Hyper-induction of host Interferon β by a Listeria monocytogenes strain naturally over-expressing the multi-drug 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 Interferon β (IFNβ), which, surprisingly, promotes 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 IFNβ. We have identified L. monocytogenes strain LO28 as able to hyper-induce IFNβ production in infected cells, ∼30-fold more than the common laboratory clone 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele in the transcriptional regulator BrtA, and correspondingly de-represses expression of MdrT. Surprisingly, while de-repression of MdrT resulted in hyper-stimulation of IFNβ, this 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.