THE GAMMA-INTERFERON GENE KNOCKOUT MOUSE - A HIGHLY SENSITIVE MODEL FOR EVALUATION OF THERAPEUTIC AGENTS AGAINST CRYPTOSPORIDIUM-PARVUM

Cryptosporidiosis is a serious disease in malnourished children and in people with malignancies or AIDS. Current rodent models for evaluatin g drug therapy against cryptosporidiosis have many limitations, includ ing the need for a high inoculum, the absence of symptoms resembling t hose seen in humans, and the need to maintain exogenous immunosuppress ion, We have developed a gamma interferon knockout (GKO) mouse model w ith which to evaluate therapies against C, parvum and have used paromo mycin for evaluation of this model. The GKO model offers considerable improvements over other systems, since it requires no additional immun osuppression and adult mice can be infected with as few as 10 oocysts (compared with 10(7) for SCID mice). Infected mice develop profound ga strointestinal dysfunction due to extensive infection and severe mucos al damage involving the entire small intestine. Clinical symptoms, whi ch include depression, anorexia, weight loss, and wasting, result in d eath within 2 to 4 weeks. The time of death depends on the oocyst chal lenge dose. Paromomycin modulated parasitological and clinical paramet ers in highly predictable and significant ways, including prevention o f death. In addition, examination of the extensively infected gut prov ided an important insight into the dynamics between a specific drug tr eatment, its impact on the extent and the site of parasite distributio n, and clinical outcome. These uniform symptoms of weight loss, wastin g, and death are powerful new parameters which bring this model closer to the actual disease seen in humans and other susceptible mammalian species.