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

Ferguson DJ, Roberts CW, Phan L, Mui E and McLeod R, et al. Enzymes of type 2 fatty acid synthesis, apicoplast differentiation and division, and division associated proteins and their phylogeny in Eimeria tenella. IJP 2007 Jan;37(1):33-51.

Muench SP, Prigge ST, Zhu L, Kirisits MJ, Roberts CW, Wernimont S, McLeod R, Rice DW. Expression, purification and preliminary crystallographic analysis of the Toxoplasma gondii enoyl reductase. Acta Crystallograph Sect F Struct Biol Cryst Commun. 2006 Jun 1;62(Pt 6):604-6.

Muench SP, Prigge ST, McLeod R, Rafferty JB, Kirisits MJ, Roberts CW, Mui EJ, Rice DW. Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Acta Crystallogr D Biol Crystallogr. 2007 Mar;63(Pt 3):328-38.

Lu J, Muench SP, Rice DW, Roberts CW, McLeod R, Prigge S. Type I and type II fatty acid biosynthesis in Eimeria tenella: enoyl reducatse activity and structure. Parasitology. 134(Pt 14):1949-62, 2007.

Botte C, Saidani N, Mondragon r, Mondragon M, Isaac G, Mui E, McLeod R, Dubremetz JF, Vial H, Welti R, Cesbron-Delauw MF, Mercier C, Marechal E. Subcellular localization and dynamics of a digalactolipid-like eitope in Toxoplasma gondii. J Lipid Res.49:746-762, 2008. PMID: 18182683.

Welti R, Mui E, Wernimont S, Kirisits M, Roberts CW, McLeod R. Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids. Biochemistry. Nov 2007. PMID: 17988103

Mui EJ, Schiehser G, Milhous WK, Hsu H, Roberts CW, Kirisits M, Muench S, Rice D, Dubey JP, Fowble, JW, Rathod P, Queener S, Liu SR, Jacobus D, McLeod R.  Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. Plos Neglected Tropical Diseases, 2(3):e190 pp1-6 2008.

Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K, Mayr T, Kirisits MJ, Wollmann R, Ferguson DJ, Roberts CW, Hwang JH, Trendler T, Kennan RP, Suzuki Y, Reardon C, Hickey WF, Chen L, McLeod R. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation. 23;5:48.

Jamieson SE, de Roubaiz LA, Cortina-Borja M, Tan HK, Mui EJ, Cordell HJ, Kirisits MJ, Miller EN, Peacock CS, Hargrave AC, Coyne JJ, Boyer K, Bessieres MH, Buffolano W, Ferret N, Franck J, Kieffer F, Meier P, Nowakowska DE, Paul M, Peyron F, Stray-Pedersen B, Prusa AR, Thulliez P, Wallon M, Petersen E, McLeod R, Gilbert RE, Blackwell J. COL2A1 and ABCA4 Are Epigenetically Modified and Associated With Congenital Toxoplasmosis. PLoS ONE, In Press 2008.