Leukotrienes in the susceptibility and resistence to infection by Histoplasma capsulatum.

• Grant number: 08/01543-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2008
• End date: February 29, 2012
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Lúcia Helena Faccioli
• Grantee: Adriana Secatto
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 02/12856-2 - Modulation of innate and acquired immune responses by leukotrienes and prostaglandins, AP.TEM

Abstract

Histoplasma capsulatum is a dimorphic pathogenic fungus and responsible for histoplasmosis, disease for severe pulmonary lesions, characterized by a leukocyte accumulation around the fungus, resulting in granuloma formation. The infection occurs mainly by the inhalation of conidia or small fragments of mycelium that reach the alveoli, where they develop into yeasts - the pathogenic form of this fungus. In the last several years, studies regarding the function of leukotrienes are not only restricted to their role as mediators of inflammatory response, but also as mediators able to modulate the synthesis and release of cytokines, and thus the immune response. Moreover, the role of leukotrienes in the host defense mechanisms against infectious agents has also been demonstrated. In a recent work, we detected high levels of LTB4 and LTC4 in the lung of Histoplasma capsulatum-infected mice and showed that these mediators play an important role in the protection against the infection. The inhibition synthesis of these mediators by treatment of the H. capsulatum-infected mice with MK 886 resulted in dissemination and proliferation of the fungus into various organs, decrease synthesis IFN-g, IL-12 and a death rate of 100%. Recent work of literature shows that the susceptibility or resistance of different strains of animals to certain infections, such as, Leishmania amazonensis is associated to production levels of LTs. Cells obtained from BALB/c mice (susceptible) produce less LTs when compared with their production by cells from C3H/HePAS mice (resistence). However, it is still unknow the role of LTs in relation to the resistance and susceptibility to infection by H. capsulatum. C57BL /6 mice are susceptible to infection by H. capsulatum. Also, previous data obtained by our group showed that sv129 mice are more resistant to infection H. capsulatum compared to C57BL /6 mice.Therefore, our aim is to evaluate whether the resistance and susceptibility of sv129 in C57BL/6 mice, respectively, is related to differential levels of LTs synthesis, important to modulate the immune response. To investigate the our hypothesis, in vivo and in vitro experiments will be perfomed.