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Review 1: "Daytime variation in SARS-CoV-2 infection and cytokine production"

This study provides novel insight into time of day of SARS-CoV-2 infection and macrophage response, which could have therapeutic implications. However, reviewers suggest that claims could be misleading and were not adequately supported by their analytic methods.

Published onOct 23, 2020
Review 1: "Daytime variation in SARS-CoV-2 infection and cytokine production"
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key-enterThis Pub is a Review of
Daytime variation in SARS-CoV-2 infection and cytokine production
Daytime variation in SARS-CoV-2 infection and cytokine production
Description

Abstract S. Ray and A. Reddy recently anticipated the implication of circadian rhythm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of the coronavirus disease (Covid-19). In addition to its key role in the regulation of biological functions, the circadian rhythm has been suggested as a regulator of viral infections. Specifically, the time of day of infection was found critical for illness progression, as has been reported for influenza, respiratory syncytial and parainfluenza type 3 viruses. We analyzed circadian rhythm implication in SARS-CoV-2 virus infection of isolated human monocytes, key actor cells in Covid-19 disease, from healthy subjects. The circadian gene expression of Bmal1 and Clock genes was investigated with q-RTPCR. Monocytes were infected with SARS-CoV-2 virus strain and viral infection was investigated by One-Step qRT-PCR and immunofluorescence. Interleukin (IL)-6, IL-1β and IL-10 levels were also measured in supernatants of infected monocytes. Using Cosinor analysis, we showed that Bmal1 and Clock transcripts exhibited circadian rhythm in monocytes with an acrophase and a bathyphase at Zeitgeber Time (ZT)6 and ZT17. After forty-eight hours, the amount of SARS-CoV-2 virus increased in the monocyte infected at ZT6 compared to ZT17. The high virus amount at ZT6 was associated with significant increased release in IL-6, IL-1β and IL-10 compared to ZT17. Our results suggest that time day of SARS-CoV-2 infection affects viral infection and host immune response. They support consideration of circadian rhythm in SARS-CoV-2 disease progression and we propose circadian rhythm as a novel target for managing viral progression.Importance The implication of circadian rhythm (CR) in pathogenesis of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recently anticipated. The time of day of infection is critical for illness progression as reported for influenza, respiratory syncytial and parainfluenza type 3 viruses. In this study, we wondered if SARS-CoV-2 infection and cytokine production by human monocytes, innate immune cells affected by Covid-19, were regulated by CR. Our results suggest that time day of SARS-CoV-2 infection affects viral infection and host immune response. They support consideration of circadian rhythm in SARS-CoV-2 disease progression and we propose circadian rhythm as a novel target for managing viral progression.

RR:C19 Evidence Scale rating by reviewer:

  • Misleading. Serious flaws and errors in the methods and data render the study conclusions misinformative. The results and conclusions of the ideal study are at least as likely to conclude the opposite of its results and conclusions than agree. Decision-makers should not consider this evidence in any decision.

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Review:

General comments

The manuscript presented by Aissatou B. Diallo et al entitled “Daytime variation in SARS-CoV-2 infection and cytokine production” reveals inflammatory indices of SARS-CoV-2 infection in human monocytes isolated from peripheral blood mononuclear cells isolated from healthy donors. The title is misleading because it does not specify if this is a human study or human isolated cells or experimental animal research. Authors should use proper specifics in the manuscript title. The authors are addressing an important question in terms of the day of the time of SARS-CoV-2 infection, however, there are basic experimental flaws which need to be addressed before the manuscript can be considered for publications.

Specific comments

1.         The manuscript demonstrates effect of Zeitgeber time (ZT) in regard to SARS-CoV-2 infection and the subsequent inflammation in the freshly cultured human monocytes. But the time of the samples collected are very important to know the functionality of the monocytes based on the ZT.

2.         As such if the time of sample collection was random, and samples were employed in research within 48 hours, there has to synchronization of the cell cultures done before the exposure of these cells with SARS-CoV-2 and counting on the ZT time period. Generally, the circadian synchronization is done with 50% horse serum shock for a period of 2 hours under 37 degrees Celsius with 5% carbon dioxide, when the peripheral clock of the cells is matched up to ZT0 at the time of beginning of serum shock treatment. Later cells are exposed to the test agents involved in the study. Authors must confirm if they synchronized the cells to circadian clock and then exposed the cells to SARS-CoV-2. Methods section should be reworded accordingly.

3.         It is also known that synchronization and the testing agent effects are reliably measured after 6 hours. So, if authors could repeat the study with the synchronization step included, the data would be more meaningful and reliable. 

4.           The analytic methods used to decipher the inflammatory status in the circadian variation are compelling, but the manuscript cannot be accepted in its present form.

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