{"doi":"10.1101/2024.12.24.630260","title":"IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2","abstract":"ABSTRACT Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 ( hACE2 ) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1β-driven NF-κB transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":492765,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9588,"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":1338975,"name":"Rachel E. Khan","orcid":"0000-0002-7393-204X","position":1,"is_corresponding":false},{"id":762385,"name":"Chris Mantsounga","orcid":"0000-0003-3494-9081","position":2,"is_corresponding":false},{"id":1174716,"name":"Sheila Sharma","orcid":"0000-0002-3796-2786","position":3,"is_corresponding":false},{"id":1338976,"name":"Julia Pierce","orcid":"0000-0003-2755-5543","position":4,"is_corresponding":false},{"id":1339463,"name":"Elizabeth Amelotte","orcid":null,"position":5,"is_corresponding":false},{"id":713411,"name":"Celia Butler","orcid":null,"position":6,"is_corresponding":false},{"id":650731,"name":"Andrew Farinha","orcid":null,"position":7,"is_corresponding":false},{"id":1338977,"name":"Crystal Parry","orcid":"0000-0002-6223-545X","position":8,"is_corresponding":false},{"id":434937,"name":"Olivya Caballero","orcid":null,"position":9,"is_corresponding":false},{"id":594498,"name":"J. A. Morrison","orcid":null,"position":10,"is_corresponding":false},{"id":1339464,"name":"Saketh Uppuluri","orcid":null,"position":11,"is_corresponding":false},{"id":1319981,"name":"Jeffrey J. Whyte","orcid":null,"position":12,"is_corresponding":false},{"id":456268,"name":"Joshua L. Kennedy","orcid":"0000-0002-1919-9051","position":13,"is_corresponding":false},{"id":1245287,"name":"Xuming Zhang","orcid":"0000-0002-0305-101X","position":14,"is_corresponding":false},{"id":1001755,"name":"Gaurav Choudhary","orcid":"0000-0003-3891-1910","position":15,"is_corresponding":false},{"id":525292,"name":"Rachel M. Olson","orcid":"0000-0002-6973-4331","position":16,"is_corresponding":false},{"id":82855,"name":"Alan Morrison","orcid":"0000-0002-2412-7669","position":17,"is_corresponding":false},{"id":712603,"name":"Cadence Lee","orcid":"0000-0002-5437-4273","position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":null,"created_at":"2026-07-19T02:08:56.210382Z","pmid":"39763770","pmcid":null,"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":[]}