title: Hyperinduction of host beta interferon by a Listeria monocytogenes strain naturally overexpressing the multidrug efflux pump MdrT.
abstract: Many pathogens regulate or modify their immune-stimulating ligands to avoid detection by their infected hosts. Listeria monocytogenes, a facultative intracellular bacterial pathogen, interacts with multiple components of mammalian innate immunity during its infection cycle. During replication within the cytosol of infected cells, L. monocytogenes utilizes two multidrug efflux pumps, MdrM and MdrT, to secrete the small nucleic acid second messenger cyclic-di-AMP (c-di-AMP). Host recognition of c-di-AMP triggers the production of type I interferons, including beta interferon (IFN-β), which, surprisingly, promote L. monocytogenes virulence. In this study, we have examined the capacity of multiple laboratory and clinical isolates of L. monocytogenes to stimulate host production of IFN-β. We have identified the L. monocytogenes strain LO28 as able to hyperinduce IFN-β production in infected cells ∼30-fold more than the common laboratory clone L. monocytogenes strain 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele of the transcriptional regulator BrtA and correspondingly derepresses expression of MdrT. Surprisingly, while derepression of MdrT resulted in hyperstimulation of IFN-β, it results in significant attenuation in multiple mouse models of infection. While type I interferons may promote L. monocytogenes virulence, this study demonstrates that unregulated expression of the c-di-AMP-secreting efflux pump MdrT significantly restricts virulence in vivo by an unknown mechanism.
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Kierstyn T
authors.initials: KT
authors.lastname: Schwartz
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Carleton
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Quillin
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Rollins
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: Jess H
authors.initials: JH
authors.lastname: Leber
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D019450:Genes, MDR; D016899:Interferon-beta / Q000096:biosynthesis*; D008089:Listeria monocytogenes / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017422:Sequence Analysis, DNA
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D016899:Interferon-beta; D006152:Cyclic GMP