COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase

Matthew J. Cummings (), Barnabas Bakamutumaho, Julius J. Lutwama, Nicholas Owor, Xiaoyu Che, Maider Astorkia, Thomas S. Postler, John Kayiwa, Jocelyn Kiconco, Moses Muwanga, Christopher Nsereko, Emmanuel Rwamutwe, Irene Nayiga, Stephen Kyebambe, Mercy Haumba, Henry Kyobe Bosa, Felix Ocom, Benjamin Watyaba, Bernard Kikaire, Alin S. Tomoiaga, Stevens Kisaka, Noah Kiwanuka, W. Ian Lipkin and Max R. O’Donnell
Additional contact information
Matthew J. Cummings: Columbia University
Barnabas Bakamutumaho: Uganda Virus Research Institute
Julius J. Lutwama: Uganda Virus Research Institute
Nicholas Owor: Uganda Virus Research Institute
Xiaoyu Che: Columbia University
Maider Astorkia: Columbia University
Thomas S. Postler: Columbia University
John Kayiwa: Uganda Virus Research Institute
Jocelyn Kiconco: Uganda Virus Research Institute
Moses Muwanga: Entebbe Regional Referral Hospital
Christopher Nsereko: Entebbe Regional Referral Hospital
Emmanuel Rwamutwe: Entebbe Regional Referral Hospital
Irene Nayiga: Entebbe Regional Referral Hospital
Stephen Kyebambe: Entebbe Regional Referral Hospital
Mercy Haumba: Uganda Virus Research Institute
Henry Kyobe Bosa: Uganda Peoples’ Defence Forces
Felix Ocom: Ministry of Health
Benjamin Watyaba: Uganda Virus Research Institute
Bernard Kikaire: Uganda Virus Research Institute
Alin S. Tomoiaga: Columbia University
Stevens Kisaka: Makerere University School of Public Health
Noah Kiwanuka: Makerere University School of Public Health
W. Ian Lipkin: Columbia University
Max R. O’Donnell: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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 profile the peripheral blood proteome and transcriptome to characterize 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 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 are generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scale 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 is 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 acute respiratory infections, we show that activation of epidermal and platelet-derived growth factor pathways are 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.

Date: 2024
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DOI: 10.1038/s41467-024-45204-3

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