Rima McLeod, M.D.

Immunobiology of Toxoplasmosis

Research Summary

Toxoplasmosis causes loss of sight, hearing and brain damage in congenitally infected individuals. It also causes substantial morbidity and mortality in individuals immunocompromised by organ transplantation, malignancy or vasculitis and their therapy or AIDS.

Our laboratory has discovered Toxoplasma gondii specific secretory IgA (mouse and human) which can block T. gondii invasion of enterocytes, T. gondii specific cytolytic T cells, and demonstrated that a temperature sensitive mutant T gondii can confer protection against peroral and congenital T. gondii infection in a murine model. We have also demonstrated marked differences in genetic susceptibility to this infection and identified some of the responsible genetic loci. In separate experiments, we have discovered T. gondii antigen specific unresponsiveness in congenitally infected infants.

Our current experiments involve protective and harmful immune responses (in mice and humans) and constructing recombinant vectors for delivery of those epitopes that elicit protective immunity. Specifically, our research involves (1) defining T.Gondii epitopes recognized by protective CTL lymphocytes, (2) determining whether the critical protective immune function is cytolytic T cell function or gamma interferon production or both, and (3) incorporating the genes which encode proteins which contain epitopes that elicit protection into a DNA vaccine. This construct will be used to immunize human MHC transgenic mice (on a susceptible H-2^b background) to determine whether it will protect against peroral and congenital infection.

We also are characterizing immunogenetics and pathogenesis and protection in this infection.

Selected Papers

Brown C, David C, Kahn SJ and McLeod R. (1994). Effect of human MHC class I genes on outcome of T. gondii cyst formation. J Immunol, 152:4537-41.

McLeod R, Buschman E, Arbuckle LD and Skamene E. (1995). Immunogenetics in the analysis of resistance to intracellular pathogens. R Ahmed and A Sher (Eds.). Immunity to InfectionCurrent Opinion in Immunol, 7:539-552.

Roberts F, Roberts CW, Johnson J, Kyle DE, Krell T, Coggins JR, Coombs GH, Milhous WK, Tzipori S, Ferguson DJP, Chakrabarti D, McLeod R. (1998). Evidence for the shikimate pathway in apicomplexan parasites. Nature, 393:801-805.

Mack D, Johnson J, Roberts F, Roberts C, Estes R, David C, Grumet C, Estes R and McLeod R. (1999). HLA-Class II genes modify outcome of Toxoplasma gondii infection. (Rapid Communication) Int'l J Parasitol, 29:1351-1358.

Kirisits M, Mui E, McLeod R. (2000). Measurement of the efficacy of vaccines and antimicrobial therapy against infection with Toxoplasma gondii. Int'l J. for Parasitol., In Press.