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Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of \u223c6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.<\/jats:p>","DOI":"10.1084\/jem.20210583","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T02:22:19Z","timestamp":1622600539000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":224,"title":["Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-2457","authenticated-orcid":true,"given":"Nagarjuna R.","family":"Cheemarla","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"},{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, CT 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1607-1335","authenticated-orcid":true,"given":"Timothy A.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"},{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, CT 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2285-0324","authenticated-orcid":true,"given":"Valia T.","family":"Mihaylova","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-2307","authenticated-orcid":true,"given":"Bao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"},{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, CT 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2105-3799","authenticated-orcid":true,"given":"Dejian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 3"},{"name":"Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-3186","authenticated-orcid":true,"given":"Guilin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale School of Medicine, New Haven, CT 3"},{"name":"Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5543-8366","authenticated-orcid":true,"given":"Marie L.","family":"Landry","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"},{"name":"Department of Internal Medicine, Yale School of Medicine, New Haven, CT 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9767-9942","authenticated-orcid":true,"given":"Ellen F.","family":"Foxman","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT 1"},{"name":"Department of Immunobiology, Yale School of Medicine, New Haven, CT 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"2023072804494821300_bib1","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.mehy.2011.09.021","article-title":"Virus interference. 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