Acid pH Increases SARS-CoV-2 Infection and the Risk of Death by COVID-19
Leandro Jimenez, Ana Campos Codo, Vanderson De Souza Sampaio, Antonio E R Oliveira, Lucas Kaoru Kobo Ferreira, Gustavo Gastão Davanzo, Lauar De Brito Monteiro, João Victor Virgilio-Da-Silva, Mayla Gabriela Silva Borba, Gabriela Fabiano De Souza, Nathalia Zini, Flora De Andrade Gandolfi, Stéfanie Primon Muraro, José Luiz Proença-Modena, Fernando Almeida Val, Gisely Cardoso Melo, Wuelton Marcelo Monteiro, Maurício Lacerda Nogueira, Marcus Vinícius Guimarães Lacerda, Pedro M Moraes-Vieira, Helder I Nakaya
Frontiers in Medicine, doi:10.3389/fmed.2021.637885
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.
DATA AVAILABILITY STATEMENT The original contributions generated for this study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.
ETHICS STATEMENT The studies involving human participants were reviewed and approved by Brazilian Committee of Ethics in Human Research (CAAE: 30152620.1.0000.0005 and 30615920.2.0000.0005 for North region cohort, and 31588920.0.0000.5415 for Southeast region cohort). The patients/participants provided their written informed consent to participate in this study.
AUTHOR CONTRIBUTIONS LJ, AO, LF, and HN performed the transcriptome analyses. AC, GD, LB, JV, GF, SM, JL, and PM-V performed the experimental work. VS, MB, NZ, FA, MN, FV, GC, WM, and ML performed the clinical analysis. HN coordinated the study. LJ and HN wrote the manuscript with inputs from all of the coauthors. All authors contributed to the article and approved the submitted version.
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed. 2021.637885/full#supplementary-material
Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations,..
References
Alexeyenko, Lee, Pernemalm, Guegan, Dessen et al., Network enrichment analysis: extension of gene-set enrichment analysis to gene networks, BMC Bioinformatics,
doi:10.1186/1471-2105-13-226Bourgonje, Abdulle, Timens, Hillebrands, Navis et al., Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19), J Pathol,
doi:10.1002/path.5471Chen, Tan, Kou, Duan, Wang et al., Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool, BMC Bioinformatics,
doi:10.1186/1471-2105-14-128Chen, Wu, Chen, Yang, Chen, Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study, BMJ,
doi:10.1136/bmj.m1091Cheung, Hung, Chan, Lung, Tso et al., Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong Cohort: systematic review and meta-analysis, Gastroenterology,
doi:10.1053/j.gastro.2020.03.065Clarke, Belyaev, Lambert, Turner, Epigenetic regulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1 under conditions of cell energy stress, Clin Sci (Lond),
doi:10.1042/CS20130291Codo, Davanzo, Monteiro, De Souza, Muraro et al., Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis, Cell Metab,
doi:10.2139/ssrn.3606770Freedberg, Conigliaro, Wang, Tracey, Callahan et al., Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: a propensity score matched retrospective cohort study, Gastroenterology,
doi:10.1053/j.gastro.2020.05.053Freedberg, Lebwohl, Abrams, The impact of proton pump inhibitors on the human gastrointestinal microbiome, Clin Lab Med,
doi:10.1016/j.cll.2014.08.008Henry, Aggarwal, Wong, Benoit, Vikse et al., Lactate dehydrogenase levels predict coronavirus disease 2019 (COVID-19) severity and mortality: a pooled analysis, Am J Emerg Med,
doi:10.1016/j.ajem.2020.05.073Kiselev, Kirschner, Schaub, Andrews, Yiu et al., SC3: consensus clustering of single-cell RNA-seq data, Nat Methods,
doi:10.1038/nmeth.4236Li, Li, Zhang, Wang, Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues, Infect Dis Poverty,
doi:10.1186/s40249-020-00662-xOwen, White, Severson, Braden, Bailey et al., Single cell RNA-seq reveals profound transcriptional similarity between Barrett's oesophagus and oesophageal submucosal glands, Nat Commun,
doi:10.1038/s41467-018-06796-9Pedersen, Chodavarapu, Lazartigues, Forkhead box transcription factors of the FOXA class are required for basal transcription of angiotensinconverting enzyme 2, J Endocr Soc,
doi:10.1210/js.2016-1071Pinto, Oliveira, Singh, Jimenez, Gonçalves et al., ACE2 expression is increased in the lungs of patients with comorbidities associated with severe COVID-19, J Infect Dis,
doi:10.1093/infdis/jiaa332Prada, Lima, Nakaya, MetaVolcanoR: Gene Expression Meta-analysis Visualization Tool
Ritchie, Phipson, Wu, Hu, Law et al., limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res,
doi:10.1093/nar/gkv007Senkel, Lucas, Klein-Hitpass, Ryffel, Identification of target genes of the transcription factor HNF1beta and HNF1alpha in a human embryonic kidney cell line, Biochim Biophys Acta,
doi:10.1016/j.bbaexp.2005.10.003Severson, Owen, White, Lu, Schuster-Böckler, BEARscc determines robustness of single-cell clusters using simulated technical replicates, Nat Commun,
doi:10.1038/s41467-018-03608-ySun, Chen, Hu, Wu, Liang et al., Does famotidine reduce the risk of progression to severe disease, death, and intubation for COVID-19 patients? A systemic review and meta-analysis, Dig Dis Sci,
doi:10.1007/s10620-021-06872-zTariq, Saha, Furqan, Hassett, Pardi et al., Prevalence and mortality of COVID-19 patients with gastrointestinal symptoms: a systematic review and meta-analysis, Mayo Clin Proc,
doi:10.1016/j.mayocp.2020.06.003Won, Lee, Park, Kim, Park et al., Development of a laboratory-safe and low-cost detection protocol for SARS-CoV-2 of the coronavirus disease 2019 (COVID-19), Exp Neurobiol,
doi:10.5607/en20009Yan, Chen, Sun, Ahmed, Bhan et al., Will proton pump inhibitors lead to a higher risk of COVID-19 infection and progression to severe disease? A Meta-analysis, Jpn J Infect Dis,
doi:10.7883/yoken.JJID.2021.074Zhang, Han, Zhang, Duan, Shang et al., Diarrhea and altered inflammatory cytokine pattern in severe coronavirus disease 2019: impact on disease course and in-hospital mortality, J Gastroenterol Hepatol,
doi:10.1111/jgh.15166Zhang, Wu, Zhao, Liu, Zhou et al., Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells, Am J Physiol Lung Cell Mol Physiol,
doi:10.1152/ajplung.90415.2008Zou, Chen, Zou, Han, Hao et al., Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection, Front Med,
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