Listeria monocytogenes Strain-Specific Impairment of the TetR Regulator Underlies the Drastic Increase in Cyclic di-AMP Secretion and Beta Interferon-Inducing Ability

Among a number of laboratory strains of Listeria monocytogenes used in experimental infection, strain LO28 is highly ca-pable of inducing robust beta interferon (IFN-) production in infected macrophages. In this study, we investigated the molecular mechanism of the IFN--inducing ability of LO28 by comparing it with that of strain EGD, a low-IFN--induc-ing strain. It was found that LO28 secretes a large amount of IFN--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 ofmdrT expression. The introduction of a null mutation intomdrT abolished the ability of LO28 to induce IFN- production. Examination of genes responsible for the regulation ofmdrT 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 re-placed, it was confirmed that the distinct ability of LO28 is attributable mostly to tetRmutation. We concluded that the strong IFN--inducing ability of LO28 is due to a genetic defect in tetR resulting in the overexpression ofmdrT and a con-comitant increase in the secretion of cyclic di-AMP through MdrT. Listeriamonocytogenes is a Gram-positive, facultative intracellu-lar parasitic bacterium which sometimes causes a severe infec-tion in newborns, elderly people, and immunocompromised pa-tients, with a high mortality rate (3, 8, 41, 43). L. monocytogenes invades various types of host cells, including macrophages, and i