This Article Full Text Full Text (PDF) Other Versions of this Article: IAI.00308-08v1 76/8/3784    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Liu, J. Articles by Rutherford, M. S. PubMed PubMed Citation Articles by Liu, J. Articles by Rutherford, M. S.

 Previous Article  |  Next Article 

Infection and Immunity, August 2008, p. 3784-3792, Vol. 76, No. 8
0019-9567/08/$08.00+0     doi:10.1128/IAI.00308-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Inhibition of Apoptosis in Cryptosporidium parvum-Infected Intestinal Epithelial Cells Is Dependent on Survivin

Jin Liu, Shinichiro Enomoto, Cheryl A. Lancto, Mitchell S. Abrahamsen, and Mark S. Rutherford^*

Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108

Received 7 March 2008/ Returned for modification 25 March 2008/ Accepted 22 May 2008

Cryptosporidium parvum is an obligate intracellular protozoan capable of causing severe diarrheal disease in a wide variety of mammals, including humans. C. parvum infection has been associated with induction of apoptosis in exposed epithelial cells, and we now demonstrate that apoptosis is restricted to a subset of cells actively infected with C. parvum. Approximately 20% of the infected cells underwent apoptosis within 48 h of infection, suggesting that the majority of the infected cells are rescued from apoptosis. C. parvum infection resulted in low-level activation of multiple members of the caspase family, including caspase-2, -3, -4, -6, -8, and -9. The kinetics of caspase activation correlated with apoptosis over a 48-h time course. Pan caspase inhibitors reduced apoptosis of epithelial cells infected by C. parvum. Furthermore, C. parvum infection inhibited staurosporine-induced apoptosis and caspase-3/7 activation at 24 h and 48 h. Infection with C. parvum led to upregulation of genes encoding inhibitors of apoptosis proteins (IAPs), including c-IAP1, c-IAP2, XIAP, and survivin. Knockdown of survivin gene expression, but not that of c-IAP1, c-IAP2, or XIAP expression, increased caspase-3/7 activity as well as apoptosis of infected cells and decreased C. parvum 18S rRNA levels. These data suggest that the apoptotic response of infected intestinal epithelial cells is actively suppressed by C. parvum via upregulation of survivin, favoring parasite infection.

Published ahead of print on 2 June 2008.

Editor: W. A. Petri, Jr.

These authors contributed equally to this work.