QseC Signaling in the Outbreak O104:H4 Escherichia coli Strain Combines Multiple Factors during Infection

Abstract

Enteroaggregative Escherichia coli (EAEC) from the O104:H4 specific serotype caused a large outbreak of bloody diarrhea with some complicated cases of hemolytic-uremic syndrome (HUS) in Europe in 2011. The outbreak strain consisted in an EAEC capable to produce the Shiga toxin (Stx) subtype 2a, a characteristic from enterohemorrhagic E. coli. QseBC two-component system detects AI-3/Epi/NE and mediates the chemical signaling between pathogen and mammalian host. This system coordinates a cascade of virulence genes expression in important human enteropathogens. The blocking of QseC of EAEC C227-11 (Stx+) strain by N-phenyl-4-{[(phenylamino) thioxomethyl]amino}-benzenesulfonamide (also known as LED209) in vivo demonstrated a lower efficiency of colonization. The periplasmic protein VisP, which is related to survival mechanisms in a colitis model of infection, bacterial membrane maintenance, and stress resistance, here presented high levels of expression during the initial infection within the host. Under acid stress conditions, visP expression levels were differentiated in an Stx-dependent way. Together, these results emphasize the important role of VisP and the histidine kinase sensor QseC in the C227-11 (Stx+) outbreak strain for the establishment of the infectious niche process in the C57BL/6 mouse model and of LED209 as a promising antivirulence drug strategy against these enteric pathogens. IMPORTANCE EAEC is a remarkable etiologic agent of acute and persistent diarrhea worldwide. The isolates harbor specific subsets of virulence genes and their pathogenesis needs to be better understood. Chemical signaling via histidine kinase sensor QseC has been shown as a potential target to elucidate the orchestration of the regulatory cascade of virulence factors.

The Release of Norepinephrine in C57BL/6J Mice Treated with 6-Hydroxydopamine (6-OHDA) is Associated with Translocations in Enteric Escherichia coli via the QseC Histidine Kinase Receptor

“…Moreover, qseC can also recognize the human hormone molecules EPI and NE [ 17 ], and is capable of sensing and recognizing the signal molecule AI-3 produced by bacteria. Previous studies have confirmed that the exercise ability of qseC -negative mutant strains is significantly weaker than that of wild-type strains, while the complementary strains partially restore the exercise capacity of gene-deficient strains compared to the qseC -deficient strains [ 18 – 20 ]. The QseC receptors can significantly increase the activity of wild strains, but it has little effect on qseC -negative mutant strains [ 21 ].…”

Escherichia coli as a Multifaceted Pathogenic and Versatile Bacterium

“…Emerging processes are responsible for the HyPEC occurrences. Herein, the combined enteroaggregative features in a rare serotype was responsible to high attachment to cells and a biofilm formation (Navarro-Garcia, 2014; Ribeiro et al, 2019). Moreover, this strain has gained stx2 gene lambdoid phage integrated in the genome, thus it may release the Shiga-toxin.…”

“…Hybrid pathogenic (HyPEC) main features described Bielaszewska et al, 2011;Rasko et al, 2011;Muniesa et al, 2012;Navarro-Garcia, 2014;Ribeiro et al, 2019. …”

Bacterial signaling as an antimicrobial target

“…The kinase activity of QseC is promiscuous and also activates the non-cognate RRs, KdpE and QseF, which substantially expands the QseC regulon [43] (Figure 3). Genetic studies have demonstrated that QseC is an important activator of virulence in pathogenic E. coli and in the closely related murine pathogen Citrobacter rodentium [44][45][46]90]. In enterohemorrhagic and enteropathogenic E. coli, QseC regulates the locus of enterocyte effacement (LEE), a pathogenicity island that is essential for causing disease [44,45,90].…”

“…Consequently, pharmacological inhibition of QseC with LED209 is effective in attenuating pathogen virulence and disease in diverse models of acute infection [46,49,51,90], thus demonstrating the potential efficacy of QseC as an anti-virulence target in numerous pathogens. LED209 was identified through a screen of a small molecule chemical library.…”