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

项目摘要 SARS-CoV-2/新冠肺炎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 被称为世代交换(GenX)的干预计划可以增强一种关键的生物介质 这一弱势人群的抗病毒耐药性(I型干扰素反应)。我们之前的研究 已经确定了一种由压力触发的基因组程序，称为“保守的转录反应 逆境“(CTRA)。CTRA被战斗或逃跑的应激反应激活，并使免疫细胞 降低抗病毒活性和刺激炎症，这两者在COVID的背景下都是有害的- 19.我们之前对面对逆境时的生物韧性的研究也发现，CTRA是 幸福感水平较高的人的幸福感会降低，包括生活目标、再生力、 以及亲社会的参与。在本研究中，我们将进行随机对照干预 试验(n=160)，以测试一项促进幸福的代际指导计划是否 新一代干扰素(GenX)可增强I型干扰素应答，降低高炎性反应 生活在社会经济弱势城市的老年非裔美国女性和男性的反应 社区。我们的假设是，GenX将：1)增加I型干扰素抗病毒反应；2) 减少高炎症倾向，以及3)降低临床呼吸道病毒感染率和症状 疾病(新城疫、流感和感冒)。目的：确定猪抗病毒耐药的生物学机制。 对于这一特定人群，我们还将分析特定的抗病毒细胞类型(例如，浆细胞样树突状细胞， 单核细胞)和基因调控过程(例如，转录因子活性和单细胞基因 表达)。这些衡量标准将被用来确定哪些生物因素在 保护年长的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、既往慢性 疾病、体力活动不足、睡眠不佳、社交孤立/孤独)，以及6)哪些生物因素 受到GenX的影响。最后，我们检验了这样一种假设，即GenX对两位女性都有积极影响 男性，教育水平低或高，以及背景低或高的人 风险因素(例如，超重/肥胖、慢性病、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广泛的生物行为干预计划 可扩展的，涉及已定义的抗病毒耐药性的生物机制，并利用社会支持和 减轻年龄和社会劣势对寄主的不利影响的幸福感 易患冠状病毒感染的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.