Little is known about the pathobiology of SARS-CoV-2 infection in sub-Saharan Africa, where severe COVID-19 fatality rates are among the highest in the world and the immunological landscape is unique. In a prospective cohort study of 306 adults encompassing the entire clinical spectrum of SARS-CoV-2 infection in Uganda, we integrated profiling of the peripheral blood proteome and transcriptome to dissect the immunopathology of COVID-19 across multiple phases of the pandemic. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and extensive redox imbalance define core biological signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures were generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scaled with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants. Independent of clinical severity, Delta phase COVID-19 was distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T-cell depletion, and impaired host protein synthesis. Combining these analyses with a contemporary Ugandan cohort of adults hospitalized with influenza and other severe respiratory infections, we found activation of epidermal and platelet-derived growth factor pathways to be distinct features of COVID-19, deepening translational understanding of mechanisms potentially underlying SARS-CoV-2-associated pulmonary fibrosis. Collectively, our findings provide biological rationale for use of broad and targeted immunotherapies for severe COVID-19 in sub-Saharan Africa, illustrate the relevance of local viral and host factors to SARS-CoV-2 immunopathology, and highlight underemphasized yet therapeutically exploitable immune pathways driving COVID-19 severity.

In cryopreserved serum samples from adults with SARS-CoV-2 infection and influenza and non-influenza severe acute respiratory infection in Uganda, concentrations of 48 soluble immune mediators were quantified using the Human Cytokine/Chemokine 48-Plex Discovery Assay Array (Eve Technologies, Calgary, Alberta, Canada; MilliporeSigma, Burlington, MA, USA). Samples from different pathogen and clinical severity groups were randomized across sample plates and analyzed by technicians blinded to pathogen and severity status. Soluble mediators were quantitated in duplicate with the mean concentration used for analysis presented. Values below the lower limit of assay quantification were replaced with the lowest value that could be reliably quantified for that particular mediator. Values above the upper limit of quantification were replaced with the highest standard curve value for each particular mediator.