TY - JOUR
T1 - COVID-19 Diarrhea is Inflammatory, Caused by Direct Viral Effects Plus Major Role of Virus-induced Cytokines
AU - Donowitz, Mark
AU - Tse, Chung Ming
AU - Sarker, Rafiq
AU - Lin, Ruxian
AU - Dokladny, Karol
AU - Rawat, Manmeet
AU - Horwitz, Ivy
AU - Ye, Chun Yan
AU - McNamara, George
AU - In, Julie
AU - Kell, Alison
AU - Guo, Chenxu
AU - JuiTsai, Shang
AU - Vong, Tyrus
AU - Karaba, Andrew
AU - Singh, Varsha
AU - Sachithanandham, Jaiprasath
AU - Pekosz, Andy
AU - Cox, Andrea
AU - Bradfute, Steven
AU - Zachos, Nicholas C.
AU - Gould, Steven
AU - Kovbasnjuk, Olga
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
KW - CaCC
KW - Cytokines
KW - DRA
KW - Diarrhea
KW - NHE3
KW - SARS-CoV-2
KW - Virus-like Particles
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U2 - 10.1016/j.jcmgh.2024.101383
DO - 10.1016/j.jcmgh.2024.101383
M3 - Article
C2 - 39089626
AN - SCOPUS:85202876934
SN - 2352-345X
VL - 18
JO - CMGH
JF - CMGH
IS - 5
M1 - 101383
ER -