INFLUENCE OF TLR2, TLR4 AND TLR9 MODULATION IN THE RESPONSE OF T OF REGULATORY CELLS IN INDIVIDUALS WITH LATENT TUBERCULOSIS IN FRONT THE IN VITRO CHALLENGE WITH Mycobacterium tuberculosis
Name: FLAVIA DIAS COÊLHO DA SILVA
Publication date: 10/07/2018
Advisor:
Name |
Role |
|---|---|
| RODRIGO RIBEIRO RODRIGUES | Advisor * |
Examining board:
| Name |
Role |
|---|---|
| FAUSTO EDMUNDO LIMA PEREIRA | Internal Examiner * |
| MOISES PALACI | Internal Examiner * |
| RODRIGO RIBEIRO RODRIGUES | Advisor * |
| SANDRA LÚCIA VENTORIN VON ZEIDLER | External Examiner * |
Summary: Latent tuberculosis infection (LTBI) affects approximately a quarter of the world's population. During LTBI, M. tuberculosis (Mtb) survives in a state of dormancy, which reactivates latent infection, which resumes normal growth and metabolism. Macrophages / monocytes (MO) play a central role in the mycobacterial pathogenesis, since they are the main cellular niche for Mtb during infections. The protective immune response, which the MO are part of is influenced by suppressive mechanisms, among them the increase of the activity of T regulatory cells (Tregs). Tregs have the ability to control tissue damage by decreasing adequate control of mycobacterial replication, and may also be involved in the reactivation and dissemination of Mtb. Toll-like receptors (TLRs) participate in the response to the infection by detecting and regulating it, and TLR2, TLR4 and TLR9 are known to recognize components of Mtb, which influence the response to kinetics and cytokine production by infection. We sought to assess the influence of TLR2, TLR4 and TLR9 agonists and antagonist in peripheral blood and Mtb-challenged whole blood cultures of individuals with LTBI (TST+ group) relative to the negative control (TST- group), investigating the frequency of Tregs and MO cells, the microbicidal activity and the dosage of cytokine IL10, IL17, TGFβ and IFNγ among these groups. Higher frequency of MO (CD14+ CD16+ HLA-DR+, CD14+ TLR2+ HLA-DR+, CD14+ TLR4+ HLA-DR+, CD14+ TLR9+ HLA-DR+) was observed in the peripheral blood of LTBI/TST+ individuals. In the action of TLR2, TLR4 and TLR9 agonists or of TLR9 antagonist, under the frequency of Tregs cells from Mtb-challenged whole blood cultures, there was a higher frequency of these cells in the TST+ group, which was reduced after the use of TLR9 antagonist (chloroquine). As regards the influence of Mtb infection on the cultures, the microbicidal activity was lower in the TST+ group. In cultures infected with Mtb and TLRs-modulated, there was a reduction of the microbicidal activity in the TST+ group, during stimulation with TLR2 agonist, and, in the same individuals, in the stimulus with TLR9 antagonist, it was observed the restoration of the microbicidal activity. As for the dosage of cytokine in the same cultures, there was a higher production of IL10, IL17 and IFNγ in the TST+ group, especially after modulation with chloroquine, compared to the TST- group. In summary, LTBI differs from the control TST- by the higher frequency of Tregs and MO and the lower microbicidal activity, WHEREas the TLR9 blockade, by the use of chloroquine, resulted in the reduction of Treg cell frequency, in the higher production of IL17, IFNγ and IL10 and in the improvement of the microbicidal activity of LTBI in relation to TST-.
