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Infection and Immunity, February 1999, p. 844-852, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

A Role for Host Phosphoinositide 3-Kinase and Cytoskeletal Remodeling during Cryptosporidium parvum Infectiondagger

John R. Forney,1,Dagger Daryll B. DeWald,1 Shiguang Yang,2 Clarence A. Speer,3 and Mark C. Healey1,2,*

Department of Biology, College of Science,1 and Department of Animal, Dairy, and Veterinary Sciences, College of Agriculture,2 Utah State University, Logan, Utah 84322, and Veterinary Molecular Biology Laboratory, Montana State University, Bozeman, Montana 597173

Received 21 May 1998/Returned for modification 9 September 1998/Accepted 4 November 1998

Cryptosporidium parvum preferentially infects epithelial cells lining the intestinal mucosa of mammalian hosts. Parasite development and propagation occurs within a unique intracellular but extracytoplasmic parasitophorous vacuole at the apical surface of infected cells. Parasite-induced host cell signaling events and subsequent cytoskeletal remodeling were investigated by using cultured bovine fallopian tube epithelial (BFTE) cells inoculated with C. parvum sporozoites. Indirect-immunofluorescence microscopy detected host tyrosine phosphorylation within 30 s of inoculation. At >30 min postinoculation, actin aggregates were detected at the site of parasite attachment by fluorescein isothiocyanate-conjugated phalloidin staining as well as by indirect immunolabeling with monoclonal anti-actin. The actin-binding protein villin was also detected in focal aggregates at the site of attachment. Host cytoskeletal rearrangement persisted for the duration of the parasitophorous vacuole and contributed to the formation of long, branched microvilli clustered around the cryptosporidial vacuole. The phosphoinositide 3-kinase inhibitor wortmannin significantly inhibited (P < 0.05) C. parvum infection when BFTE cells were pretreated for 60 min at 37°C prior to inoculation. Similarly, treatment of BFTE cells with the protein kinase inhibitors genistein and staurosporine and the cytoskeletally acting compounds 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazapine, cytochalasin D, and 2,3-butanedione monoxime significantly inhibited (P < 0.05) in vitro infection at 24 h postinoculation. These findings demonstrate a prominent role for phosphoinositide 3-kinase activity during the early C. parvum infection process and suggest that manipulation of host signaling pathways results in actin rearrangement at the site of sporozoite attachment.

* Corresponding author. Mailing address: Department of Animal, Dairy, and Veterinary Sciences, College of Agriculture, Utah State University, Logan, UT 84322-5600. Phone: (435) 797-1901. Fax: (435) 797-3959. E-mail: mchealey{at}cc.usu.edu.

dagger Journal paper no. 7060 of the Utah Agricultural Experiment Station.

Dagger Present address: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, DC 20307-5100.

Infection and Immunity, February 1999, p. 844-852, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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