Together with HIV/AIDS and tuberculosis, malaria is a major infectious disease. Two thirds of the global population is at risk for malaria with sub-Saharan Africa accounting for about 90% of the deaths. Morbidity due to severe complications of this disease is extremely high among young children and pregnant women in this area. There is currently no vaccine available and drugs and insecticides are losing their effectiveness as the parasite and mosquito vectors, respectively, develop resistance to these tools of control. The major focus of the work in my laboratory is elucidation of the mechanisms of protective immunity against blood-stage malaria. One of our aims is to identify the cells and cytokines responsible for initiating innate immunity and inducing adaptive immunity to intraerythrocytic Plasmodium parasites, the causative agents of malaria. For our studies, we use a murine model of malaria in resistant and susceptible inbred mice infected with the rodent parasite, P. chabaudi AS. This rodent parasite is considered to have many similarities to the major human malaria parasite P. falciparum. We have identified that dendritic cells, NK cells, macrophages, and CD4+ T helper cells play important roles in the cell-mediated and antibody-dependent innate and adaptive immune responses required to control blood parasitemia and to clear and resolve the infection. We have also identified that a network of cytokines, involving IFN-gama, IL-12, TNF-alpha and GM-CSF, is critical for the development of protective immunity. Since anemia is a major cause of morbidity and mortality in children and pregnant women with severe malaria in sub-Saharan Africa, we are also examining cytokine regulation of erythropoiesis using in vivo and in vitro approaches. In collaboration with Dr. Philippe Gros, we are also identifying the major genes and their functions involved in susceptibility to malaria using the approaches of whole genome scanning, positional cloning and the candidate gene approach as well as transcriptional profiling of target tissues using cDNA microarrays and identification of important cell phenotypes by flow cytometry. Information obtained from our studies is important for the development of an efficacious vaccine strategy against blood-stage P. falciparum infection.
Stevenson MM, Ing R, Berretta F, Miu J.
Regulating the adaptive immune response to blood-stage malaria: role of dendritic cells and CD4⁺Foxp3⁺ regulatory T cells. Int J Biol Sci. 2011;7(9):1311-22. Epub 2011 Oct 25.
Moreno Y, Gros PP, Tam M, Segura M, Valanparambil R, Geary TG, Stevenson MM.
Proteomic analysis of excretory-secretory products of Heligmosomoides polygyrus assessed with next-generation sequencing transcriptomic information. PLoS Negl Trop Dis. 2011 Oct;5(10):e1370. Epub 2011 Oct 25.
Laroque A, Min-Oo G, Tam M, Radovanovic I, Stevenson MM, Gros P.
Genetic control of susceptibility to infection with Plasmodium chabaudi chabaudi AS in inbred mouse strains. Genes Immun. 2012 Feb;13(2):155-63. doi: 10.1038/gene.2011.67. Epub 2011 Oct 6.
Berretta F, St-Pierre J, Piccirillo CA, Stevenson MM.
IL-2 contributes to maintaining a balance between CD4+Foxp3+ regulatory T cells and effector CD4+ T cells required for immune control of blood-stage malaria infection. J Immunol. 2011 Apr 15;186(8):4862-71. Epub 2011 Mar 9.
Miu J, Saleh M, Stevenson MM.
Caspase-12 deficiency enhances cytokine responses but does not protect against lethal Plasmodium yoelii 17XL infection. Parasite Immunol. 2010 Nov-Dec;32(11-12):773-8.
Labbé K, Miu J, Yeretssian G, Serghides L, Tam M, Finney CA, Erdman LK, Goulet ML, Kain KC, Stevenson MM, Saleh M.
Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling. J Immunol. 2010 Nov 1;185(9):5495-502. Epub 2010 Sep 27.
Min-Oo G, Ayi K, Bongfen SE, Tam M, Radovanovic I, Gauthier S, Santiago H, Rothfuchs AG, Roffê E, Sher A, Mullick A, Fortin A, Stevenson MM, Kain KC, Gros P.
Cysteamine, the natural metabolite of pantetheinase, shows specific activity against Plasmodium. Exp Parasitol. 2010 Aug;125(4):315-24. Epub 2010 Feb 26.
Min-Oo G, Willemetz A, Tam M, Canonne-Hergaux F, Stevenson MM, Gros P.
Mapping of Char10, a novel malaria susceptibility locus on mouse chromosome 9. Genes Immun. 2010 Mar;11(2):113-23. Epub 2009 Oct 29.