RNA-based mechanisms of virulence control in Enterobacteriaceae

Abstract

Enteric pathogens of the family Enterobacteriaceae colonize various niches within animals and humans in which they compete with intestinal commensals and are attacked by the host immune system. To survive these hostile environments they possess complex, multilayer regulatory networks that coordinate the control of virulence factors, host-adapted metabolic functions and stress resistance. An important part of these intricate control networks are RNA-based control systems that enable the pathogen to fine-tune its responses. Recent next-generation sequencing approaches revealed a large repertoire of conserved and species-specific riboregulators, including numerous cis- and trans-acting non-coding RNAs, sensory RNA elements (RNA thermometers, riboswitches), regulatory RNA-binding proteins and RNA degrading enzymes which regulate colonization factors, toxins, host defense processes and virulence-relevant physiological and metabolic processes. All of which are important cues for pathogens to sense and respond to fluctuating conditions during the infection. This review covers infection-relevant riboregulators of E. coli, Salmonella, Shigella and Yersinia, highlights their versatile regulatory mechanisms, complex target regulons and functions, and discusses emerging topics and future challenges to fully understand and exploit RNA-based control to combat bacterial infections.

Keywords: CsrA; RNA thermometers; gene regulation; regulated RNA degradation; regulatory RNAs; riboswitches; virulence.

Figure 1.

Overview of RNA-based control mechanisms employed by enteric pathogens of the family Enterobacteriaceae. mRNA translation can be controlled by RNA thermometers and by riboswitches within the 5′-UTR of target mRNAs in response to temperature or metabolites. Transcription, translation and/or stability of target transcripts can be modulated by cis-encoded asRNAs or trans-encoded ncRNAs. The RNA-binding protein CsrA modulates mRNA expression by interfering with translational initiation. The CsrB and CsrC RNAs counteract its activity. RNases control processing and degradation of ncRNAs and target transcripts. RNA-modifying enzymes change the efficiency of translation.

Figure 2.

RNA-based control mechanism of E. coli and Salmonella. (A) Riboregulators controlling the colonization factors of pathogenic E. coli important for efficient cell adhesion and invasion. (B) Riboregulators coordinating the expression of Salmonella pathogenicity factors, responsible for cell entry, intracellular persistence and proliferation. The riboregulators are given in black and the target genes in green for flagella biosynthesis, in red for curli formation, in purple for pili production, and in blue for T3SS genes encoded on the pathogenicity islands LEE of EHEC/EPEC (A) or SPI-1 and SPI-2 of Salmonella (B).