Publicação
Impact of mycobacterial recognition by toll like receptors in the regulation of IL-10 and T helper type of responses
| Resumo: | The early immune recognition of mycobacteria is of most importance for the initiation of microbicidal mechanisms and modulation of adaptive immune responses. Macrophages and dendritic cells (DCs) are important players of the innate immune response and are among the first cells to sense mycobacteria. This initial recognition of the pathogen is only possible due to pattern recognition receptors (PRRs) on host cells, such as toll like receptors (TLRs), which activation culminates in the production of cytokines that will act as autocrine but also paracrine factors. A balanced cytokine environment is fundamental, as uncontrolled pro-inflammatory responses might culminate in tissue damage, however, an immune suppressive environment could lead to an impaired ability to control infection. In this thesis, we addressed the impact of mycobacterial recognition on cytokine production by mouse macrophages and DCs, with an emphasis on the regulation of IL-10 expression. We have also addressed the specific contribution of TLR2 in the establishment of T helper (Th)17 type of responses upon mycobacterial infection in mice. Firstly, we compared the regulation of IL-10 by macrophages infected with two strains of Mycobacterium tuberculosis whose macrophage activation can be mainly mediated by TLR2 or by TLR4. We found that both strains can induce IL-10 production, however TLR2 triggering led to a rapid and strong degradation of the IL-10 mRNA, while TLR4 triggering led to the stability of IL-10 mRNA, thereby resulting in different amounts of IL-10 production. The stabilization of the IL-10 mRNA was found to be the result of the TLR4-induced activation of the TRIF/p38 pathway, thus uncovering a novel pathway for IL-10 regulation at the post-transcriptional level in the context of infection by mycobacteria. Secondly, we observed that, when compared to M. tuberculosis, Mycobacterium bovis BCG was a potent inducer of IL-10 production by DCs, which strongly contributed for the low amounts of IL-12 induced by this mycobacterium. Considering the importance of TLR2 in the recognition of both bacteria, our results also suggest that M. bovis BCG is a stronger activator of TLR2, when compared to M. tuberculosis. Thirdly, we have dissected the role of TLR2 recognition during an in vivo M. tuberculosis infection. We showed for the first time that TLR2 is of major importance for the maintenance of Th17 responses in the lung, and consequently for the expression of CXCL9, CXCL10 and CXCL11, chemokines implicated in protective recall responses to M. tuberculosis. This study provides insights into the role of TLR2 in response to M. tuberculosis with implications in the pathophysiology of the disease and vaccine design.Overall, our studies provide insights on how pro and anti-inflammatory responses can be differently triggered by distinct strains and species of mycobacteria and its implications on our understanding of the host-pathogen interactions with consequences on the design of novel preventive and therapeutic strategies. |
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| Autores principais: | Coelho, Maria Rosinda Teixeira |
| Ano: | 2012 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | português |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | The early immune recognition of mycobacteria is of most importance for the initiation of microbicidal mechanisms and modulation of adaptive immune responses. Macrophages and dendritic cells (DCs) are important players of the innate immune response and are among the first cells to sense mycobacteria. This initial recognition of the pathogen is only possible due to pattern recognition receptors (PRRs) on host cells, such as toll like receptors (TLRs), which activation culminates in the production of cytokines that will act as autocrine but also paracrine factors. A balanced cytokine environment is fundamental, as uncontrolled pro-inflammatory responses might culminate in tissue damage, however, an immune suppressive environment could lead to an impaired ability to control infection. In this thesis, we addressed the impact of mycobacterial recognition on cytokine production by mouse macrophages and DCs, with an emphasis on the regulation of IL-10 expression. We have also addressed the specific contribution of TLR2 in the establishment of T helper (Th)17 type of responses upon mycobacterial infection in mice. Firstly, we compared the regulation of IL-10 by macrophages infected with two strains of Mycobacterium tuberculosis whose macrophage activation can be mainly mediated by TLR2 or by TLR4. We found that both strains can induce IL-10 production, however TLR2 triggering led to a rapid and strong degradation of the IL-10 mRNA, while TLR4 triggering led to the stability of IL-10 mRNA, thereby resulting in different amounts of IL-10 production. The stabilization of the IL-10 mRNA was found to be the result of the TLR4-induced activation of the TRIF/p38 pathway, thus uncovering a novel pathway for IL-10 regulation at the post-transcriptional level in the context of infection by mycobacteria. Secondly, we observed that, when compared to M. tuberculosis, Mycobacterium bovis BCG was a potent inducer of IL-10 production by DCs, which strongly contributed for the low amounts of IL-12 induced by this mycobacterium. Considering the importance of TLR2 in the recognition of both bacteria, our results also suggest that M. bovis BCG is a stronger activator of TLR2, when compared to M. tuberculosis. Thirdly, we have dissected the role of TLR2 recognition during an in vivo M. tuberculosis infection. We showed for the first time that TLR2 is of major importance for the maintenance of Th17 responses in the lung, and consequently for the expression of CXCL9, CXCL10 and CXCL11, chemokines implicated in protective recall responses to M. tuberculosis. This study provides insights into the role of TLR2 in response to M. tuberculosis with implications in the pathophysiology of the disease and vaccine design.Overall, our studies provide insights on how pro and anti-inflammatory responses can be differently triggered by distinct strains and species of mycobacteria and its implications on our understanding of the host-pathogen interactions with consequences on the design of novel preventive and therapeutic strategies. |
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