COVID-19 Diarrhea is Inflammatory, Caused by Direct Viral Effects Plus Major Role of Virus-induced CytokinesSummary

Mark Donowitz; Chung-Ming Tse; Rafiq Sarker; Ruxian Lin; Karol Dokladny; Manmeet Rawat; Ivy Horwitz; ChunYan Ye; George McNamara; Julie In; Alison Kell; Chenxu Guo; Shang JuiTsai; Tyrus Vong; Andrew Karaba; Varsha Singh; Jaiprasath Sachithanandham; Andy Pekosz; Andrea Cox; Steven Bradfute; Nicholas C. Zachos; Steven Gould; Olga Kovbasnjuk

Cellular and Molecular Gastroenterology and Hepatology (Jan 2024)

COVID-19 Diarrhea is Inflammatory, Caused by Direct Viral Effects Plus Major Role of Virus-induced CytokinesSummary

Mark Donowitz,
Chung-Ming Tse,
Rafiq Sarker,
Ruxian Lin,
Karol Dokladny,
Manmeet Rawat,
Ivy Horwitz,
ChunYan Ye,
George McNamara,
Julie In,
Alison Kell,
Chenxu Guo,
Shang JuiTsai,
Tyrus Vong,
Andrew Karaba,
Varsha Singh,
Jaiprasath Sachithanandham,
Andy Pekosz,
Andrea Cox,
Steven Bradfute,
Nicholas C. Zachos,
Steven Gould,
Olga Kovbasnjuk

Affiliations

Mark Donowitz: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Physiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Correspondence Address correspondence to: Mark Donowitz, MD; The Johns Hopkins University School of Medicine; Ross 925; 720 Rutland Ave; Baltimore, Maryland 21205.
Chung-Ming Tse: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Rafiq Sarker: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Ruxian Lin: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Karol Dokladny: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Manmeet Rawat: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Ivy Horwitz: University of New Mexico Center for Global Health, Albuquerque, New Mexico
ChunYan Ye: University of New Mexico Center for Global Health, Albuquerque, New Mexico
George McNamara: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Julie In: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Alison Kell: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Chenxu Guo: Department of Biological Chemistry, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Shang JuiTsai: Department of Biological Chemistry, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Tyrus Vong: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Andrew Karaba: Division of Infectious Diseases, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Varsha Singh: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Jaiprasath Sachithanandham: Department of Microbiology and Immunology, Bloomberg School of Public Health of the Johns Hopkins University, Baltimore, Maryland
Andy Pekosz: Department of Microbiology and Immunology, Bloomberg School of Public Health of the Johns Hopkins University, Baltimore, Maryland
Andrea Cox: Division of Infectious Diseases, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Steven Bradfute: Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; University of New Mexico Center for Global Health, Albuquerque, New Mexico
Nicholas C. Zachos: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Steven Gould: Department of Biological Chemistry, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
Olga Kovbasnjuk: Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

Journal volume & issue: Vol. 18, no. 5
p. 101383

Abstract

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Background & Aims: Diarrhea occurs in up to 50% of cases of COVID-19. Nonetheless, the pathophysiologic mechanism(s) have not been determined. Methods: This was examined using normal human enteroid monolayers exposed apically to live SARS-CoV-2 or non-replicating virus-like particles (VLPs) bearing the 4 SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes. Results: Live virus and VLPs incrieased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3, and DRA. Interleukin (IL)-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA and protein. Neither VLPs nor IL-6 plus IL-8 alone altered Cl- secretion, but together they caused Cl- secretion, which was Ca2+-dependent, CFTR-independent, blocked partially by a specific TMEM16A inhibitor, and entirely by a general TMEM16 family inhibitor. VLPs and irradiated virus, but not IL-6 plus IL-8, produced Ca2+ waves that began within minutes of VLP exposure, lasted for at least 60 minutes, and were prevented by pretreatment with apyrase, a P2Y1 receptor antagonist, and general TMEM16 family inhibitor but not by the specific TMEM16A inhibitor. Conclusions: The pathophysiology of COVID-19 diarrhea appears to be a unique example of a calcium-dependent inflammatory diarrhea that is caused by direct viral effects plus the virus-induced intestinal epithelial cytokine secretion.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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