O papel do receptor do tipo Toll 6 na resposta imune contra a infecção pela bactéria Mycobacterium avium

Abstract

The innate immune response corresponds to the first line defense against infections, with the Toll-like receptors (TLRs) being important to pathogen recognition. The activation of TLRs leads to the production of cytokines and other immune mechanisms necessary to the efficient control of infections. The Mycobacterium avium is an important opportunistic pathogen that infects principally immunocompromised individuals. In the present study we evaluated the participation of TLR6 in the recognition and control of M. avium infection. The luciferase assay in HEK 293 cells showed that TLR6 acts synergistically with TLR2 and they are important for M. avium recognition. Supporting this result, M. avium infection leads to a higher expression of TLR6 and TLR2 in mice bone marrow derived macrophages (BMMs) and dendritic cells (BMDCs). Moreover, TLR6-deficiency reduces the production of TNF-_, IL-12 and IL-6 in BMDCs and increases the susceptibility of BMMs to infection. Analysis of the intracellular signaling pathways revealed that phosphorilation of JNK, ERK1/2 and p38 is dependent on TLR6 in both cell types stimulated with M. avium. Additionally, MyD88, TLR6 and TLR2 influence the activation of NF-_B in dendritic cells, although these receptors are only partially relevant in macrophages. The in vivo analysis demonstrated that TLR6-defficient mice infected with M. avium showed a higher bacterial burden in spleen, liver and lungs compared to wild type animals, indicating that this receptor is necessary for the efficient control of this infection. However, TLR6 is not involved in the production of IFN-_ or TNF-_ by splenocytes. The level of these cytokines was altered only in MyD88 KO mice. In parallel with this finding, the flow cytometry analysis demonstrated that only in MyD88-defficient mice the percentage of CD4+ or CD8+ T lymphocytes producing IFN-_ in spleen was reduced. In contrast, IFN- _ level was significantly lower in TLR6 or TLR2 KO mouse lungs, when compared to 9 wild type animals. Nevertheless, the liver granuloma area was found to be reduced only in MyD88 KO mice. Finally, blocking of TLR6 in THP-1 human monocytic cell line infected with M. avium reduced the production of TNF-_ and activation of MAPKs, indicating that the mouse findings observed here be extrapolated to humans.