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

McLeod R, Kieffer F, Sautter M, Hosten T, Pelloux H. Why prevent, diagnose and treat congenital toxoplasmosis?Mem Inst Oswaldo Cruz. 2009 Mar;104(2):320-44. Review.PMID: 19430661

Jamieson SE, Cordell H, Petersen E, McLeod R, Gilbert RE, Blackwell JM. Host genetic and epigenetic factors in toxoplasmosis.Mem Inst Oswaldo Cruz. 2009 Mar;104(2):162-9.PMID: 19430638

Lees MP, Fuller SJ, McLeod R, Boulter NR, Miller CM, Zakrzewski AM, Mui EJ, Witola WH, Coyne JJ, Hargrave AC, Jamieson SE, Blackwell JM, Wiley JS, Smith NC. P2X7 receptor-mediated killing of an intracellular parasite, Toxoplasma gondii, by human and murine macrophages.J Immunol. 2010 Jun 15;184(12):7040-6. Epub 2010 May 19.PMID: 20488797

Noble AG, Latkany P, Kusmierczyk J, Mets M, Rabiah P, Boyrer K, Jalbrzikowski J, Wroblewski K, Karrison T, Swisher CN, Mierler WF, Meier P, Mcleod R and the Toxoplasmosis Study Group.Chorioretinal Lesions in Mothers of Children with Congenital Toxoplasmosis in The National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Scientia Medica. 2010.

Jamieson SE, Peixoto-Rangel AL, Hargrave AC, Roubaix LA, Mui EJ, Boulter NR, Miller EN, Fuller SJ, Wiley JS, Castellucci L, Boyer K, Peixe RG, Kirisits MJ, Elias Lde S, Coyne JJ, Correa-Oliveira R, Sautter M, Smith NC, Lees MP, Swisher CN, Heydemann P, Noble AG, Patel D, Bardo D, Burrowes D, McLone D, Roizen N, Withers S, Bahia-Oliveira LM, McLeod R, Blackwell JM. Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.Genes Immun. 2010 Jul;11(5):374-83. Epub 2010 Jun 10.PMID: 20535134

Tan T, Mui E, Cong H, Witola W, Montpetit A, Muench S, Sidney J, Alexander J, Sette A, Grigg M, Reed S, Maewal A, Kim S, Boothroyd J, McLeod R. Identification of T. gondii epitopes, adjuvants, & host genetic factors that influence protection of mice & humans. Vaccine. 28: 3977-89, 2010. PMCID: 2895808

Henriquez FL, Woods S, Cong H, McLeod R, Roberts CW.Immunogenetics of Toxoplama gondii informs vaccine design.Trends Parasitol. 2010 Jun 25. [Epub ahead of print]PMID: 20580611
       

Tipparaju S, Muench S, Mui E, Ruzheinikov S, Hutson S, Kirisits M, Prigge S, Roberts C, Henriquez F, Kozikowski AP, Rice D, McLeod R. Rational Development of Novel Inhibitors of Toxoplasma gondii Enoyl Reductase. J Med Chem 53: 6287-300, 2010. PMCID: 2932859