Abstract
ABSTRACTEnterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) is a major foodborne pathogen that causes severe illness in humans worldwide. The genome of O157 contains 177 genomic islands known as O islands (OIs), including Shiga toxin-converting phages (OI-45 and OI-93) and the locus for enterocyte effacement (LEE) pathogenicity island (OI-148). However, most genes in OIs are uncharacterized and code for unknown functions. In this study, we demonstrated, for the first time, that OI-9 encodes a novel transcriptional activator, Z0346 (named OvrB), which is required for bacterial adherence to host cells and LEE gene expression in O157. OvrB directly binds to the promoter region of LEE1 and activates the transcription of ler (encoding a master regulator of LEE genes), which in turn activates LEE1–5 genes to promote O157 adherence. Furthermore, mouse oral infection assays showed that OvrB promotes O157 colonization in the mouse intestine. Finally, OvrB is shown to be a widespread transcriptional activator of virulence genes in other enterohemorrhagic and enteropathogenic Escherichia coli serotypes. Our work significantly expands the understanding of bacterial virulence control and provides new evidence suggesting that horizontally transferred regulator genes mediate LEE gene expression.
Highlights
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) is an important human gastrointestinal pathogen with the capacity to colonize asymptomatically and cause illnesses ranging from mild watery diarrhea to hemorrhagic colitis and in extreme cases hemolytic uremic syndrome, which is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure [1]
The genes responsible for AE lesions are located within a large pathogenicity island of the bacterial genome known as the locus of enterocyte effacement (LEE), which contains 41 genes grouped into five operons (LEE1–LEE5)
Domain structure analysis revealed that both Z0342 and OvrB contain an N-terminal DNA-binding helix-turn-helix (HTH) motif and a C-terminal co-inducer-binding domain, which are conserved in the LysR-type transcriptional regulator (LTTR) family (Figure 1(b))
Summary
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) is an important human gastrointestinal pathogen with the capacity to colonize asymptomatically and cause illnesses ranging from mild watery diarrhea to hemorrhagic colitis and in extreme cases hemolytic uremic syndrome, which is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure [1]. An essential feature of O157 virulence is the ability of cells to form attaching and effacing (AE) lesions on host epithelium that induce the extensive rearrangement of the actin cytoskeleton of epithelial cells, culminating in the formation of pedestal-like structures underneath the bacterial cell [2]. The genes responsible for AE lesions are located within a large pathogenicity island of the bacterial genome known as the locus of enterocyte effacement (LEE), which contains 41 genes grouped into five operons (LEE1–LEE5). LEE1, LEE2, and LEE3 encode the components of the type III secretion system (T3SS) that allows direct injection of bacterial effector proteins into host cells to subvert host cell signaling pathways and AE lesion formation [3]. Shiga toxins (Stx), which are the other main virulence factors, consist of two major types, Stx and Stx2 [8]. All EHEC strains produce one or both of the Stx [9], and EHEC O157:H7 strain EDL933 used in this study produces both Stx and Stx2 [10]
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