title: Sonic hedgehog-dependent induction of microRNA 31 and microRNA 150 regulates Mycobacterium bovis BCG-driven toll-like receptor 2 signaling.
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.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
authors.forename: Devram Sampat
authors.initials: DS
authors.lastname: Ghorpade
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.forename: Srini V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Shripad A
authors.initials: SA
authors.lastname: Patil
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D009163:Mycobacterium bovis / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D059467:Transcriptome; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000662:veterinary; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D053823:Hedgehog Proteins; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C554019:MIRN130 microRNA, human; C533097:MIR150, human; C529101:Mirn150 microRNA, mouse; C539917:Mirn31 microRNA, mouse