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Journal of Clinical Microbiology, September 1998, p. 2503-2508, Vol. 36, No. 9
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Gamma Interferon Gene Knockout Mouse: a Highly Sensitive Model for Evaluation of Therapeutic Agents against Cryptosporidium parvum

Jeffrey K. Griffiths,1,2,3 Cynthia Theodos,1 Melissa Paris,1 and Saul Tzipori1,3,*

Division of Infectious Disease, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536,1 and Department of Family Medicine and Community Health, Tufts University School of Medicine,2 and Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center,3 Boston, Massachusetts 02111

Received 18 March 1998/Returned for modification 6 May 1998/Accepted 12 June 1998

Cryptosporidiosis is a serious disease in malnourished children and in people with malignancies or AIDS. Current rodent models for evaluating drug therapy against cryptosporidiosis have many limitations, including the need for a high inoculum, the absence of symptoms resembling those seen in humans, and the need to maintain exogenous immunosuppression. We have developed a gamma interferon knockout (GKO) mouse model with which to evaluate therapies against C. parvum and have used paromomycin for evaluation of this model. The GKO model offers considerable improvements over other systems, since it requires no additional immunosuppression and adult mice can be infected with as few as 10 oocysts (compared with 107 for SCID mice). Infected mice develop profound gastrointestinal dysfunction due to extensive infection and severe mucosal damage involving the entire small intestine. Clinical symptoms, which include depression, anorexia, weight loss, and wasting, result in death within 2 to 4 weeks. The time of death depends on the oocyst challenge dose. Paromomycin modulated parasitological and clinical parameters in highly predictable and significant ways, including prevention of death. In addition, examination of the extensively infected gut provided an important insight into the dynamics between a specific drug treatment, its impact on the extent and the site of parasite distribution, and clinical outcome. These uniform symptoms of weight loss, wasting, and death are powerful new parameters which bring this model closer to the actual disease seen in humans and other susceptible mammalian species.

* Corresponding author. Mailing address: Division of Infectious Disease, Tufts University School of Veterinary Medicine, North Grafton, MA 01536. Phone: (508) 839-7955. Fax: (508) 839-7977. E-mail: stzipori{at}infonet.tufts.edu.

Journal of Clinical Microbiology, September 1998, p. 2503-2508, Vol. 36, No. 9
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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