{"doi":"10.1371/journal.ppat.1010479","title":"CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses","abstract":"Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.","journal":"PLoS Pathogens","year":2022,"id":238733,"datarank":0.5983476069846413,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.0,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":232293,"name":"Judith Olejnik","orcid":"0000-0002-1748-7981","position":1,"is_corresponding":false},{"id":551221,"name":"Jacob Berrigan","orcid":null,"position":2,"is_corresponding":false},{"id":863920,"name":"Annuurun Nisa","orcid":null,"position":3,"is_corresponding":false},{"id":232294,"name":"Ellen L. Suder","orcid":"0000-0001-9466-9204","position":4,"is_corresponding":false},{"id":331884,"name":"Hisashi Akiyama","orcid":"0000-0001-9228-0465","position":5,"is_corresponding":false},{"id":863921,"name":"Maohua Lei","orcid":null,"position":6,"is_corresponding":false},{"id":863190,"name":"Sita Ramaswamy","orcid":"0000-0003-1479-6954","position":7,"is_corresponding":false},{"id":657487,"name":"Sanjay Tyagi","orcid":"0000-0001-7303-5827","position":8,"is_corresponding":false},{"id":863922,"name":"Yuri Bushkin","orcid":null,"position":9,"is_corresponding":false},{"id":232302,"name":"Elke Mühlberger","orcid":"0000-0003-3547-9376","position":10,"is_corresponding":false},{"id":69465,"name":"Suryaram Gummuluru","orcid":"0000-0002-8606-8481","position":11,"is_corresponding":false},{"id":808538,"name":"Sallieu Jalloh","orcid":null,"position":0,"is_corresponding":true}],"reference_count":114,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:22:31.741535Z","pmid":"36279285","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":[]}