Editors' ChoiceHost-Pathogen Interactions

Sonic Hedgehog Mediates Pathogen-Specific Response

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Sci. Signal.  22 Jan 2013:
Vol. 6, Issue 259, pp. ec20
DOI: 10.1126/scisignal.2003982

Signaling by ligands of the Hedgehog family plays an important role in cell fate decisions in various developmental contexts and has been implicated in some innate immune responses. Ghorpade et al. report that Sonic hedgehog (SHH) plays a role in the host response to infection by the BCG strain of Mycobacterium bovis (M. bovis BCG), a relative of M. tuberculosis that is used to make the tuberculosis vaccine. Binding of SHH to its receptor Patched (PTCH) relieves repression of the seven-transmembrane protein Smoothened (SMO), leading to activation of GLI family transcription factors. In cultured mouse macrophages, infection with M. bovis BCG stimulated markers of SHH signaling, including an increase in SHH, GLI1, GLI2, SMO, and PTCH1 transcripts, an increase in the nuclear abundance of GLI1, and secretion of SHH. SHH signaling was not stimulated in macrophages infected with M. smegmatis or several representative Gram-positive and Gram-negative pathogens. Application of the proinflammatory cytokine tumor necrosis factor α (TNF-α), which is produced by mycobacteria-infected macrophages, stimulated expression of SHH, GLI1, and GLI2 and nuclear accumulation of GLI1 in cultured macrophages. Pretreating mice or cultured mouse macrophages with either a TNF-α antagonist or an antibody that binds to TNF-α before infection with M. bovis BCG reduced markers of activated SHH signaling. Macrophages lacking Toll-like receptor 2 (TLR2) or TNF-α or that were treated with a small-interfering RNA targeting the TLR2 effector MyD88 demonstrated reduced activation of SHH signaling as compared with macrophages from wild-type mice. Although TLR2 was required for the increase in SHH signaling after infection, results from time course experiments indicated that SHH signaling fed back to repress TLR2 signaling. Monocytes derived from human pulmonary tuberculosis patients showed increased SHH and GLI1 expression relative to those isolated from healthy individuals, and brain tissue from human tuberculosis meningitis patients showed increased abundance of SHH, GLI1, and PTCH relative to brain tissue from healthy individuals. Micro RNAs miR-31 and miR-150 were increased in monocytes isolated from tuberculosis patients and in M. bovis BCG–infected mice. Experiments in cultured mouse macrophages were consistent with TNF-α–induced SHH signaling triggering the increased expression of the genes encoding these miRNAs. Expression of these miRNAs in cultured macrophages repressed TLR2 signaling, and experiments with MyD88 luciferase reporter constructs suggested that miR-31 and miR-150 targeted the 3'-untranslated region of MyD88 to reduce its expression. Although it was not determined whether miR-31 and miR-150 were direct transcriptional targets of SHH signaling, these data point to a model in which M. bovis–induced production of a proinflammatory cytokine stimulates SHH signaling, which fine tunes the immune response to the pathogen by reducing TLR2 signaling. How this response is elicited by M. bovis, but not by a related mycobacterium or by unrelated Gram-positive and Gram-negative bacteria, remains unknown.

D. S. Ghorpade, S. Holla, S. V. Kaveri, J. Bayry, S. A. Patil, K. N. Balaji, Sonic hedgehog-dependent induction of microRNA 31 and microRNA 150 regulates Mycobacterium bovis BCG-driven Toll-like receptor 2 signaling. Mol. Cell. Biol. 33, 543–556 (2013). [Abstract] [Full Text]