{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T19:49:30Z","timestamp":1772221770653,"version":"3.50.1"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T00:00:00Z","timestamp":1736985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["U19AI144297"],"award-info":[{"award-number":["U19AI144297"]}]},{"name":"NIH","award":["U19AI144297"],"award-info":[{"award-number":["U19AI144297"]}]},{"name":"NIH","award":["U19AI144297"],"award-info":[{"award-number":["U19AI144297"]}]},{"name":"NIH","award":["U19AI144297"],"award-info":[{"award-number":["U19AI144297"]}]},{"name":"NIH","award":["CA125123"],"award-info":[{"award-number":["CA125123"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Current understanding of viral dynamics of SARS-CoV-2 and host responses driving the pathogenic mechanisms in COVID-19 is rapidly evolving. Here, we conducted a longitudinal study to investigate gene expression patterns during acute SARS-CoV-2 illness. Cases included SARS-CoV-2 infected individuals with extremely high viral loads early in their illness, individuals having low SARS-CoV-2 viral loads early in their infection, and individuals testing negative for SARS-CoV-2. We could identify widespread transcriptional host responses to SARS-CoV-2 infection that were initially most strongly manifested in patients with extremely high initial viral loads, then attenuating within the patient over time as viral loads decreased. Genes correlated with SARS-CoV-2 viral load over time were similarly differentially expressed across independent datasets of SARS-CoV-2 infected lung and upper airway cells, from both in vitro systems and patient samples. We also generated expression data on the human nose organoid model during SARS-CoV-2 infection. The human nose organoid-generated host transcriptional response captured many aspects of responses observed in the above patient samples, while suggesting the existence of distinct host responses to SARS-CoV-2 depending on the cellular context, involving both epithelial and cellular immune responses. Our findings provide a catalog of SARS-CoV-2 host response genes changing over time and magnitude of these host responses were significantly correlated to viral load.<\/jats:p>","DOI":"10.1371\/journal.pone.0317033","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T13:50:43Z","timestamp":1737035443000},"page":"e0317033","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Longitudinal host transcriptional responses to SARS-CoV-2 infection in adults with extremely high viral load"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4016-7588","authenticated-orcid":true,"given":"Vasanthi","family":"Avadhanula","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad 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Butler","year":"2021","journal-title":"Nat Commun."},{"key":"pone.0317033.ref023","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S1473-3099(20)30196-1","article-title":"Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study","volume":"20","author":"KKW To","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"pone.0317033.ref024","doi-asserted-by":"crossref","first-page":"e3000849","DOI":"10.1371\/journal.pbio.3000849","article-title":"In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age","volume":"18","author":"NAP Lieberman","year":"2020","journal-title":"PLoS Biol"},{"key":"pone.0317033.ref025","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"JD Storey","year":"2003","journal-title":"Proc Natl 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Dis"},{"key":"pone.0317033.ref032","doi-asserted-by":"crossref","first-page":"733171","DOI":"10.3389\/fimmu.2021.733171","article-title":"Transcriptional Profiling and Machine Learning Unveil a Concordant Biosignature of Type I Interferon-Inducible Host Response Across Nasal Swab and Pulmonary Tissue for COVID-19 Diagnosis.","volume":"12","author":"C Zhang","year":"2021","journal-title":"Front Immunol."},{"key":"pone.0317033.ref033","doi-asserted-by":"crossref","first-page":"105310","DOI":"10.1016\/j.isci.2022.105310","article-title":"Host transcriptional responses in nasal swabs identify potential SARS-CoV-2 infection in PCR negative patients.","volume":"25","author":"AM Saravia-Butler","year":"2022","journal-title":"iScience"},{"key":"pone.0317033.ref034","article-title":"A Newly Engineered A549 Cell Line Expressing ACE2 and TMPRSS2 Is Highly Permissive to SARS-CoV-2, Including the Delta and Omicron Variants.","volume":"14","author":"C-W Chang","year":"2022","journal-title":"Viruses"},{"key":"pone.0317033.ref035","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41590-021-01091-0","article-title":"Innate immunity: the first line of defense against SARS-CoV-2","volume":"23","author":"MS Diamond","year":"2022","journal-title":"Nat Immunol"},{"key":"pone.0317033.ref036","doi-asserted-by":"crossref","first-page":"104799","DOI":"10.1016\/j.micpath.2021.104799","article-title":"The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong","volume":"153","author":"D Darif","year":"2021","journal-title":"Microb Pathog"},{"key":"pone.0317033.ref037","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2922-4","article-title":"A molecular cell atlas of the human lung from single-cell RNA sequencing","volume":"587","author":"KJ Travaglini","year":"2020","journal-title":"Nature"},{"key":"pone.0317033.ref038","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/jnci\/59.1.221","article-title":"One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice","volume":"59","author":"J Fogh","year":"1977","journal-title":"J Natl Cancer Inst"},{"key":"pone.0317033.ref039","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1038\/s41467-020-18781-2","article-title":"Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.","volume":"11","author":"SP Sajuthi","year":"2020","journal-title":"Nat Commun."},{"key":"pone.0317033.ref040","article-title":"Viral Load of Severe Acute Respiratory Syndrome Coronavirus 2 in Adults During the First and Second Wave of Coronavirus Disease 2019 Pandemic in Houston, Texas: The Potential of the Superspreader.","author":"V Avadhanula","year":"2021","journal-title":"J Infect 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