Increased Expression of Chondroitin Sulfotransferases following AngII may Contribute to Pathophysiology Underlying Covid-19 Respiratory Failure: Impact may be Exacerbated by Decline in Arylsulfatase B Activity

  1. Sumit Bhattacharyya
  2. Kumar Kotlo
  3. Joanne K. Tobacman

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Abstract

The precise mechanisms by which Covid-19 infection leads to hypoxia and respiratory failure have not yet been elucidated. Interactions between sulfated glycosaminoglycans (GAGs) and the SARS-CoV-2 spike glycoprotein have been identified as participating in viral adherence and infectivity. The spike glycoprotein binds to respiratory epithelium through the angiotensin converting enzyme 2 (ACE2) receptor, which endogenously interacts with Angiotensin (Ang) II to yield Angiotensin 1-7. In this report, we show that stimulation of human vascular smooth muscle cells by Ang II leads to increased mRNA expression of two chondroitin sulfotransferases (CHST11 and CHST15), which are required for synthesis of chondroitin 4-sulfate (C4S) and chondroitin 4,6-disulfate (CSE), respectively. Also, increased total sulfated GAGs, increased sulfotransferase activity, and increased expression of the proteoglycans biglycan, syndecan, perlecan, and versican followed treatment by Ang II. Candesartan, an Angiotensin II receptor blocker (Arb), largely, but incompletely, inhibited these increases, and the differences from baseline remained significant. These results suggest that another effect of Ang II also contributes to the increased expression of chondroitin sulfotransferases, total sulfated GAGs, and proteoglycans. We hypothesize that activation of ACE2 may contribute to these increases and suggest that the SARS-CoV-2 spike glycoprotein interaction with ACE2 may also increase chondroitin sulfotransferases, sulfated GAGs, and proteoglycans and thereby contribute to viral adherence to bronchioalveolar cells and to respiratory compromise in SARS-CoV-2 infection.

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  1. Version published to 10.1101/2020.06.25.171975v2 on bioRxiv
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    SciScore for 10.1101/2020.06.25.171975: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Circulating leukocytes were isolated from whole blood samples obtained from patients aged 2-17, followed at Rush University Medical Center (RUMC) for cystic fibrosis, asthma, or other conditions under a protocol approved by RUMC and the University of Illinois at Chicago (UIC) Institutional Review Boards [29].
    Consent: Patients 8 years of age and older signed assent forms, and parents of all subjects signed consent forms, permitting collection of peripheral blood samples.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    IL-6 in the samples was captured into the wells of a microtiter plate pre-coated with specific anti-IL-6 monoclonal antibody, and the immobilized IL-6 was detected by a biotinylated second antibody and streptavidin-horseradish peroxidase (HRP)-conjugate with the chromogenic substrate hydrogen peroxide/ tetramethylbenzidine (TMB)
    anti-IL-6
    suggested: None
    Software and Algorithms
    SentencesResources
    Briefly, the BlyscanTM assay kit (Biocolor Ltd, Newtownabbey, N. Ireland) was used for detection of the sulfated GAG, based on the reaction of 1,9-dimethylmethylene blue with the sulfated oligosaccharides in the GAG chains.
    GAG
    suggested: None
    Statistical analysis: Data were analyzed using InStat software (GraphPad, San Diego, CA) or Excel spreadsheet software by unpaired t-tests, two-tailed, with adjustment for equal or unequal standard deviation, or by one-way ANOVA with Tukey-Kramer post-test.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Excel
    suggested: None

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    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.

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  3. Version published to 10.1101/2020.06.25.171975v1 on bioRxiv