Rotavirus toxin NSP4 induces diarrhea by activation of TMEM16A and inhibition of Na+ absorption
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Rotavirus infection is the most frequent cause for severe diarrhea in infants, killing more than 600,000 every year. The nonstructural protein NSP4 acts as a rotavirus enterotoxin, inducing secretory diarrhea without any structural organ damage. Electrolyte transport was assessed in the colonic epithelium from pups and adult mice using Ussing chamber recordings. Western blots and immunocytochemistry was performed in intestinal tissues from wild-type and TMEM16A knockout mice. Ion channel currents were recorded using patch clamp techniques. We show that the synthetic NSP4114–135 peptide uses multiple pro-secretory pathways to induce diarrhea, by activating the recently identified Ca2+-activated Cl− channel TMEM16A, and by inhibiting Na+ absorption by the epithelial Na+ channel ENaC and the Na+/glucose cotransporter SGLT1. Activation of secretion and inhibition of Na+ absorption by NSP4114–135, respectively, could be potently suppressed by wheat germ agglutinin which probably competes with NSP4114–135 for binding to an unknown glycolipid receptor. The present paper gives a clue as to mechanisms of rotavirus-induced diarrhea and suggests wheat germ agglutinin as a simple and effective therapy.
KeywordsRotavirus NSP4 Ca2+-activated Cl− channels TMEM16A ENaC Epithelial Na+ channels SGLT1 Colonic epithelium Diarrhea
This study is supported by the Deutsche Forschungsgemeinschaft DFG SFB699 A6/A7, DFG KU 756/8-2, and TargetScreen2 (EU-FP6-2005-LH-037365). KK was a research fellow of the University of Sydney Medical Foundation. We thank Dr. Brian Harfe and Dr. Jason Rock (University of Gainesville, Florida, USA) for supplying TMEM16A null mice and anti-mouse TMEM16A antibody and Ms. Marisa Sousa for her help with the TRPC-knockout animals.
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