title: Listeria monocytogenes strain-specific impairment of the TetR regulator underlies the drastic increase in cyclic di-AMP secretion and beta interferon-inducing ability.
abstract: Among a number of laboratory strains of Listeria monocytogenes used in experimental infection, strain LO28 is highly capable of inducing robust beta interferon (IFN-β) production in infected macrophages. In this study, we investigated the molecular mechanism of the IFN-β-inducing ability of LO28 by comparing it with that of strain EGD, a low-IFN-β-inducing strain. It was found that LO28 secretes a large amount of IFN-β-inducing factor, which turned out to be cyclic di-AMP. The secretion of cyclic di-AMP was dependent on MdrT, a multidrug resistance transporter, and LO28 exhibited a very high level of mdrT expression. The introduction of a null mutation into mdrT abolished the ability of LO28 to induce IFN-β production. Examination of genes responsible for the regulation of mdrT expression revealed a spontaneous 188-bp deletion in tetR of LO28. By constructing recombinant strains of LO28 and EGD in which tetR from each strain was replaced, it was confirmed that the distinct ability of LO28 is attributable mostly to tetR mutation. We concluded that the strong IFN-β-inducing ability of LO28 is due to a genetic defect in tetR resulting in the overexpression of mdrT and a concomitant increase in the secretion of cyclic di-AMP through MdrT.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Motohiro
authors.initials: M
authors.lastname: Matsuura
authors.forename: Takamasa
authors.initials: T
authors.lastname: Nomura
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Sato
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
mesh_terms: D000818:Animals; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions; D016899:Interferon-beta / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000235:genetics / Q000472:pathogenicity*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012097:Repressor Proteins / Q000172:deficiency* / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D004269:DNA, Bacterial; D015226:Dinucleoside Phosphates; D026901:Membrane Transport Proteins; D012097:Repressor Proteins; C528998:cyclic diadenosine phosphate; C034811:tetracycline resistance-encoding transposon repressor protein; D016899:Interferon-beta