lung following clearance of influenza, with innate, type I and type II cytokine signatures in almost all mice. Males, on the other hand, had higher levels of IL-6 and other macrophage-related cytokines, but no evidence of a type I or type II response. The immune landscape was similar in the lungs between males and females postinfection, but males had a higher regulatory T cell to T1 ratio compared with female mice. Cytokine production positively correlated with the frequency of T1 cells and exudate macrophages, as well as the number of cells in the bronchoalveolar lavage fluid. Furthermore, female lungs were enriched for metabolites involved in the glycolytic pathway, suggesting glycolysis is higher in female lungs compared with males after viral clearance. These data suggest juvenile female mice have persistent and excessive lung inflammation beyond the point of viral clearance, whereas juvenile males had a more immunosuppressive phenotype. This study identifies sex-based differences in persistent lung inflammation following influenza infection in an outbred, juvenile animal model of pediatric infection. These findings indicate the importance of considering sex and age as variable in infectious disease research.
儿童易感染流感，由于缺乏或仅有有限的既往免疫力，他们可能会出现严重的疾病表现。尽管流感对这一人群的影响不成比例，但儿科流感研究仍未受到足够关注，尤其是在确定病毒清除后持续存在的长期后果的发病机制方面。在本研究中，将幼年远交系雄性和雌性小鼠感染流感，并在病毒清除后进行分析，以确定性别如何影响对流感的持续炎症反应。结果发现，雌性小鼠在流感清除后肺部维持更广泛的细胞因子反应，几乎所有小鼠都有先天性、I型和II型细胞因子特征。另一方面，雄性小鼠的IL-6和其他与巨噬细胞相关的细胞因子水平较高，但没有I型或II型反应的证据。感染后雄性和雌性小鼠肺部的免疫格局相似，但与雌性小鼠相比，雄性小鼠的调节性T细胞与T1细胞的比例更高。细胞因子的产生与T1细胞和渗出巨噬细胞的频率以及支气管肺泡灌洗液中的细胞数量呈正相关。此外，雌性小鼠肺部富含参与糖酵解途径的代谢物，这表明病毒清除后雌性小鼠肺部的糖酵解水平高于雄性。这些数据表明，幼年雌性小鼠在病毒清除后肺部存在持续且过度的炎症，而幼年雄性小鼠则具有更具免疫抑制性的表型。本研究确定了在儿科感染的远交、幼年动物模型中，流感感染后持续性肺部炎症存在基于性别的差异。这些发现表明在传染病研究中考虑性别和年龄作为变量的重要性。
