title: Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b.
abstract: Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.
authors.affiliation: Center for Microbial Interface Biology, Integrated Ohio State University, Columbus, OH 43210, USA.
authors.forename: Murugesan V S
authors.initials: MV
authors.lastname: Rajaram
authors.forename: Bin
authors.initials: B
authors.lastname: Ni
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Morris
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Brooks
authors.forename: Tracy K
authors.initials: TK
authors.lastname: Carlson
authors.forename: Baskar
authors.initials: B
authors.lastname: Bakthavachalu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schoenberg
authors.forename: Jordi B
authors.initials: JB
authors.lastname: Torrelles
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020871:RNA Stability; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014774:Virulence / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; C531888:MIRN125 microRNA, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; C064351:lipomannan; C482128:MAP2K2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D048370:MAP Kinase Kinase 2