Multimodal immune profiling to determine mechanisms of COVID-19 clinical trajectory in Uganda

项目摘要 COVID-19大流行是世纪以来最严重的全球健康危机。在高收入国家， 在过去18个月里，由于提供了 高质量的重症监护和免疫调节剂，如皮质类固醇和 白细胞介素-6拮抗剂。这些治疗药物的有效使用是由转化研究驱动的 将失调的免疫炎症反应确定为严重COVID-19的关键病理特征。 随着高收入国家在COVID-19预防方面取得进展，大流行负担已转移到中低收入国家， 收入国家，现在占与COVID-19相关的每日死亡率的40%以上。这一负担尤其 在撒哈拉以南非洲（SSA），COVID-19的反复激增已经压倒了脆弱的健康状况， 系统和病死率都是世界上最高的。虽然免疫学背景下， 由于艾滋病毒负担高和住院成人年龄相对较轻， 其他因素，对该地区严重COVID-19的免疫病理学知之甚少。通过 哥伦比亚大学和乌干达病毒研究所建立了合作关系， 在乌干达前瞻性地招募了400多名患有COVID-19的患者，涵盖了疾病的整个严重程度。 利用这一独特的队列，本研究的总体目标是确定COVID-19的生物学机制 临床严重程度在乌干达使用多模式方法宿主免疫谱。康贝特人将以 中国成年COVID-19患者可溶性免疫生物标志物与重症危重症的关系 乌干达使用最小偏差机器学习方法（目标1）;识别生物途径和免疫细胞 使用全血RNA测序数据的乌干达严重危急COVID-19相关图谱（目标2）; 并整合生物标志物和RNA测序数据，以确定HIV感染对先天和 COVID-19中的适应性免疫反应（Aim 3）。直接针对NIH COVID-19研究重点，我们的 研究结果将（i）促进对免疫病理学机制的基本理解， 在撒哈拉以南非洲和其他脆弱的高艾滋病毒负担环境中，严重的COVID-19，以及（ii）对COVID-19患者进行分类， 19例患者分为生物学驱动和具有临床意义的亚组， 可以更精确地研究和开发。

PROJECT SUMMARY The COVID-19 pandemic is the greatest global health crisis in over a century. In high-income countries (HICs), outcomes for patients with severe COVID-19 have improved markedly over the past 18 months due to provision of high-quality critical care and administration of immunomodulatory agents such as corticosteroids and interleukin-6 antagonists. Effective use of these therapeutic agents was driven by translational investigations that identified dysregulated immune-inflammatory responses as key pathological features in severe COVID-19. Following advances in COVID-19 prevention in HICs, the pandemic burden has shifted to low- and middle- income countries, which now account for >40% of daily mortality related to COVID-19. This burden is particularly severe in sub-Saharan Africa (SSA), where recurrent COVID-19 surges have overwhelmed fragile health systems and case fatality rates are among the highest in the world. Although the immunological context of COVID-19 in SSA is unique due to high HIV burden and the relatively young age of hospitalized adults, among other factors, little is known about the immunopathology of severe COVID-19 in the region. Through an established collaboration between Columbia University and Uganda Virus Research Institute, we have prospectively enrolled over 400 patients with COVID-19 in Uganda across the entire spectrum of illness severity. Leveraging this unique cohort, the overall goal of this study is to determine biological mechanisms of COVID-19 clinical severity in Uganda using a multimodal approach to host immune profiling. We will determine the relationship between soluble immune biomarkers and severe-critical illness among adults with COVID-19 in Uganda using minimally-biased machine learning methods (Aim 1); identify biological pathways and immune cell profiles associated with severe-critical COVID-19 in Uganda using whole-blood RNA sequencing data (Aim 2); and integrate biomarker and RNA-sequencing data to determine the effect of HIV-infection on innate and adaptive immune responses in COVID-19 (Aim 3). Directly addressing NIH COVID-19 research priorities, our results will (i) advance fundamental understanding of the immunopathological mechanisms driving the burden of severe COVID-19 in SSA and other vulnerable, high HIV burden settings, and (ii) classify patients with COVID- 19 into biologically-driven and clinically-meaningful subgroups for whom locally-responsive treatment strategies can be more precisely investigated and developed.