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

  1. Nagarjuna R. Cheemarla
  2. Timothy A. Watkins
  3. Valia T. Mihaylova
  4. Bao Wang
  5. Dejian Zhao
  6. Guilin Wang
  7. Marie L. Landry
  8. Ellen F. Foxman

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

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.

Article activity feed

  1. Version published to 10.1084/jem.20210583
  2. ScreenIT

    SciScore for 10.1101/2021.01.22.21249812: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    RESOURCE AVAILABILITY: EXPERIMENTAL MODEL AND SUBJECT DETAILS: Quantification and statistical analysis, RT-qPCR data: GraphPad Prism (version 9.0.0) was used for data analysis.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There are several important caveats to our study. First, our data indicate a relatively limited effect of the SARS-CoV-2-induced interferon response on initial viral replication when it is the only virus present, at least at high MOI (Fig 6). However, the recruitment of cells of the immune system to the respiratory tract, as indicated by our RNAseq data (Fig 1), could considerably amplify ISG induction in vivo. Recent work showing that interferon deficiencies are linked to severe COVID-19 indicates the importance of interferon-mediated defense against this virus in vivo (Bastard et al., 2020; Pairo-Castineira et al., 2020; Zhang et al., 2020). Second, in vivo virus-host-virus interactions could be more complicated than those seen in organoid culture; for example, if a viral infection results in residual lung damage this could exacerbate rather than protect against a subsequent viral respiratory illness. Studying virus-host-virus interactions in vivo will be an important future direction of this study. For assessing viral interference, it will be critical not only to look at co-occurrence or sequential occurrence of viral infections, but also to measure the antiviral response in vivo. For example, symptomatic upper respiratory tract infections induce greater ISG responses than asymptomatic, and the latter may not cause significant interference(Yahya et al., 2017). Such studies will be facilitated by increasing development of nasopharyngeal swab-based methods to assess the airw...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.01.22.21249812v2 on medRxiv
  4. Version published to 10.1101/2021.01.22.21249812v1 on medRxiv