Papel da enzima 5-lipoxigenase na infecção oral por Toxoplasma gondii

Abstract

5-lipoxygenase (5-LO) is an enzyme required for production of leukotrienes and lipoxins and interferes with parasitic infections. In vitro, Toxoplasma gondii inhibits leukotriene B4 (LTB4) production and mice deficient in 5-LO are highly susceptible to infection. The aim of this study was to investigate the role of the 5-LO pathway in susceptible C57BL/6 mice infected by oral route with T. gondii. For this propose, C57BL/6 mice were treated with MK886, an inhibitor of 5-LO pathway, or with LTB4, in order to simulate an increased enzyme activity. In addition, once Strongyloides venezuelensis induces 5-LO activity, mice were treated with S. venezuelensis antigen (AgSv) to induce this pathway. Initially, it was observed that T. gondii itself decreased 5-LO expression in small intestine of mice with susceptible (H2b) or resistant (H2d) major histocompatibility complex (MHC) haplotype to T. gondii infection. AgSv treatment increased the expression of 5-LO in the small intestine, however, the parasite reduced 5-LO even in treated mice. Nevertheless, AgSv treatment controlled the replication of T. gondii in the small intestine of mice. In contrast, treatment with MK886 reinforce this reduction of 5- LO during infection, once treated infected-mice presented higher intestinal parasitism and lower local production of IL-6, IFN-γ, and TNF. Treatment with LTB4 decreased parasite replication in the small intestine, liver and lung, as well as reduced the histological damage in the liver and lung, although does not alter the cytokine profile or histological damage in the small intestine of infected mice. In addition, in the small intestine, LTB4 enhanced -defensin 1 expression, an antimicrobial peptide produced by Paneth cells which are important for intestinal homeostasis and, preserved the numbers of this cell phenotype, despite presenting lower compared with uninfected mice. Moreover, LTB4 treatment increased T. gondii- and Escherichia coli-specific IgA levels in the small intestine of infected animals. Altogether, these data demonstrated that T. gondii itself interferes in the 5-LO pathway, and the inhibition of this pathway is beneficial for the parasite; conversely, treatment with LTB4, an end-product of the pathway, had a protective role in the small intestine during experimental infection, highlighting the important relationship between 5-LO and toxoplasmosis.