Effect of the induction and suppression of iNOS levels over control of Cryptococcus gattii infection

Abstract

The variants of the genus Cryptococcus are classified into C. neoformans and C. gattii species according to the biochemical, ecological, epidemiological and clinical aspects. C. gattii infection is a primary infection because the pathogen has a predilection for immunocompetent individuals. C. gattii infection affects humans by inhalation of propagules, spores and/or dehydrated yeast, which reach the pulmonary alveoli. The lungs are primarily reached by C. gattii, which has a high predilection for lung tissue favoring the cryptococcomas. Cryptococcus spp yeast can be detected by alveolar macrophages that initiate the anti-cryptococcal immune response. The phagosome containing the yeast is responsible for exposure to reactive oxygen (ROS) and nitrogen species, which favors the protection against experimental cryptococcosis. In this context, the M1 macrophage polarization, characterized by iNOS expression, and M2 macrophage, which express Arginase-1, play role in the progression of cryptococcosis. However, the effect of balance of M1 and M2 macrophages in the lung tissue overtime during the C. gattii infection is unknown. Our group reported that C. gattii infection induces the prevalence of iNOS expression in the lungs overtime during the C. gattii infection, and this fact occurs in the period of pathogen spreading. Thus, the current proposal aim to evaluate the effect of induction and suppression of iNOS levels, through the administration of IFN-g or IL-4, in the control of C. gattii infection. Our approach is based on the infusion of IFN-g or IL-4, via intratracheal and subcutaneous routes, to regulate the levels of iNOS expression in the pulmonary tissue. The effect of regulation of iNOS expression overtime during the C. gattii infection will be evaluated as follows: fungal burden in the pulmonary and brain tissues in different periods; quantification of pro and anti-inflammatory cytokinex in different tissues; measurement of GXM in the serum; determinate the survival curve of mice infected with C. gattii and treated with IFN-g or IL-4.