Article abstract

Nature Immunology 8, 610 - 618 (2007)
Published online: 7 May 2007 | doi:10.1038/ni1468

Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages

Sushil Kumar Pathak1, Sanchita Basu1, Kunal Kumar Basu1, Anirban Banerjee1, Shresh Pathak1, Asima Bhattacharyya1,3, Tsuneyasu Kaisho2, Manikuntala Kundu1 & Joyoti Basu1

Expression of early secreted antigenic target protein 6 (ESAT-6) by Mycobacterium tuberculosis is associated with lower innate immune responses to infection. Here we show that ESAT-6 inhibited activation of transcription factor NF-kappaB and interferon-regulatory factors (IRFs) after Toll-like receptor (TLR) signaling; inhibition of TLR signaling by ESAT-6 required the kinase Akt. Direct binding of ESAT-6 to TLR2 activated Akt and prevented interaction between the adaptor MyD88 and 'downstream' kinase IRAK4, thus abrogating NF-kappaB activation. The six carboxy-terminal amino acid residues of ESAT-6 were required and sufficient for the TLR2-mediated inhibitory effect. A critical function for the carboxy-terminal peptide of ESAT-6 in restricting MyD88-dependent TLR signaling emphasizes the possibility that mimetic inhibitory peptides could be used to restrict innate immune responses in situations in which prolonged TLR signaling has deleterious effects.

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  1. Bose Institute, Department of Chemistry, Kolkata 700 009, India.
  2. Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
  3. Present address: Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.

Correspondence to: Joyoti Basu1 e-mail: joyoti@vsnl.com

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