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The MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages

Abstract : Efflux pumps are membrane protein complexes conserved in all living organisms. Beyond being involved in antibiotic extrusion in several bacteria, efflux pumps are emerging as relevant players in pathogen-host interactions. We have investigated on the possible role of the efflux pump network in Shigella flexneri, the etiological agent of bacillary dysentery. We have found that S. flexneri has retained 14 of the 20 pumps characterized in Escherichia coli and that their expression is differentially modulated during the intracellular life of Shigella. In particular, the emrKY operon, encoding an efflux pump of the Major Facilitator Superfamily, is specifically and highly induced in Shigella-infected U937 macrophage-like cells and is activated in response to a combination of high K + and acidic pH, which are sensed by the EvgS/EvgA two-component system. Notably, we show that following S. flexneri infection, macrophage cytosol undergoes a mild reduction of intracellular pH, permitting EvgA to trigger the emrKY activation. Finally, we present data suggesting that EmrKY is required for the survival of Shigella in the harsh macrophage environment, highlighting for the first time the key role of an efflux pump during the Shigella invasive process. Efflux pumps (EPs) are present in all living organisms and represent an important and consistent group of transporter proteins, which contribute to the resistance to compounds used for treating different diseases 1,2. In Gram negative bacteria, EPs either form tripartite complexes able to traverse both membranes, including the inner membrane, a membrane fusion protein and an outer membrane protein, or are present as single-component efflux transporter in the inner membrane 2. According to their sequence similarity, composition, transport function , energy source and substrates, EPs are grouped into five families: the ATP binding cassette (ABC) superfam-ily, the major facilitator superfamily (MFS), the multidrug and toxic compound extrusion (MATE) family, the small multidrug resistance (SMR) family and the resistance nodulation division (RND) family 1. The importance of EPs has been associated with their ability to extrude a wide range of antibiotics resulting in the emergence of multidrug resistance in many bacteria, including pathogens 1,2. In the last years, several studies have identified numerous functions for EPs that go beyond antibiotic extru-sion: these functions range from bacterial interactions with plant or animal hosts, to detoxification of metabolic intermediates and maintenance of cellular homeostasis 3,4. An interesting aspect concerns the involvement of EPs in the virulence of several bacterial pathogens 3,5. In enteric pathogens such as Salmonella Typhimurium, Listeria monocytogenes, and Vibrio cholera it has been shown that EPs are relevant virulence factors contributing to persistence and replication in a bile rich environment 6-8. Moreover, in Salmonella EPs are critical for the invasion and survival within macrophages and intestinal epithelial cells and contribute to the different steps of the pathogenicity process 9-11 , while in Vibrio cholera, besides favouring the colonization of the intestine, EPs are also required for the full expression of the major virulence determinants 12. EPs contribute also to the pathogenicity of Pseudomonas aeruginosa and Stenotrophomonas maltophilia, where they play a significant role in biofilm formation 13-15 , and of Campylobacter jejuni and Neisseria gonorrhea, where they are involved in the colonization of the host epithelia 16,17. Shigella is an intracellular pathogen responsible of a life-threatening enteric syndrome in humans 18. Invasion of the colonic epithelium by Shigella is the result of a complex multistep process. After ingestion, Shigella gains
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Martina Pasqua, Milena Grossi, Sara Scinicariello, Laurent Aussel, Frédéric Barras, et al.. The MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages. Scientific Reports, Nature Publishing Group, 2019, 9 (1), ⟨10.1038/s41598-019-39749-3⟩. ⟨hal-02187079⟩

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