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

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 againstC. 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.

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

“…The interferon gamma knockout (IFN-γ KO) mouse is another widely used Cryptosporidium animal model 17,[39][40][41] . Unlike lethal infection reported by some investigators, C. parvum infection of IFN-γ KO mice produces a self-resolving acute infection in our hands.…”

Humoral immune response in IL‐12 and IFN‐γ deficient mice after infection with Cryptosporidium parvum

“…Adult mice genetically deficient in IFN-γ have been shown to be highly susceptible to infection with C. parvum. However, the clinical outcome of the infection has been described differently by various groups (11,15,16,19,(37)(38)(39)(40)(41). In most experiments, animals developed a chronic infection whereas the survival rates ranged from 100% to almost zero.…”

Host Responses to Cryptosporidium Infection

“…Several observations suggest that IFN␥ is a major effector cytokine of the immune response against Cryptosporidium infection. IFN␥ knockout mice or mice treated with anti-IFN␥ antibody are highly susceptible to Cryptosporidium infection 11,71,72 and have increased numbers of infected enterocytes and oocyst shedding. 11,68 Conversely, treatment with recombinant IFN␥ diminishes the parasite load of infected intestinal epithelium.…”