Avaliação da resposta imune protetiva de camundongos BALB/c à infecção por Leishmania (Viannia) guyanensis: papel de espécies reativas do oxigênio e de linfócitos T helper

Abstract

Certain mouse strains, such as BALB/c, develop uncontrollable skin lesions, while others, such as C57BL/6, can control the skin infection after inoculation with L. major or L. amazonensis. In the murine model, the resolution or progression of disease caused by L. major appears to be determined by the preferential activation of Th1 or Th2 cells, respectively. In the presence of a Th1 response, macrophages activated primarily by Th1-derived IFN- become capable of eliminating the parasite by producing nitric oxide (NO), which is toxic to the parasite. The polarization of the response into Th1 or Th2, however, is not as clear for other Leishmania species. For example, mice of the C57BL/10 strain, while capable of curing a L. major infection, fail to resolve the lesion when infected with L. amazonensis. When infected with L. major, these mice produce high levels of IFN- and no IL-4, but if the infection is with L. amazonensis, IL-4 is produced but not IFN-. Thus, the same host reacts differently to different Leishmania species, and therefore, resistance and susceptibility, as well as the Th1/Th2 response pattern, depend not only on the host genetic background but also on the infecting species or even the strain. Another interesting example of the same mouse strain presenting completely different responses to infection by two Leishmania species is the BALB/c strain. Completely susceptible to infection by L. major and L. amazonensis, these mice develop minimal or no lesions when infected with L. guyanensis. In vitro, macrophages from BALB/c mice eliminate L. guyanensis but not L. amazonensis infection. We have already shown that this elimination is dependent on the respiratory burst and reactive oxygen species (ROS) induced by the infection, and that the parasite dies by apoptosis. These examples demonstrate that the immune response to infection by various Leishmania species is quite complex and cannot be explained simply by the Th1/Th2 dichotomy, but must have an important involvement of innate immunity mechanisms. The objective of this project was to investigate the role of the respiratory burst (innate immunity) and the T helper cell response (adaptive immunity) in the resistance of BALB/c mice to L. guyanensis infection. In brief, we investigated some aspects of the host response after infection with L. guyanensis, namely, the actual role of ROS using apocynin, a specific inhibitor of the respiratory burst, and the type of adaptive response (Th1 or Th2), through the expression of the cytokines IFN- and IL-4, in the infection outcome of these mice. We found that ROS are important for containing infection in the first few weeks and that in subsequent weeks, mice produce IFN- but not IL-4, a hallmark of a Th1 response. Since our group has previously shown that L. guyanensis is sensitive to NO, our results demonstrate that ROS can control infection in the early during the infection and indicate that activation of a Th1-type response should control infection later on.