Inflammation Fuels Colicin Ib-Dependent Competition of Salmonella Serovar Typhimurium and E. coli in Enterobacterial Blooms

Abstract

The host's immune system plays a key role in modulating growth of pathogens and the intestinal microbiota in the gut. In particular, inflammatory bowel disorders and pathogen infections induce shifts of the resident commensal microbiota which can result in overgrowth of Enterobacteriaceae (“inflammation-inflicted blooms”). Here, we investigated competition of the human pathogenic Salmonella enterica serovar Typhimurium strain SL1344 (S. Tm) and commensal E. coli in inflammation-inflicted blooms. S. Tm produces colicin Ib (ColIb), which is a narrow-spectrum protein toxin active against related Enterobacteriaceae. Production of ColIb conferred a competitive advantage to S. Tm over sensitive E. coli strains in the inflamed gut. In contrast, an avirulent S. Tm mutant strain defective in triggering gut inflammation did not benefit from ColIb. Expression of ColIb (cib) is regulated by iron limitation and the SOS response. CirA, the cognate outer membrane receptor of ColIb on colicin-sensitive E. coli, is induced upon iron limitation. We demonstrate that growth in inflammation-induced blooms favours expression of both S. Tm ColIb and the receptor CirA, thereby fuelling ColIb dependent competition of S. Tm and commensal E. coli in the gut. In conclusion, this study uncovers a so-far unappreciated role of inflammation-inflicted blooms as an environment favouring ColIb-dependent competition of pathogenic and commensal representatives of the Enterobacteriaceae family.

The Pyromaniac Inside You: Salmonella Metabolism in the Host Gut

“…It has thus been speculated that bacteriocins could aid the producing strain in competing against other Enterobacteriaceae that utilize the corresponding siderophores (83). Experimental support for this idea comes from the observation that the bacteriocin colicin Ib, which is produced by some S. Typhimurium isolates (e.g., the laboratory strain SL1344), can give the pathogen a competitive advantage over the commensal E. coli K-12 strain during growth in the inflamed gut (78). Colicin Ib binds to Cir, a TonB-dependent outer membrane receptor involved in the uptake of the siderophore N-(2,3-dihydroxybenzoyl)-L-serine, which is a precursor of enterobactin (49).…”

“…Colicin Ib binds to Cir, a TonB-dependent outer membrane receptor involved in the uptake of the siderophore N-(2,3-dihydroxybenzoyl)-L-serine, which is a precursor of enterobactin (49). Interestingly, production of colicin Ib does not give S. Typhimurium a competitive advantage over E. coli in the absence of intestinal inflammation (78). TonB-dependent outer membrane siderophore receptors are produced during iron starvation, while the ferric uptake regulator (Fur) represses the corresponding genes under iron-replete conditions (48,97).…”

“…TonB-dependent outer membrane siderophore receptors are produced during iron starvation, while the ferric uptake regulator (Fur) represses the corresponding genes under iron-replete conditions (48,97). The reduced availability of iron in the intestinal lumen during inflammation induces expression of Cir, thereby rendering E. coli susceptible to colicin Ib produced by S. Typhimurium (78). Thus, the inflamed intestine might be a playground in which pathogenic and commensal representatives of the Enterobacteriaceae battle for dominance using bacteriocins.…”

Counterinsurgency Doctrine Applied to Infectious Disease

“…(Cornforth and Foster 2013). Bacteria will instigate the host to attack other bacteria (indirect antagonism; Rolfe 1984, Sansonetti 2004) and even directly attack each other dependent on the inflammation of the host (Nedialkova et al 2014). In the past, host-generated stress signals activating bacterial pathogenesis were viewed as a sign of weakness triggering opportunistic predation -literally blood in the water, at times.…”

The therapeutic potential of bacteriocins as protein antibiotics

“…In fact, protein bacteriocin-encoding genes can be found in the genomes of most Gram-negative pathogens, including P. aeruginosa, E. coli and K. pneumoniae ( [14] and Sharp et al unpublished data). Importantly, they are highly specific antibacterials that kill only bacteria closely related to the producer and are deployed during the fight for resources with competitor strains [14][15][16]. This specificity makes them attractive as therapeutics as they offer a more targeted approach.…”