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 in human congenital infections, and to develop optimal methods to interrupt congenital transmission of Toxoplasma and treat congenital toxoplasmosis. To further characterize immune response which protect mice that ingest Toxoplasma, inbred strains of mice will be used to evaluate the role of cytotoxic cells, H2 haplotype, Ity/Lsh/Bcg and H13 loci in protection against lethal toxoplasmosis. As a correlate of these studies, assays will be performed to determine whether there are Toxoplasma antigens on the surface of infected or antigen pulsed mouse macrophages that render them targets for lysis. Mechanisms causing depressed T cell function and lack of splenic lymphocyte blastogenesis to Toxoplasma antigens at a time when peritoneal macrophages are activated will be evaluated with the mouse model. Influence of Toxoplasma antigen specific cloned helper T lymphocytes, high titers of specific anti-Toxoplasma antibody, activated macrophages or an attenuated mutant Toxoplasma on acquisition of peroral or congenital Toxoplasma will be determined with the mouse model. Study of immune responses in human congenital infections will be by evaluation of lymphocyte blastogenic responses to Toxoplasma antigens, measurement of T cell subsets, and lymphocyte and monocyte function. To develop 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 studies prospectively to determine optimal treatment regimens and establish pharmacokinetics of the antimicrobial agents used.
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