TY - JOUR
T1 - Blood Group O-Dependent cellular responses to cholera toxin
T2 - Parallel clinical and epidemiological links to severe cholera
AU - Kuhlmann, F. Matthew
AU - Santhanam, Srikanth
AU - Kumar, Pardeep
AU - Luo, Qingwei
AU - Ciorba, Matthew A.
AU - Fleckenstein, James M.
N1 - Funding Information:
This work was supported by funding from the Department of Veterans Affairs(grant 5I01BX001469); grant R01AI89894 from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID); CTSA grant UL1 TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH), and the Digestive Diseases Research Core Center at Washington University School of Medicine; grant P30 DK52574 from the National Institute of Diabetes and Digestive and Kidney Diseases. Matthew A. Ciorba was supported by grants DK100737, DK089016, and DK109384 from the NIDDK, AI095776 from the NIAID, and a Crohn's and Colitis Foundation Senior Research Award.
Publisher Copyright:
Copyright © 2016 by The American Society of Tropical Medicine and Hygiene.
PY - 2016/8
Y1 - 2016/8
N2 - Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals. Likewise, using CRISPR/Cas9 engineering, a functional group O line (HT-29-A-/-) was generated from a parent group A HT-29 line. CT stimulated robust cAMP responses in HT-29-A-/- cells relative to HT-29 cells. These findings provide a direct molecular link between blood group O expression and differential cellular responses to CT, recapitulating clinical and epidemiologic observations.
AB - Because O blood group has been associated with more severe cholera infections, it has been hypothesized that cholera toxin (CT) may bind non-O blood group antigens of the intestinal mucosae, thereby preventing efficient interaction with target GM1 gangliosides required for uptake of the toxin and activation of cyclic adenosine monophosphate (cAMP) signaling in target epithelia. Herein, we show that after exposure to CT, human enteroids expressing O blood group exhibited marked increase in cAMP relative to cells derived from blood group A individuals. Likewise, using CRISPR/Cas9 engineering, a functional group O line (HT-29-A-/-) was generated from a parent group A HT-29 line. CT stimulated robust cAMP responses in HT-29-A-/- cells relative to HT-29 cells. These findings provide a direct molecular link between blood group O expression and differential cellular responses to CT, recapitulating clinical and epidemiologic observations.
UR - http://www.scopus.com/inward/record.url?scp=84982860491&partnerID=8YFLogxK
U2 - 10.4269/ajtmh.16-0161
DO - 10.4269/ajtmh.16-0161
M3 - Article
C2 - 27162272
AN - SCOPUS:84982860491
SN - 0002-9637
VL - 95
SP - 440
EP - 443
JO - American Journal of Tropical Medicine and Hygiene
JF - American Journal of Tropical Medicine and Hygiene
IS - 2
ER -