CNS-mediated fever after Adolescent Intermittent Ethanol

项目总结/摘要 酒精使用通常始于青春期早期，大约50-70%的15岁青少年已经报告饮酒 使用（世界卫生组织，2018）。人体和临床前研究表明，酒精会增加 对细菌和病毒感染的脆弱性（Szabo，2015），尽管青少年对不良反应的敏感性 酒精对免疫功能的影响尚不清楚。重要的是，神经免疫功能被严重改变， 然而，CNS介导的宿主防御过程的作用还没有被证实。 测定由广泛传播的新型冠状病毒SARS-CoV-2及其 COVID-19相关的疾病状态揭示了某些人口统计数据的独特脆弱性。虽然 COVID-19不利后果的最大脆弱性是年龄，越来越多的数据表明，男性患者 COVID-19表现出更严重的疾病严重程度、更高的并发症发生率和更高的死亡率。 关于病毒感染严重程度的差异以及对疫苗的反应， 个体我们认为，青春期滥用酒精的历史可能会为不良反应的发生奠定基础。 对病毒感染和疫苗接种的反应。我们之前的工作表明，青少年间歇性乙醇（AIE） 接触会使免疫功能产生持久的、性别特异性的变化。AIE暴露严重受损 当用细菌抗原体内攻击时循环淋巴细胞中的细胞因子表达 脂多糖（LPS），这是一种在雄性中稳健的作用，在雌性中完全不存在。类似的迹象 随后在海马体中观察到对轻度组织损伤的反应中抑制的细胞因子诱导， 与其他研究报告受损的发热反应时，青少年酒精暴露大鼠受到挑战， LPS，一种TLR 4依赖性炎症原。尽管这些发现表明AIE可能会产生一种 我们实验室最近的研究表明，酒精的影响 可能是病原体特异性的。具体来说，AIE加重了对聚肌胞的发热反应 (Poly I：C），一种用于模拟病毒感染的合成双链（ds）RNA，表明TLR 3- 依赖性炎症过程可能因青少年乙醇暴露而病理致敏。额外 数据表明，急性乙醇可能会干扰解热药物的疗效，引起人们对以下问题的关注： 青少年酗酒和改变反应的药物治疗感染以后的生活。 因此，本提案将检验青少年间歇性乙醇可能代表潜在和 以前未考虑的人口统计学变量，预测性别特异性的不利COVID-19结果， 生活考虑到SARS-CoV-2的快速进化和菌株变体的发展， Poly I：C模型提供了一个机会，可以建立适用于两种情况的宿主防御的一般特征 当前的全球流行病，以及未来的病毒爆发。

Project Summary/Abstract Alcohol use commonly starts in early adolescence with about 50–70% of 15 year-olds already reporting alcohol use (World Health Organization, 2018). Human and pre-clinical studies have shown that alcohol increases vulnerability to both bacterial and viral infections (Szabo, 2015), though adolescent sensitivity to the untoward effects of alcohol on immune function remain unclear. Importantly, neuroimmune function is severely altered by binge-like alcohol exposure in rodent models yet the role of CNS-mediated host defense processes has not been determined. The emergence of a global pandemic driven by widespread novel coronavirus SARS-CoV-2 and its associated disease state, COVID-19, has revealed unique vulnerabilities for certain demographics. Although the greatest vulnerability to adverse outcomes of COVID-19 is age, increasing data demonstrate that male patients with COVID-19 exhibit enhanced disease severity, higher complication rates, and higher mortality However, there remains great mystery regarding differences in viral infection severity, and the response to vaccine, across individuals. We propose that a history of alcohol misuse during adolescence may set the stage for adverse reactions to viral infection and vaccinations. Our prior work has shown that Adolescent Intermittent Ethanol (AIE) exposure produced long-lasting, sex-specific changes in immune function. AIE exposure substantially impaired cytokine expression in circulating lymphocytes when challenged in vivo with the bacterial antigen lipopolysaccharide (LPS), an effect that was robust in males, and completely absent in females. Similar signs of suppressed cytokine induction were subsequently observed in the hippocampus in response to mild tissue injury, with other studies reporting impaired fever responses when adolescent alcohol-exposed rats were challenged a week later with LPS, a TLR4-dependent inflammogen. Although these findings suggest that AIE may produce a global impairment in inflammatory processes, recent work from our lab suggests that the influence of alcohol may be pathogen-specific. Specifically, AIE exacerbated the febrile response to polyinosine-polycytidylic acid (Poly I:C), a synthetic double-stranded (ds)RNA that is used to model viral infections, suggesting that TLR3- dependent inflammatory processes may be pathologically sensitized by adolescent ethanol exposure. Additional data suggests that acute ethanol may interfere with the efficacy of anti-pyretic drugs, raising concerns regarding adolescent binge drinking and altered responding to pharmacotherapeutic treatments for infection later in life. Therefore, this proposal will test the hypothesis that Adolescent Intermittent Ethanol may represent a latent and previously unconsidered demographic variable that predicts sex-specific adverse COVID-19 outcomes later in life. Given the rapid evolution of SARS-CoV-2 and the development of strain variants, the more general viral model of Poly I:C affords the opportunity to establish general features of host defense that are applicable to both the current global pandemic, as well as viral outbreaks of the future.