Multimodal immune profiling of SARS-CoV-2 in Uganda – soluble immune mediators

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.