Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomi...

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Published in:	The Journal of experimental medicine Vol. 218; no. 8
Main Authors:	Cheemarla, Nagarjuna R, Watkins, Timothy A, Mihaylova, Valia T, Wang, Bao, Zhao, Dejian, Wang, Guilin, Landry, Marie L, Foxman, Ellen F
Format:	Journal Article
Language:	English
Published:	United States 02.08.2021
Subjects:	Adult Aged Aged, 80 and over Angiotensin-Converting Enzyme 2 - genetics Case-Control Studies Chemokine CXCL10 - metabolism COVID-19 - immunology COVID-19 - virology Disease Susceptibility - immunology Female Gene Expression Profiling Host-Pathogen Interactions - physiology Humans Immunity, Innate - physiology Interferons - genetics Interferons - immunology Interferons - metabolism Male Middle Aged Nasopharynx - virology Picornaviridae Infections - immunology Picornaviridae Infections - virology SARS-CoV-2 - genetics SARS-CoV-2 - physiology Viral Load Virus Replication
ISSN:	1540-9538, 1540-9538
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Abstract	Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. 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 ∼6 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.
AbstractList	Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. 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 ∼6 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. Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. 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 ∼6 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.Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. 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 ∼6 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.
Author	Cheemarla, Nagarjuna R Landry, Marie L Foxman, Ellen F Wang, Bao Mihaylova, Valia T Watkins, Timothy A Wang, Guilin Zhao, Dejian
Author_xml	– sequence: 1 givenname: Nagarjuna R orcidid: 0000-0002-8860-2457 surname: Cheemarla fullname: Cheemarla, Nagarjuna R organization: Department of Immunobiology, Yale School of Medicine, New Haven, CT – sequence: 2 givenname: Timothy A orcidid: 0000-0002-1607-1335 surname: Watkins fullname: Watkins, Timothy A organization: Department of Immunobiology, Yale School of Medicine, New Haven, CT – sequence: 3 givenname: Valia T orcidid: 0000-0003-2285-0324 surname: Mihaylova fullname: Mihaylova, Valia T organization: Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT – sequence: 4 givenname: Bao orcidid: 0000-0002-6472-2307 surname: Wang fullname: Wang, Bao organization: Department of Immunobiology, Yale School of Medicine, New Haven, CT – sequence: 5 givenname: Dejian orcidid: 0000-0002-2105-3799 surname: Zhao fullname: Zhao, Dejian organization: Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT – sequence: 6 givenname: Guilin orcidid: 0000-0002-7835-3186 surname: Wang fullname: Wang, Guilin organization: Yale Center for Genomic Analysis, Yale School of Medicine, New Haven, CT – sequence: 7 givenname: Marie L orcidid: 0000-0001-5543-8366 surname: Landry fullname: Landry, Marie L organization: Department of Internal Medicine, Yale School of Medicine, New Haven, CT – sequence: 8 givenname: Ellen F orcidid: 0000-0001-9767-9942 surname: Foxman fullname: Foxman, Ellen F organization: Department of Immunobiology, Yale School of Medicine, New Haven, CT
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References	34424267 - J Exp Med. 2021 Oct 4;218(10):e20211667. doi: 10.1084/jem.20211667 33532783 - medRxiv. 2021 Jan 27:2021.01.22.21249812. doi: 10.1101/2021.01.22.21249812
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Title	Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics
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