Long term objectives are to reduce morbidity and mortality due to congenital Toxoplasma gondii, infection through improved use of antimicrobial agents and understanding its pathogenesis.
Specific aims are to (1) develop optimal methods to evaluate, treat and provide follow up care for children suffering from congenital toxoplasmosis and (2) better understand pathogenesis and containment of this infection. An ongoing, prospective, randomized treatment trial will be continued, as initially planned, to determine early and long term outcome for treated children. Cognitive, motor, ocular and audiologic outcome will be determined following treatment with one of two dosages of pyrimethamine plus sulfadiazine. As congenital toxoplasmosis can now be diagnosed using amniocentesis and T. gondii B1 gene reverse transcription PCR and the infected fetus can be treated in utero, outcome also will be characterized for such congenitally infected, treated children. Evaluation of the cohort of older, untreated """"""""historical control"""""""" children with retinal disease will be continued. These children also provide an ideal and well characterized group of patients for a future randomized, placebo- controlled study of effect of antimicrobial agents active against encysted bradyzdites on relapsing chorioretinitis. Mechanism(s) of T. gondii antigen specific lymphocyte unresponsiveness in congenitally infected infants will be determined. Studies will include determination of whether there are suppressive cell populations or peripheral anergy and characterization of T cell receptor usage, cytokines produced, and effect of T. gondii infection on antigen presenting cell costimulatory molecules. As a tissue correlate of cytokines produced by peripheral blood cells, regional brain and eye histopathology and cytokine patterns in human congenital toxoplasmosis will be characterized. To define human HLA resistance and susceptibility genes, HLA haplotypes of the following individuals will be determined, compared with known background HLA frequencies for these populations and correlated with either transmission of congenital infection or severity of disease: women acutely infected during gestation who have and have not transmitted infection, infected infants, monozygotic and dizygotic twin pairs concordant or discordant for manifestations of infection, and Filipino and Hmong individuals (who appear to have particularly severe and frequent congenital toxoplasmosis). These studies will determine how to best provide medical care to children afflicted with congenital toxoplasmosis and will provide a better understanding of the pathogenesis and host factors important in containment of this infection in humans.
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