Do immunomodulatory lectins of Toxoplasma gondii confer protection against Leishmania major infection?

• Grant number: 14/13259-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2014
• End date: September 30, 2015
• Field of knowledge: Biological Sciences - Immunology - Immunochemistry
• Principal Investigator: Maria Cristina Roque Antunes Barreira
• Grantee: Arthur Cadamuro Guedes
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/04088-0 - Lectin from pathogens, AP.TEM

Abstract

Leishmaniasis is an endemic disease in Brazil. There are more than 20 different species of the genus Leishmania able to cause disease, that may vary from skin lesions to visceral forms, which are often lethal. The treatment of leishmaniasis is based on the use of pentavalent antimonials. They are efficient in the most part of the cases, but may be toxic and inefficient in the most severe forms of the disease, depending on factors such as the variation in sensitivity to the drug by the different species of parasites, as well as their ability to develop resistance to the drugs. In general, infection gives rise to strong immune response, but the parasite has mechanisms to evade immune responses, such as the regulation of antigen presentation by APCs, inhibition of cytokine production, inhibition of complement lysis, among others. Th1 immune responses confer resistance against the infection, while the development of Th2 responses confer susceptibility. Thus, immunotherapies that enhance the magnitude of Th1 responses against the parasite may represent an important strategy in combating the disease. In this sense, our group has demonstrated that the lectins of Toxoplasma gondii microneme, TgMIC1 and TgMIC4, induce the production of pro-inflammatory cytokines by murine macrophages, such as TNF-±, IL-6, IL-1² and IL-12, being that the last one plays a key role in the induction of Th1 responses. The results observed in vitro allowed us to propose that the prophylactic use of lectin in vivo could be able to induce the development of Th1 responses and promote the protection against infection by intracellular pathogens. Although the administration of TgMICs to mice prior to infection with T. gondii led to increased resistance to the infection, this model did not allow us to accurately characterize the contribution of innate and adaptive responses to the observed outcome. For this reason we are proposing to study the effect of T. gondii lectins administration in the experimental murine L. major infection. We assume that, in BALB/c mice, which are naturally susceptible to infection by L. major due to the development of Th2 immune responses to the parasite, the treatment with T. gondii TgMIC1 and TgMIC4 may improve the development of Th1 responses with concomitant resistance to the infection. To this end, BALB/c mice will be treated subcutaneously with TgMIC1 or TgMIC4 and, after 10 days, the animals will be infected with L. major in the right footpad. We will evaluate the immune response profile by quantifying cytokines in the popliteal lymph nodes and characterizing the kinetics of lesion development and parasite load in infected organs from the mice.