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Nat Commun
. 2024 Feb 17;15(1):1475.
doi: 10.1038/s41467-024-45204-3. COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Matthew J Cummings 1 2 , Barnabas Bakamutumaho 3 , Julius J Lutwama 3 , Nicholas Owor 3 , Xiaoyu Che 4 5 , Maider Astorkia 4 , Thomas S Postler 6 , John Kayiwa 3 , Jocelyn Kiconco 3 , Moses Muwanga 7 , Christopher Nsereko 7 , Emmanuel Rwamutwe 7 , Irene Nayiga 7 , Stephen Kyebambe 7 , Mercy Haumba 3 , Henry Kyobe Bosa 8 9 , Felix Ocom 9 , Benjamin Watyaba 10 , Bernard Kikaire 10 11 , Alin S Tomoiaga 12 13 , Stevens Kisaka 14 15 , Noah Kiwanuka 14 , W Ian Lipkin 4 16 17 , Max R O'Donnell 12 4 17 ; Collaboration for Clinical and Laboratory Characterization of COVID-19 in Uganda
Collaborators, Affiliations
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.
. 2024 Feb 17;15(1):1475.
doi: 10.1038/s41467-024-45204-3. COVID-19 immune signatures in Uganda persist in HIV co-infection and diverge by pandemic phase
Matthew J Cummings 1 2 , Barnabas Bakamutumaho 3 , Julius J Lutwama 3 , Nicholas Owor 3 , Xiaoyu Che 4 5 , Maider Astorkia 4 , Thomas S Postler 6 , John Kayiwa 3 , Jocelyn Kiconco 3 , Moses Muwanga 7 , Christopher Nsereko 7 , Emmanuel Rwamutwe 7 , Irene Nayiga 7 , Stephen Kyebambe 7 , Mercy Haumba 3 , Henry Kyobe Bosa 8 9 , Felix Ocom 9 , Benjamin Watyaba 10 , Bernard Kikaire 10 11 , Alin S Tomoiaga 12 13 , Stevens Kisaka 14 15 , Noah Kiwanuka 14 , W Ian Lipkin 4 16 17 , Max R O'Donnell 12 4 17 ; Collaboration for Clinical and Laboratory Characterization of COVID-19 in Uganda
Collaborators, Affiliations
- PMID: 38368384
- PMCID: PMC10874401
- DOI: 10.1038/s41467-024-45204-3
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.