{"doi":"10.1084/jem.20232192","title":"Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung","abstract":"Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in \"infection pseudotime\" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.","journal":"The Journal of Experimental Medicine","year":2024,"id":418796,"datarank":0.5775221402565088,"base_score":3.8501476017100584,"endowment":3.8501476017100584,"self_citation_contribution":0.5775221402565088,"citation_network_contribution":0.0,"self_endowment_contribution":0.5775221402565088,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":46,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":12147,"name":"Kyle J. 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Martínez-Colón","orcid":"0000-0001-6792-8004","position":9,"is_corresponding":false},{"id":241151,"name":"Aimee Beck","orcid":"0000-0003-4762-6417","position":10,"is_corresponding":false},{"id":284654,"name":"Daniel Dan Liu","orcid":"0000-0003-0100-5973","position":11,"is_corresponding":false},{"id":52009,"name":"Aaron J. Wilk","orcid":"0000-0003-1430-5852","position":12,"is_corresponding":false},{"id":74001,"name":"Maurizio Morri","orcid":"0009-0003-5577-4265","position":13,"is_corresponding":false},{"id":1035688,"name":"Winston Trope","orcid":"0000-0003-0927-0405","position":14,"is_corresponding":false},{"id":558809,"name":"Rob Bierman","orcid":"0000-0001-8513-7425","position":15,"is_corresponding":false},{"id":29969,"name":"Irving L. Weissman","orcid":"0000-0002-9077-7467","position":16,"is_corresponding":false},{"id":4863,"name":"Joseph B. Shrager","orcid":"0000-0003-0859-0589","position":17,"is_corresponding":false},{"id":11049,"name":"Stephen R. Quake","orcid":"0000-0002-1613-0809","position":18,"is_corresponding":false},{"id":74115,"name":"Christin S. Kuo","orcid":"0000-0001-9227-5578","position":19,"is_corresponding":false},{"id":558818,"name":"Julia Salzman","orcid":"0000-0001-7630-3436","position":20,"is_corresponding":false},{"id":270551,"name":"W. E. Moerner","orcid":"0000-0002-2830-209X","position":21,"is_corresponding":false},{"id":226842,"name":"Peter S. Kim","orcid":"0000-0001-6503-4541","position":22,"is_corresponding":false},{"id":52017,"name":"Catherine A. Blish","orcid":"0000-0001-6946-7627","position":23,"is_corresponding":false},{"id":104362,"name":"Mark A. 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