{"doi":"10.1016/j.bbadis.2024.167322","title":"Upregulation of inflammatory genes and pathways links obesity to severe COVID-19","abstract":"Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which 2-3-month-old K18-hACE2 (K18) mice were fed a western high-fat diet (WD) or normal chow (NC) over 3 months before intranasal infection with a sublethal dose of SARS-CoV2 WA1 (a strain ancestral to the Wuhan variant). After infection, the WD-fed K18 mice lost significantly more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNA-seq analysis of lungs and adipose tissue revealed a diverse landscape of various immune cells, inflammatory markers, and pathways upregulated in the infected WD-fed K18 mice when compared with the infected NC-fed control mice. The transcript levels of IL-6, an important marker of COVID-19 disease severity, were upregulated in the lung at 6-9 days post-infection in the WD-fed mice when compared to NC-fed mice. Transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients found that the obese patients had an increase in the expression of genes and the activation of pathways associated with inflammation as compared to normal-weight patients (n = 2). The K18 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype. These results also indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 WA1 infection in the K18 mouse model would be a suitable model for dissecting the cellular and molecular mechanisms underlying pathogenesis.","journal":"Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease","year":2024,"id":438610,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"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":704987,"name":"Calder Ellsworth","orcid":"0000-0001-7111-525X","position":1,"is_corresponding":false},{"id":923776,"name":"Mst Shamima Khatun","orcid":"0009-0004-3889-0720","position":2,"is_corresponding":false},{"id":633099,"name":"Chenxiao Wang","orcid":"0000-0002-4324-0042","position":3,"is_corresponding":false},{"id":1248760,"name":"Zheng Chen","orcid":"0000-0002-0261-8061","position":4,"is_corresponding":false},{"id":1221782,"name":"Shumei Liu","orcid":"0000-0001-5262-0015","position":5,"is_corresponding":false},{"id":259611,"name":"Cecily C. 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Blair","orcid":"0000-0001-9616-9414","position":15,"is_corresponding":false},{"id":246970,"name":"Jay K. Kolls","orcid":"0000-0001-5151-6304","position":16,"is_corresponding":false},{"id":104951,"name":"Franck Mauvais‐Jarvis","orcid":"0000-0002-0874-0754","position":17,"is_corresponding":false},{"id":237300,"name":"Xuebin Qin","orcid":"0000-0001-9875-983X","position":18,"is_corresponding":false},{"id":633850,"name":"Joshua M. 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