Multimodal Immune Profiling to Determine Mechanisms of COVID-19 Clinical Trajectory in Uganda

We conducted a prospective cohort study of adults (RESERVE-U-C19) admitted to Entebbe Regional Referral Hospital (ERRH), a national COVID-19 referral center, across three viral variant-driven phases of the pandemic in Uganda. In this cohort, which reflects the entire spectrum of SARS-CoV-2 infection, we integrated clinical data with serum proteomics (N=306) and whole-blood transcriptomics (N=100) to determine a range of host responses associated with COVID-19 severity, SARS-CoV-2/HIV co-infection, and circulating viral variants. 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 metabolic 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, with Delta phase COVID-19 distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T-cell depletion, impaired host protein synthesis, and upregulation of viral cell entry and trafficking pathways. Data from this study available through dbGaP include raw RNA-Seq data from whole-blood of adult participants (N=100). ]]>
Patients were prospectively enrolled in the RESERVE-U-C19 study if they were: Admitted to ERRH during the study periodWere ≥ 5 years of ageHad laboratory-confirmed SARS-CoV-2 infection by polymerase-chain-reaction (PCR) testing of a naso/oropharyngeal swab sample at a Ministry of Health-accredited laboratory, and Were able to provide written informed consent or had a surrogate available to do so. Pregnant females were excluded. Although patients 5-17 years of age were enrolled in the RESERVE-U-C19 cohort, given variations in normal physiologic parameters, COVID-19 severity criteria, and SARS-CoV-2 host responses across age groups, we included only adults (age ≥ 18 years) for this study's analyses. ]]>