{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T17:41:54Z","timestamp":1791481314671,"version":"4.3.4"},"reference-count":58,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Major Project of Guangzhou National Laboratory","award":["GZNL2024A01003"],"award-info":[{"award-number":["GZNL2024A01003"]}]},{"name":"Fund of the Key Laboratory of Tissue Microenvironment and Tumor of Chinese Academy of Sciences","award":["202002"],"award-info":[{"award-number":["202002"]}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2022MC072"],"award-info":[{"award-number":["ZR2022MC072"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Coronavirus Disease 2019 (COVID-19) and other lower respiratory tract diseases (LRTDs), including bacterial pneumonia and acute respiratory distress syndrome, share overlapping clinical features but arise from distinct pathophysiological mechanisms. The molecular signatures that distinguish these diseases remain insufficiently characterized in African populations, where genetic background, endemic infections, and environmental exposures may substantially shape immune responses. We integrated spatially resolved single-cell transcriptomic profiles from lung autopsy specimens of 30 Malawian patients, including 10 with COVID-19, 12 with other LRTDs, and 8 non-LRTD controls. In total, 61,391 cells representing 15 cell types and 36,602 gene expression features were analyzed. Using an integrated machine learning framework that combined nine feature-ranking algorithms with incremental feature selection, we identified potential molecular signatures that could discriminate among disease states within this cohort. The optimal classification models achieved weighted F1 scores greater than 0.94, demonstrating a robust capacity to differentiate COVID-19 from other LRTDs in our dataset. Notably, the macrophage-associated state in COVID-19 was dominated by an IFN-\u03b3 response with upregulation of CD163 and HLA-DQA2, contrasting sharply with the type I\/III interferon signature reported in European cohorts. In addition, we observed cell-type-specific COVID-19 signatures, including downregulation of CAV1 in AT1 cells, consistent with epithelial damage; dysregulation of SFTPC in AT2 cells, suggesting surfactant dysfunction; and upregulation of NFKBIA in neutrophils, indicating altered inflammatory regulation. Gene Ontology enrichment further revealed universal disruption of protein synthesis machinery, along with cell-type-specific alterations in immune activation, epithelial repair, and inflammatory signaling pathways.<\/jats:p>","DOI":"10.3390\/life16050771","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T10:01:30Z","timestamp":1777975290000},"page":"771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Machine Learning Identification of Cell-Type-Specific Molecular Signatures Distinguishing COVID-19 from Other Lower Respiratory Tract Diseases"],"prefix":"10.3390","volume":"16","author":[{"given":"Yusheng","family":"Bao","sequence":"first","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianchao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3068-1583","authenticated-orcid":false,"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Information Engineering, Shanghai Maritime University, Shanghai 201306, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyan","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Guangdong AIB Polytechnic College, Guangzhou 510507, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-9693","authenticated-orcid":false,"given":"Tao","family":"Huang","sequence":"additional","affiliation":[{"name":"Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"},{"name":"Department of Artificial Intelligence and Digital Health, CAS Engineering Laboratory for Nutrition, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-7979","authenticated-orcid":false,"given":"Yu-Dong","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s12985-021-01627-8","article-title":"Impact of COVID-19 pandemic on the prevalence of respiratory viruses in children with lower respiratory tract infections in china","volume":"18","author":"Liu","year":"2021","journal-title":"Virol. 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