Listeria monocytogenes multidrug resistance transporters activate a cytosolic surveillance pathway of innate immunity

Gregory T. Crimmins, Anat A. Herskovits, Kai Rehder, Kelsey E. Sivick, Peter Lauer, Thomas W. Dubensky, Daniel A. Portnoy

Research output: Contribution to journalArticlepeer-review

Abstract

To gain insight into the interaction of intracellular pathogens with host innate immune pathways, we performed an unbiased genetic screen of Listeria monocytogenes mutants that induced an enhanced or diminished host innate immune response. Here, we show that the major facilitator superfamily of bacterial multidrug resistance transporters (MDRs) controlled the magnitude of a host cytosolic surveillance pathway, leading to the production of several cytokines, including type I IFN. Mutations mapping to repressors of MDRs resulted in ectopic expression of their cognate transporters, leading to host responses that were increased up to 20-fold over wild-type bacteria, and a 20-fold decrease in bacterial growth in vivo. Mutation of one of the MDRs, MdrM, led to a 3-fold reduction in the IFN-β response to L. monocytogenes infection, indicating a pivotal role for MdrM in activation of the host cytosolic surveillance system. Bacterial MDRs had previously been associated with resistance to antibiotics and other toxic compounds. This report links bacterial MDRs and host immunity. Understanding the mechanisms through which live pathogens activate innate immune signaling pathways should lead to the discovery of adjuvants, vaccines, and perhaps new classes of therapeutics. Indeed, we show that the mutants identified in this screen induced vastly altered type I IFN response in vivo as well.

Original languageEnglish
Pages (from-to)10191-10196
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number29
DOIs
StatePublished - 22 Jul 2008
Externally publishedYes

Keywords

  • Bacterial genetic screen
  • Immune response
  • Interferon-beta
  • Intracellular pathogen

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