Open AccessClostridium difficile toxin B induces autophagic cell death in colonocytes
Author(s) -
Chan Hung,
Zhao Shan,
Zhang Lin,
Ho Jeffery,
Leung Czarina C.H.,
Wong Wai T.,
Tian Yuanyuan,
Liu Xiaodong,
Kwong Thomas N.Y.,
Chan Raphael C.Y.,
Yu Sidney S.B.,
Wang Maggie H.T.,
Tse Gary,
Wong Sunny H.,
Chan Matthew T.V.,
Wu William K.K.
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13555
Subject(s) - autophagy , atg5 , programmed cell death , pi3k/akt/mtor pathway , microbiology and biotechnology , cytotoxic t cell , autophagosome , biology , protein kinase b , wortmannin , chemistry , signal transduction , apoptosis , biochemistry , in vitro
Abstract Toxin B (TcdB) is a major pathogenic factor of Clostridum difficile . However, the mechanism by which TcdB exerts its cytotoxic action in host cells is still not completely known. Herein, we report for the first time that TcdB induced autophagic cell death in cultured human colonocytes. The induction of autophagy was demonstrated by the increased levels of LC 3‐ II , formation of LC 3 + autophagosomes, accumulation of acidic vesicular organelles and reduced levels of the autophagic substrate p62/ SQSTM 1. TcdB‐induced autophagy was also accompanied by the repression of phosphoinositide 3‐kinase ( PI 3K)/Akt/mechanistic target of rapamycin ( mTOR ) complex 1 activity. Functionally, pharmacological inhibition of autophagy by wortmannin or chloroquine or knockdown of autophagy‐related genes Beclin 1, Atg5 and Atg7 attenuated TcdB‐induced cell death in colonocytes. Genetic ablation of Atg5 , a gene required for autophagosome formation, also mitigated the cytotoxic effect of TcdB. In conclusion, our study demonstrated that autophagy serves as a pro‐death mechanism mediating the cytotoxic action of TcdB in colonocytes. This discovery suggested that blockade of autophagy might be a novel therapeutic strategy for C. difficile infection.