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

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.