biostudies-literatureNyirenda JFIC NIH HHSMedical Research CouncilGates FoundationWellcome Trust3765-3777https://www.ebi.ac.uk/biostudies/studies/S-EPMC11645280biostudies-literatureUnknown30(12)Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTDs), including coronavirus disease 2019 (COVID-19), but there are minimal data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. In this study, we used histology and high-dimensional imaging to characterize fatal lung disease in Malawian adults with (n = 9) and without (n = 7) COVID-19, and we generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved COVID-19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in US, European and Asian cohorts, by type I/III interferon (IFN) responses, particularly in blNature medicineSpatially resolved single-cell atlas unveils a distinct cellular signature of fatal lung COVID-19 in a Malawian population.PMC11645280MR/W018802/1K01 TW010853MR/V025856/1MR/R010099/1INV-018138104111Banda POtto TDMvaya LSuwedi LMakwinja CPhiri CHerder VHilton ONamalima TRKhoswe SNyirenda JSilva Filho JDPhiri JJohnson CNyasulu WMelo GCMonteiro WMDenno DMKamiza SBHardy OMMarti MPalmarini MVoskuijl WBarnes KGZiwoya FMorton BFerreira LCLChasweka DNgulube TDos Reis MFMoxon CATrindade Maranhao Costa FMcGuinness DEneya CLawrence SNyirenda DJambo KSiwombo MAttipa CNdovi CIlia Gde Lacerda MVGTembo AMakwangwala KKumwenda BHaley MCouper KfalseSpatially resolved single-cell atlas unveils a distinct cellular signature of fatal lung COVID-19 in a Malawian population.Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTDs), including coronavirus disease 2019 (COVID-19), but there are minimal data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. In this study, we used histology and high-dimensional imaging to characterize fatal lung disease in Malawian adults with (n = 9) and without (n = 7) COVID-19, and we generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved COVID-19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in US, European and Asian cohorts, by type I/III interferon (IFN) responses, particularly in bl2024-01-01T00:00:00Z2024 Dec2026-06-02T10:45:50.87Z2025-04-04T01:54:57.036ZS-EPMC116452803956771810.1038/s41591-024-03354-3