{"doi":"10.1172/jci.insight.166012","title":"Cytokine storm–based mechanisms for extrapulmonary manifestations of SARS-CoV-2 infection","abstract":"Viral illnesses like SARS-CoV-2 have pathologic effects on nonrespiratory organs in the absence of direct viral infection. We injected mice with cocktails of rodent equivalents of human cytokine storms resulting from SARS-CoV-2/COVID-19 or rhinovirus common cold infection. At low doses, COVID-19 cocktails induced glomerular injury and albuminuria in zinc fingers and homeoboxes 2 (Zhx2) hypomorph and Zhx2+/+ mice to mimic COVID-19-related proteinuria. Common Cold cocktail induced albuminuria selectively in Zhx2 hypomorph mice to model relapse of minimal change disease, which improved after depletion of TNF-α, soluble IL-4Rα, or IL-6. The Zhx2 hypomorph state increased cell membrane to nuclear migration of podocyte ZHX proteins in vivo (both cocktails) and lowered phosphorylated STAT6 activation (COVID-19 cocktail) in vitro. At higher doses, COVID-19 cocktails induced acute heart injury, myocarditis, pericarditis, acute liver injury, acute kidney injury, and high mortality in Zhx2+/+ mice, whereas Zhx2 hypomorph mice were relatively protected, due in part to early, asynchronous activation of STAT5 and STAT6 pathways in these organs. Dual depletion of cytokine combinations of TNF-α with IL-2, IL-13, or IL-4 in Zhx2+/+ mice reduced multiorgan injury and eliminated mortality. Using genome sequencing and CRISPR/Cas9, an insertion upstream of ZHX2 was identified as a cause of the human ZHX2 hypomorph state.","journal":"JCI Insight","year":2023,"id":347652,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"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":1089526,"name":"Ranjan Das","orcid":"0000-0002-7951-4121","position":1,"is_corresponding":false},{"id":1089527,"name":"Joubert Banjop Kharlyngdoh","orcid":"0000-0001-5908-5115","position":2,"is_corresponding":false},{"id":498442,"name":"Eduardo Molina‐Jijón","orcid":null,"position":3,"is_corresponding":false},{"id":1090006,"name":"Hector Donoro Blazquez","orcid":null,"position":4,"is_corresponding":false},{"id":497532,"name":"Stéphanie Gambut","orcid":"0000-0002-0327-0992","position":5,"is_corresponding":false},{"id":936550,"name":"Michael Crowley","orcid":null,"position":6,"is_corresponding":false},{"id":254085,"name":"David K. Crossman","orcid":"0000-0002-0981-169X","position":7,"is_corresponding":false},{"id":1090007,"name":"Rasheed A Gbadagesin","orcid":null,"position":8,"is_corresponding":false},{"id":1090008,"name":"Sunveer S. Chugh","orcid":null,"position":9,"is_corresponding":false},{"id":1090009,"name":"Sunjeet S. Chugh","orcid":null,"position":10,"is_corresponding":false},{"id":497533,"name":"Carmen Ávila-Casado","orcid":"0000-0001-8319-811X","position":11,"is_corresponding":false},{"id":498443,"name":"Camille Macé","orcid":null,"position":12,"is_corresponding":false},{"id":498444,"name":"Lionel C. Clément","orcid":null,"position":13,"is_corresponding":false},{"id":1089528,"name":"Sumant S. Chugh","orcid":"0000-0002-1496-2804","position":14,"is_corresponding":false},{"id":1089525,"name":"Maria Del Nogal Avila","orcid":"0000-0003-3544-1423","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:12:01.859977Z","pmid":"37040185","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":[]}