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Mol. Cell. Biol. 33 (3): 543-556

Copyright © 2013 by the American Society for Microbiology. All rights reserved.

Sonic hedgehog-Dependent Induction of MicroRNA 31 and MicroRNA 150 Regulates Mycobacterium bovis BCG-Driven Toll-Like Receptor 2 Signaling

Devram Sampat Ghorpade,a Sahana Holla,a Srini V. Kaveri,b,c Jagadeesh Bayry,b,c Shripad A. Patil,d, and Kithiganahalli Narayanaswamy Balajia

Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India,a Institut National de la Santé et de la Recherche Médicale, Unité 872, Equipe 16-Immunopathology and Therapeutic Immunointervention, Paris, France,b Unité Mixte de Recherche S 872, Centre de Recherche des Cordeliers, Equipe 16-Immunopathology and Therapeutic Immunointervention, Université Pierre et Marie Curie-Paris 6, Paris, France,c Department of Microbiology, National Institute of Mental Health and Neurosciences, Bangalore, India,d

Received for publication 11 August 2012. Revision received 28 August 2012. Accepted for publication 10 November 2012.

Abstract: Hedgehog (HH) signaling is a significant regulator of cell fate decisions during embryogenesis, development, and perpetuation of various disease conditions. Testing whether pathogen-specific HH signaling promotes unique innate recognition of intracellular bacteria, we demonstrate that among diverse Gram-positive or Gram-negative microbes, Mycobacterium bovis BCG, a vaccine strain, elicits a robust activation of Sonic HH (SHH) signaling in macrophages. Interestingly, sustained tumor necrosis factor alpha (TNF-α) secretion by macrophages was essential for robust SHH activation, as TNF-α–/– macrophages exhibited compromised ability to activate SHH signaling. Neutralization of TNF-α or blockade of TNF-α receptor signaling significantly reduced the infection-induced SHH signaling activation both in vitro and in vivo. Intriguingly, activated SHH signaling downregulated M. bovis BCG-mediated Toll-like receptor 2 (TLR2) signaling events to regulate a battery of genes associated with divergent functions of M1/M2 macrophages. Genome-wide expression profiling as well as conventional gain-of-function or loss-of-function analysis showed that SHH signaling-responsive microRNA 31 (miR-31) and miR-150 target MyD88, an adaptor protein of TLR2 signaling, thus leading to suppression of TLR2 responses. SHH signaling signatures could be detected in vivo in tuberculosis patients and M. bovis BCG-challenged mice. Collectively, these investigations identify SHH signaling to be what we believe is one of the significant regulators of host-pathogen interactions.

Address correspondence to Kithiganahalli Narayanaswamy Balaji, balaji{at}

Published ahead of print 19 November 2012

Supplemental material for this article may be found at

NOD2-Nitric Oxide-responsive MicroRNA-146a Activates Sonic Hedgehog Signaling to Orchestrate Inflammatory Responses in Murine Model of Inflammatory Bowel Disease.
D. S. Ghorpade, A. Y. Sinha, S. Holla, V. Singh, and K. N. Balaji (2013)
J. Biol. Chem. 288, 33037-33048
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