Long term objectives are to reduce morbidity and mortality due to Toxoplasma infection through better understanding of immune responses to this organism and improved use of antimicrobial agents.
Specific aims are to study immune responses in a mouse model of Toxoplasma acquired by ingestion and congenitally and in human congenital infections, and to develop optimal methods to interrupt congenital transmission of Toxoplasma and treat congenital toxoplasmosis. To further characterize immune responses which protect mice that ingest Toxoplasma, the antigens recognized by and protective effect of Toxoplasma specific intestinal antibodies against peroral and congenital infection will be characterized. Attenuated tachyzoites, bradyzoites and antigens of T. gondii alone, or antigens conjugated to cholera-toxin subunit B or synthesized by a cloned portion of the T. gondii genome recombined into a mouse Salmonella plasmid will be used to attempt to produce specific intestinal IgA. Monoclonal and polyclonal antibodies will be tested for their ability to block entry into or replication within enterocytes and to interrupt peroral and/or ongenital acquisition. Antigens will be studied to determine which epitopes bind to enterocytes. Studies will also be continued to characterize the gene(s) and gene product(s) that result(s) in differences in early survival of and numbers of latent brain cysts in recombinant inbred AXB/BXA mice on the A/J (resistant) and C57B1/6J (susceptible) backgrounds. Study of immune responses in human congenital infections will be continued by evaluation of lymphocyte blastogenic responses to Toxoplasma antigens, measurement of T cell subsets, and lymphocyte functions. To development optimal strategies to manage human congenital Toxoplasma infection a serologic screening program to diagnose Toxoplasma infection acquired during pregnancy will be evaluated and congenitally infected infants identified in this program (and through collaborative arrangements) will be studied prospectively to determine optimal treatment regimens and establish pharmacokinetics of the antimicrobial agents used.
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