Acid pH Increases SARS-CoV-2 Infection and the Risk of Death by COVID-19

  1. Leandro Jimenez
  2. Ana Campos Codo
  3. Vanderson de Souza Sampaio
  4. Antonio E. R. Oliveira
  5. Lucas Kaoru Kobo Ferreira
  6. Gustavo Gastão Davanzo
  7. Lauar de Brito Monteiro
  8. João Victor Virgilio-da-Silva
  9. Mayla Gabriela Silva Borba
  10. Gabriela Fabiano de Souza
  11. Nathalia Zini
  12. Flora de Andrade Gandolfi
  13. Stéfanie Primon Muraro
  14. José Luiz Proença-Modena
  15. Fernando Almeida Val
  16. Gisely Cardoso Melo
  17. Wuelton Marcelo Monteiro
  18. Maurício Lacerda Nogueira
  19. Marcus Vinícius Guimarães Lacerda
  20. Pedro M. Moraes-Vieira
  21. Helder I. Nakaya

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect a broad range of human tissues by using the host receptor angiotensin-converting enzyme 2 (ACE2). Individuals with comorbidities associated with severe COVID-19 display higher levels of ACE2 in the lungs compared to those without comorbidities, and conditions such as cell stress, elevated glucose levels and hypoxia may also increase the expression of ACE2 . Here, we showed that patients with Barrett's esophagus (BE) have a higher expression of ACE2 in BE tissues compared to normal squamous esophagus, and that the lower pH associated with BE may drive this increase in expression. Human primary monocytes cultured in reduced pH displayed increased ACE2 expression and higher viral load upon SARS-CoV-2 infection. We also showed in two independent cohorts of 1,357 COVID-19 patients that previous use of proton pump inhibitors is associated with 2- to 3-fold higher risk of death compared to those not using the drugs. Our work suggests that pH has a great influence on SARS-CoV-2 Infection and COVID-19 severity.

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  1. Version published to 10.3389/fmed.2021.637885
  2. ScreenIT

    SciScore for 10.1101/2020.09.10.20179135: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Viral titers were obtained by plaque assays on Vero cells.
    Vero
    suggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)
    Software and Algorithms
    SentencesResources
    Acidosis and Barrett’s esophagus meta-analysis: We manually curated the Gene Expression Omnibus (GEO) repository (https://www.ncbi.nlm.nih.gov/geo/) to find esophagus transcriptome datasets related to “Barrett’s esophagus” and cell line transcriptome datasets related to “acidosis” and “pH reduction”.
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    We performed differential expression analyses using the limma package (12).
    limma
    suggested: (LIMMA, RRID:SCR_010943)
    The MetaVolcanoR package (13) was used to combine the P values using the Fisher’s method.
    MetaVolcanoR
    suggested: (MetaVolcanoR, RRID:SCR_018549)
    For enrichment analyses, we utilized the EnrichR tool (14) and fgsea R package (15) with gene sets from the Gene Ontology Biological Process database.
    EnrichR
    suggested: (Enrichr, RRID:SCR_001575)
    Ontology Biological
    suggested: None
    Data were collected and managed using REDCap (v. 10.2.1) electronic data capture tools hosted at Fundação de Medicina Tropical Dr. Heitor Vieira Dourado.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    (StataCorp LP, College Station, TX)
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: Thank you for sharing your data.

    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.

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  3. Version published to 10.1101/2020.09.10.20179135v1 on medRxiv