Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages (Nat Immunol, 2007, 8:610-618)

報告日期: 2007/11/06
報告時間: 17:10/18:00
報告學生: 顏嘉良
講評老師: 林秋烽
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Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages

Pathak S. K. et al., Nat. Immunol. 8, 610-618 (2007)

Speaker: 顏嘉良

Commentator: 林秋烽老師

Place: Room 602

Time: 2007-11-6 17:10-18:00

Abstract:

  Toll-like receptors (TLRs) are pattern recognition receptors which activate innate immune responses after ligating pathogen molecules.  Previous studies demonstrated that there are negative regulators to dampen TLR signaling in order to prevent prolonged innate immune responses.  Mycobacterium tuberculosis can produce Early Secreted Antigenic Target 6 (ESAT-6) to attenuate innate immune responses by inhibiting the production of IL-12, TNF-α and nitric oxide from macrophages.  But the mechanism through which ESAT-6 inhibits innate immune responses remained to be investigated.  This paper showed that ESAT-6 can inhibit MyD88-dependent TLR signaling and NF-κB activation by inhibits IRAK4-MyD88 interaction through direct binding with TLR2.  And the inhibitory effect of is Akt dependent.  TLR-induced p38 and interferon-regulatory factor (IRF) activation can also be inhibited by ESAT-6 stimulation.  Moreover, the authors found that the C-terminus of ESAT-6 is crucial for the inhibitory effect of ESAT-6.  These findings suggest that TLR ligation not only generate positive but also induce negative signals that can dampen the MyD88-dependent TLR signaling.  This inhibitory mechanism of TLR signaling can be used by Mycobacterium tuberculosis to subvert innate immune responses, and also provide new insight regarding the mechanism for controlling prolonged inflammation during diseases such as septic shock and asthma.

 References:

1.          A. Phillip West et al. Recognition and Signaling by Toll-Like Receptors. Annu. Rev. Cell Dev. Biol. 22, 409-437 (2006)