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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number101383
JournalCMGH
Volume18
Issue number5
DOIs
StatePublished - Jan 2024

Keywords

  • CaCC
  • Cytokines
  • DRA
  • Diarrhea
  • NHE3
  • SARS-CoV-2
  • Virus-like Particles

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint

Dive into the research topics of 'COVID-19 Diarrhea is Inflammatory, Caused by Direct Viral Effects Plus Major Role of Virus-induced Cytokines'. Together they form a unique fingerprint.

Cite this