Post by Nadica (She/Her) on Aug 6, 2024 23:03:28 GMT
COVID-19 diarrhea is inflammatory, caused by direct viral effects plus major role of virus-induced cytokines. - Published July 31, 2024
Abstract
BACKGROUND AND 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 four SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes.
RESULTS
Live virus and VLPs increased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3 and DRA. IL-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA. 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 TMEM16 A 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 min, 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.
Graphical abstract
Abstract
BACKGROUND AND 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 four SARS-CoV-2 structural proteins or irradiated virus, all of which bound and entered enterocytes.
RESULTS
Live virus and VLPs increased secretion of multiple cytokines and reduced mRNAs of ACE2, NHE3 and DRA. IL-6 plus IL-8 alone reduced NHE3 mRNA and protein and DRA mRNA. 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 TMEM16 A 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 min, 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.
Graphical abstract