{"doi":"10.1165/rcmb.2023-0077oc","title":"Meta-Analysis of COVID-19 BAL Single-Cell RNA Sequencing Reveals Alveolar Epithelial Transitions and Unique Alveolar Epithelial Cell Fates","abstract":"Abstract Single-cell RNA sequencing (scRNA-seq) of BAL cells has provided insights into coronavirus disease (COVID-19). However, reports have been limited by small patient cohorts. We performed a meta-analysis of BAL scRNA-seq data from healthy control subjects (n = 13) and patients with COVID-19 (n = 20), sourced from six independent studies (167,280 high-quality cells in total). Consistent with the source reports, increases in infiltrating leukocyte subtypes were noted, several with type I IFN signatures and unique gene expression signatures associated with transcellular chemokine signaling. Noting dramatic reductions of inferred NKX2-1 and NR4A1 activity in alveolar epithelial type II (AT-II) cells, we modeled pseudotemporal AT-II–to–AT-I progression. This revealed changes in inferred AT-II cell metabolic activity, increased transitional cells, and a previously undescribed AT-I state. This cell state was conspicuously marked by the induction of genes of the epidermal differentiation complex, including the cornified envelope protein SPRR3 (small proline-rich protein 3), upregulation of multiple KRT (keratin) genes, inferred mitochondrial dysfunction, and cell death signatures including apoptosis and ferroptosis. Immunohistochemistry of lungs from patients with COVID-19 confirmed upregulation and colocalization of KRT13 and SPRR3 in the distal airspaces. Forced overexpression of SPRR3 in human alveolar epithelial cells ex vivo did not activate caspase-3 or upregulate KRT13, suggesting that SPRR3 marks an AT-I cornification program in COVID-19 but is not sufficient for phenotypic changes.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2023,"id":364288,"datarank":0.42523607249257994,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.11331984124060453,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.11331984124060453,"corpus_percentile":56.26208710450994,"corpus_rank":5655,"citation_count":7,"citer_count":7,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6836,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":71961,"name":"Aleksandra Tata","orcid":"0000-0003-3270-0485","position":1,"is_corresponding":false},{"id":306545,"name":"Julie M. Meacham","orcid":null,"position":2,"is_corresponding":false},{"id":542113,"name":"Frank Day","orcid":null,"position":3,"is_corresponding":false},{"id":1119493,"name":"David Thrower","orcid":null,"position":4,"is_corresponding":false},{"id":12178,"name":"Purushothama Rao Tata","orcid":"0000-0003-4837-0337","position":5,"is_corresponding":false},{"id":270412,"name":"Michael B. Fessler","orcid":"0000-0002-8262-8613","position":6,"is_corresponding":false},{"id":627655,"name":"Peer W. F. Karmaus","orcid":"0000-0002-2651-0899","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:14:36.728255Z","pmid":"37523502","pmcid":"PMC10704119","fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}