CNS-mediated fever after Adolescent Intermittent Ethanol

青少年间歇性饮酒后中枢神经系统介导的发热

基本信息

批准号：
10607154
负责人：
Terrence Deak
金额：
$ 43.93万
依托单位：
STATE UNIVERSITY OF NY,BINGHAMTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10607154
关键词：
15 year old 2019-nCoV Abstinence Acute Adjuvant Adolescence Adolescent Adverse reactions Age Alcohol consumption Alcohols Bacterial Antigens Bacterial Infections Behavior Biological Models COVID-19 COVID-19 patient Chronic Complication Data Development Dexamethasone Disease Double-Stranded RNA Drug resistance Ethanol Evolution Exhibits FOS gene Female Fever Future Goals Hippocampus Host Defense Host Defense Mechanism Human Immune Immunity Impaired cognition Impairment Individual Infection Inflammatory LacZ Genes Life Lipopolysaccharides Liver Lymphocyte Mediating Modeling Neuroimmune Neuroimmunomodulation Neurons Organ Outcome Pathologic Peripheral Phagocytes Pharmaceutical Preparations Pharmacotherapy Phenotype Physiologic Thermoregulation Poly C Poly I-C Preoptic Areas Process Rat Transgene Rattus Recording of previous events Reporting Risk Rodent Model Role SARS-CoV-2 exposure ST5 gene Schedule Severities Severity of illness Sex Differences Signal Pathway Site Specificity Spleen TLR3 gene TLR4 gene Testing Therapeutic Vaccination Vaccines Variant Viral Virus Diseases Work World Health Organization adolescent alcohol exposure adolescent binge drinking adverse outcome alcohol effect alcohol exposure alcohol misuse alcohol use disorder animal model development antipyretic cytokine demographics early adolescence early alcohol use experimental study functional outcomes future outbreak immune function in vivo male mortality novel coronavirus pandemic disease pathogen preclinical study response sex tissue injury viral outbreak young adult

项目摘要

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.

项目概要/摘要饮酒通常从青春期早期开始，大约 50-70% 的 15 岁儿童已经报告饮酒使用（世界卫生组织，2018）人类和临床前研究表明酒精会增加。尽管青少年对不良事件敏感，但容易受到细菌和病毒感染（Szabo，2015）酒精对免疫功能的影响尚不清楚，重要的是，神经免疫功能受到严重影响。啮齿类动物模型中酗酒样的酒精暴露，但中枢神经系统介导的宿主防御过程的作用尚未得到证实由广泛传播的新型冠状病毒 SARS-CoV-2 及其引发的全球大流行的出现。相关疾病状态 COVID-19 揭示了某些人群的独特脆弱性。年龄是最容易受到 COVID-19 不良后果影响的因素，越来越多的数据表明，男性患者患有 COVID-19 的患者表现出疾病严重程度更高、并发症发生率更高、死亡率更高但是，关于病毒感染严重程度的差异以及对疫苗的反应，仍然存在很大的谜团我们认为，青春期滥用酒精的历史可能会为不良行为奠定基础。我们之前的研究表明，青少年间歇性乙醇（AIE）会导致病毒感染和疫苗接种的反应。接触 AIE 会导致免疫功能发生持久的、性别特异性的变化。当体内受到细菌抗原攻击时，循环淋巴细胞中细胞因子的表达脂多糖（LPS）的作用在男性中很强烈，而在女性中则完全不存在类似的迹象。随后在海马体中观察到细胞因子诱导受到抑制，以应对轻度组织损伤，其他研究报告称，当青少年暴露于酒精的老鼠受到刺激时，发烧反应受损一周后，用 LPS（一种 TLR4 依赖性炎症原）进行治疗，尽管这些发现表明 AIE 可能会产生一种 TLR4 依赖性炎症原。炎症过程的整体损害，我们实验室最近的工作表明，酒精的影响具体来说，AIE 加剧了对聚肌苷-聚胞苷酸的发热反应。 (Poly I:C)，一种合成的双链 (ds)RNA，用于模拟病毒感染，表明 TLR3- 依赖性炎症过程可能因青少年乙醇暴露而病理致敏。数据表明，急性乙醇可能会干扰退热药物的功效，引起人们的担忧青少年酗酒以及晚年感染药物治疗的反应改变。因此，本提案将检验以下假设：青少年间歇性乙醇可能代表一种潜在的、先前未考虑的人口变量，可预测稍后特定性别的 COVID-19 不良结果鉴于 SARS-CoV-2 的快速进化和毒株变种的发展，更普遍的病毒。 Poly I:C 模型提供了建立适用于两者的宿主防御一般特征的机会当前的全球大流行以及未来的病毒爆发。