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.
Highlights
Efflux pumps are membrane protein complexes conserved in all living organisms
By using the NCBI genome BLAST, homologs for each of the 20 E. coli Efflux pumps (EPs) encoding operons were searched in the genome of S. flexneri M90T, a strain widely used in laboratory to analyze Shigella-host interactions[33]
We report that many of the S. flexneri EP genes have their expression differentially modulated during the intracellular life
Summary
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. 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) superfamily, 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]. 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[9,10,11], while in Vibrio cholera, besides favouring the colonization of the intestine, EPs are required for the full expression of the major virulence determinants[12]. Once released from dying macrophages, invasive bacteria can infect the neighboring enterocytes, where they actively replicate and, without any extracellular steps, disseminate from cell-to-cell, causing severe damage and inflammatory destruction of the colonic mucosa[19]
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