Enhancing Innate Anti-Viral Resistance Through A Community-Based Intervention

项目摘要 SARS-CoV-2/COVID-19大流行对老年人的社会经济造成了不成比例的影响 弱势的非裔美国人这项研究将测试最近开发的基于社区的 被称为Generation Exchange（GenX）干预计划可以增强 抗病毒耐药（I型干扰素反应）在这个弱势群体。我们之前的研究 已经确定了一个压力触发的基因组程序，称为“保守的转录反应， 逆境”（CTRA）。CTRA由战斗或逃跑应激反应激活，并导致免疫细胞 降低抗病毒活性并刺激炎症，这两者在COVID-1背景下都是有害的。 19.我们之前对逆境中生物复原力的研究也发现，CTRA是 在幸福感高的人群中减少，幸福感包括生活的目的，繁殖力， 和亲社会的参与。在本研究中，我们将进行随机对照干预 试验（n=160），以测试是否eudaimonia促进代际指导计划，称为 Generation Xchange（GenX）可以增强I型干扰素应答并减少炎症反应。 生活在社会经济弱势城市的老年非裔美国妇女和男子的反应 社区我们的假设是，GenX将，1）增加I型干扰素抗病毒反应，2） 减少高度炎症偏倚，和3）降低临床呼吸道病毒感染率和症状性 疾病（COVID，流感和感冒）。为了明确抗病毒药物耐药的生物学机制， 这个特定的群体，我们还将分析特定的抗病毒细胞类型（例如，浆细胞样树突细胞， 单核细胞）和基因调节过程（例如，转录因子活性与单细胞基因 表达式）。这些措施将被用来确定4）哪些生物因素是最重要的， 保护老年非裔美国人免受呼吸道病毒感染，5）这些生物风险因素是如何 与其他已确定的呼吸道病毒风险因素有关（例如，超重/肥胖，既存慢性 疾病，低体力活动，睡眠不佳，社会隔离/孤独），以及6）哪些生物因素是 受GenX影响最后，我们检验了GenX对两名女性都有积极影响的假设 对于那些低或高教育水平的人，以及对于那些低或高背景的人， 风险因素（例如，超重/肥胖、慢性疾病、低体力活动、社交孤立/孤独）。 我们的首要目标是建立一个以社区为基础的生物行为干预计划， 可扩展性，涉及明确的抗病毒耐药生物学机制，并利用社会支持和 幸福感，以减轻年龄和社会不利因素对宿主的不利影响 新冠肺炎易感老年非裔美国人对呼吸道病毒感染的抵抗力。

Project Summary The SARS-CoV-2/COVID-19 pandemic has disproportionately impacted older socioeconomically disadvantaged African-Americans. This research will test whether a recently developed community-based intervention program known as Generation Exchange (GenX) can enhance a key biological mediator of antiviral resistance (Type I interferon response) in this disadvantaged population. Our previous research has identified a stress-triggered genomic program known as the “Conserved Transcriptional Response to Adversity” (CTRA). The CTRA is activated by fight-or-flight stress responses and causes immune cells to reduce antiviral activity and stimulate inflammation, both of which are detrimental in the context of COVID- 19. Our previous research on biological resilience in the face of adversity has also found that the CTRA is reduced in people with high levels of eudaimonic well-being, which includes purpose in life, generativity, and pro-social engagement. In the present study, we will conduct a randomized controlled intervention trial (n=160) to test whether a eudaimonia-promoting intergenerational mentoring program known as Generation Xchange (GenX) can enhance Type I interferon responses and reduce hyper-inflammatory responses in older African-American women and men living in a socioeconomically disadvantaged urban community. Our hypotheses are that GenX will, 1) increase Type I interferon antiviral responses, 2) reduce hyper-inflammatory bias, and 3) reduce rates of clinical respiratory virus infection and symptomatic disease (COVID, influenzas, and colds). To identify the biological mechanisms of antiviral resistance in this specific population, we will also analyze specific antiviral cell types (e.g., plasmacytoid dendritic cells, monocytes) and gene regulatory processes (e.g., transcription factor activity and single-cell gene expression). These measures will be used to determine 4) which biological factors are most important in protecting older African-Americans from respiratory virus infection, 5) how those biological risk factors are linked to other established respiratory virus risk factors (e.g., overweight/obesity, pre-existing chronic disease, low physical activity, poor sleep, social isolation/loneliness), and 6) which biological factors are impacted by GenX. Finally, we test the hypothesis that 7) GenX will show positive effects for both women and men, for those with low or high education level, and for those with low or high levels of background risk factors (e.g., overweight/obesity, chronic disease, low physical activity, social isolation/loneliness). Our overarching goal is to establish a community-based biobehavioral intervention program that is broadly scalable, involves defined biological mechanisms of antiviral resistance, and leverages social support and eudaimonic well-being to mitigate the detrimental effects of age and social disadvantage on host resistance to respiratory virus infection among COVID-vulnerable older African-Americans.