Role of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 in severity of COVID-19 infection

  1. Sandra P. Smieszek
  2. Bartlomiej Przychodzen
  3. Christos Polymeropoulos
  4. Vasilios Polymeropoulos
  5. Mihael H. Polymeropoulos

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Abstract

Coronaviruses remodel intracellular membranes to form specialized viral replication compartments, such as double-membrane vesicles where viral RNA genome replication takes place. Understanding the factors affecting host response is instrumental to design of therapeutics to prevent or ameliorate the course of infection.

As part of explorative tests in hospitalized patients with confirmed COVID-19 infection participating in ODYSSEY trial, we obtained samples for whole genome sequencing analysis as well as for viral genome sequencing. Based on our data, we confirm one of the strongest severity susceptibility locus thus far reported in association with severe COVID-19: 3p21.31 locus with lead variant rs73064425. We further examine the associated region. Interestingly based on LD analysis we report 3 coding mutations within one gene in the region of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 ( FYCO1 ). We specifically focus on the role of FYCO1 modifiers and gain-of-function variants. We report the associations between the region and clinical characteristics in this severe set of COVID-19 patients.

We next analyzed expression profiles of FYCO1 across all 466 compounds tested. We selected only those results that showed a significant reduction of expression of FYCO1 . The most significant candidate was indomethacin – an anti-inflammatory that could potentially downregulate FYCO1. We hypothesize that via its direct effects on efficiency of viral egress, it may serve as a potent therapeutic decreasing the replication and infectivity of the virus. Clinical studies will be needed to examine the therapeutic utility of indomethacin and other compounds downregulating FYCO1 in COVID-19 infection and other strains of betacoronaviruses.

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  1. ScreenIT

    SciScore for 10.1101/2021.01.22.21250070: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationClinical Trial Information: ODYSSEY is a double-blinded Phase 3 study with a planned randomization of a total of 300 hospitalized severely ill COVID-19 patients to receive either tradipitant 85 mg bid or placebo for a total of up to 14 days or discharge (CONSORT Flowchart in S.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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

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  2. Version published to 10.1101/2021.01.22.21250070v2 on medRxiv
  3. Version published to 10.1101/2021.01.22.21250070v1 on medRxiv