EXPERIMENTAL-MODELS OF TOXOPLASMOSIS - PHARMACOLOGICAL APPLICATIONS

Toxoplasma gondii is an ubiquitous protozoan parasite causing severe or life-threatening infections in immunocompromised patients and in congenitally infected infants. Animal models have been extensively used to describe the pathology of infection and to identify new effective drugs for the treatment of congenital infections, chrorioretinitis and toxoplasmic encephalitis. Although inherent differences between man and animal can reduce the relevance of data obtained experimentally, animal models have greatly improved our knowledge on the various aspects of toxoplasmosis. Toxoplasma infection can be easily obtained in most laboratory animals, with exception of rats which are partially resistant. According to the strain used, the resulting infection may be acute, subacute or chronic, and can be monitored either by the survival of animals, the histopathological examination of lesions or, preferably, by titration of parasites in infected tissues using subino-culation mice or tissue culture. This latter method has proved particularly useful to describe the kinetics of infection in host tissues and to assess the efficacy of drugs, according io their pharmacokinetics and tissue distribution. The relevance of results obtained in animal models of congenital toxoplasmosis and of chrorioretinitis is more questionable, due to the marked differences between the mode of infection in humans and in animals. Experiments performed in primates provided valuable informations for the management of therapy of congenital toxoplasmosis but were of limited interest for ocular toxoplasmosis. The pathogeny of toxoplasmic encephalitis is still poorly understood, and no experimental model is fully satisfactory to produce focal encephalitic lesions as observed in immunocompromised humans. Acute infections with highly virulent strains induce disseminated infection with major pulmonary and brain involvement, and thus can be used to assess the efficacity of drugs in these tissues. Direct inoculation of tachyzoites into brain tissue can induce focal encephalitis but this model is of difficult use for large scale studies. Although cellular immunity is mainly responsible for the control of toxoplasmosis at the chronic stage, administration of immunosuppressive drugs does not usually result in focal brain reactivation; such reactivation can only be obtained using antibodies against CD8 and CD4 T lymphocytes or interferon gamma. Another experimental approach is the use of genetically immunodeficient animals : these models ore of limited interest for pharmacological research since infection of nude or T depleted mice usually results in a dissemination of infection, however, using these models it could be clearly demonstrated that immunity plays a major adjunctive role in the control of acute infection. Concurrent infections between viruses and parasites is a common feature in immunocompromised patients and especially during AIDS. Experimental models of dual infections were developed in an attempt to explain the pathogeny of T. gondii in hosts presenting virus induced immunodeficiencies. Mice co-infected with T. gondii and the retrovirus LP-BM5, responsible for the Murine Acquired Immunodeficiency Syndrome (MAIDS), and cats co-infected with T, gondii and the Feline Immunodeficiency Virus (FIV) are more susceptible to primary acquired toxoplasmosis, but reactivation of chronic infection is unconstantly observed. These studies also showed that Toxoplasma infection also interacts with the natural course of MAIDS. Other experimental models of concurrent infections in which T. gondii was associated with other opportunistic pathogens were developed. Coinfection with Pneumocystis carinii and T. gondii has been realized in immunocompromised rats and this model was used for assessing the efficacy oi combined prophylaxis against both pathogens. These models ore certainly more difficult to realize and io standardize but are intended to closely simulate the features of the human diseases and to provide a better understanding of the complex interactions between pathogens and host defense.