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

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.