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The gamma interferon gene knockout mouse: a highly sensitive model for evaluation of therapeutic agents against
J K Griffiths1, C Theodos, M Paris
1Division of Infectious Disease, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA.
Abstract:
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 10(7) 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.
Insights
A new gamma interferon knockout (GKO) mouse model effectively simulates cryptosporidiosis in humans, showing significant gastrointestinal issues and weight loss. This model accurately predicts drug responses, offering a better system for evaluating therapies against Cryptosporidium parvum.
Area of Science:
- Immunology
- Parasitology
- Infectious Diseases
Background:
- Cryptosporidiosis poses a significant threat to immunocompromised individuals and malnourished children.
- Existing rodent models for cryptosporidiosis drug evaluation have limitations, including high inoculum requirements, lack of human-like symptoms, and need for immunosuppression.
Purpose of the Study:
- To develop and validate a novel gamma interferon knockout (GKO) mouse model for evaluating anti-cryptosporidiosis therapies.
- To assess the efficacy of paromomycin in the GKO mouse model.
Main Methods:
- Development of a gamma interferon knockout (GKO) mouse model for Cryptosporidium parvum infection.
- Infection of GKO mice with a low dose of C. parvum oocysts (10 oocysts).
- Administration and evaluation of paromomycin treatment in infected GKO mice.
Main Results:
- The GKO model requires minimal inoculum and no exogenous immunosuppression, unlike SCID mice.
- Infected GKO mice exhibited severe gastrointestinal dysfunction, mucosal damage, and clinical symptoms mirroring human cryptosporidiosis, leading to death within 2-4 weeks.
- Paromomycin treatment significantly modulated parasitological and clinical outcomes, including preventing mortality.
Conclusions:
- The GKO mouse model provides a more accurate and sensitive system for studying cryptosporidiosis pathogenesis and drug efficacy.
- This model closely replicates human disease symptoms, offering valuable insights into drug treatment dynamics and parasite-host interactions.