Identification and characterization of competition-factors of commensal E. coli and their role in inhibition of enteropathogens in the inflamed intestine
Final Report Abstract
Inflammatory conditions of the gut as caused by bacterial infections are characterized by changes in microbiota composition, or dysbiosis for short. Using a mouse colitis model, we have previously shown that infections with the human enteric pathogen Salmonella enterica serovar Typhimurium (S. Tm) trigger inflammation and dysbiosis, characterized by concomitant “blooms” of S. Tm and commensal E. coli. In this proposal, we have focused at the competition of S. Tm and commensal E. coli in inflammation-induced “blooms”. After screening for factors potentially involved in competition, we have studied the role of Colicin Ib (ColIb), an antimicrobial toxin produced by S. Tm strain SL1344 in more detail. Commensal E. coli are low-abundant members of the normal healthy gut microbiota of humans and mice. In the Salmonella mouse colitis model, some E. coli strains can grow to high density and eventually become direct competitors of S. Tm. The S. Tm strain we studied is a ColIb producer. Therefore, we asked if ColIb production played a role in competing against two different ColIb-sensitive commensal E. coli strains. To an avirulent S. Tm strain, deficient of triggering inflammation, ColIb did not confer any competitive advantage. In stark contrast, ColIbdependent competition was fuelled by the environmental conditions in inflammation-inflicted Enterobacterial “blooms”. Why? ColIb is regulated in a Fur- and LexA dependent fashion. We have confirmed that S. Tm produces and releases ColIb in vitro in response to iron limitation and DNA damage. ColIb binds to CirA, its cognate receptor on the outer membrane of E. coli, translocates to the periplasm and kills susceptible E. coli by pore formation in the inner membrane. Like the gene for ColIB, cirA is under negative control of Fur and up-regulated under iron limiting conditions. ColIb-susceptibility of E. coli increases upon iron depletion, which correlates with increased amounts of CirA in E. coli. Consequently, in in vitro cultures, ColIb-dependent competition of S. Tm and E. coli was significantly increased under iron limitation and when mitomycin C, a DNA damaging antimicrobial, was added. Lastly, we show that environmental cues in “blooms” signal SOS- and Fur-dependent transcriptional responses in Enterobacteriaceae, thereby triggering up-regulation of ColIb- and ColIb-receptor expression. Thus, the inflammatory response drives ColIbdependent bacterial competition. Evolutionary models which are based on in vitro observations suggest that colicins play a major role in mediating bacterial population dynamics in the gut. In contrast, in experimental infection models colicinogenic strains often do not display an apparent competitive advantage over colicin-sensitive strains. In this work, we have now provided an explanation for this puzzling discrepancy: our data suggest that inflammation-induced blooms form an environmental niche in which colicin-dependent bacterial competition plays an important role. This finding constitutes a new paradigm with broad implications for ecological and evolutionary theory of colicin biology. Additionally, our study contributes novel mechanistic insights how inflammatory host responses shape microbiota composition and bacterial gene expression in disease-associated Enterobacterial “blooms”.
Publications
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Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae. (2012) PNAS 109: 1269-1274
Stecher, B., Denzler R., Maier L., Bernet F., Sanders M. J., Pickard D. J., Barthel M., Westendorf A. M., Krogfelt K. A., Walker A. W., Ackermann M., Dobrindt U., Thomson N. R. & Hardt W. D.,
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Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis. PLoS Pathogens. 2014 Dec 18;10(12):e1004557
Maier L, Diard M, Sellin ME, Chouffane ES, Trautwein-Weidner K, Periaswamy B, Slack E, Dolowschiak T, Stecher B, Loverdo C, Regoes RR, Hardt WD
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Inflammation fuels colicin Ib-dependent competition of Salmonella serovar Typhimurium and E. coli in Enterobacterial blooms. PloS Pathogens. 2014 Jan;10(1):e1003844
Nedialkova L., Denzler R., Koeppel M.B., Diehl M., Ring D., Gerlach R.G. and Stecher B.
