## 2 The Csr Network
### Expanding the Csr Network  
In the previous section, we described the basis of the Csr network in _E. coli_. Orthologues of _csrA_ and _csr_ regulatory elements are detected throughout the bacterial world. Thus, Csr constitutes a conserved global regulatory network, also called Rsm (repressor of secondary metabolites) network in specific species, such as _Pectobacterium carootovorum_ and in the _Pseudomonas_ genus. Interestingly,some species encode multiple _csrA_ homologues. While a single copy of the _csrA_ gene is present in enteric bacteria (e.g., _E. coli_, _Salmonella enterica_, and _Pectobacterium_ spp.) and _P. aeruginosa_, _in silico_ analyses identified up to five homologues (_rsmA_ and _rsmE_) in specific isolates of _P. fluorescens_, _P. putida_ KT2440, and _P. syringae_[52]. The number of Csr sRNAs homologues can also vary, e.g., _Vibrio cholerae_ and _Pseudomonas fluorescens_ have been shown to contain three of them [53, 54]. As described above, CsrA regulates different processes. In addition to these direct and specific regulations, the Csr partners (proteins and sRNAs) interact with other global regulatory networks. How these interactions might influence group behavior such as quorum sensing, motility and biofilm formation remain vague, although several studies have highlighted tight connections between these different pathways (Figure 1). Some of these connections take place via CsrA. In _E. coli_, CsrA modulates the ppGpp alarmone level by directly regulating _relA_ expression and thereby linking the Csr network to stringent response [55]. In turn, ppGpp and the DksA transcription factor regulate _csrB_ and _csrC_ expression via an unknown mechanism. In _P. carootovorum_, CsrA is regulated by another regulatory cascade involving a putative _N_-acyl homoserine lactone receptor (ExpR), thereby linking quorum sensing and Csr [56]. The connection between these two pathways is also described in _E. coli_ although at another  
Figure 1: Interactions between the Csr network and global regulatory circuitries. Networks of _Escherichia coli_, _Salmonella typhimurium_, _Pectobacterium carootovorum_, _Virbio cholerae_, _Pseudomonas aeruginosa_, and _Pseudomonas fluorescens_ are represented. The CsrA/RsmA/RsmE master regulator is negatively regulated by the Csr/Rsm-sRNAs, which are positively regulated by the BarA/UvrY TCS or its orthologues. Light grey, dark grey, and black lines represent transcriptional, post-transcriptional and post-translational regulations, respectively. Solid and dashed lines represent direct and indirect regulation, respectively. For details, see in the text. level and through different actors. In this case, the SdiA protein, a LuxR homologue, activates _uvrY_ expression at the transcriptional level, thereby affecting _csrB_ expression [43]. Interestingly, the Csr network is connected to metabolism through a CsrD orthologue (MshH) in _V. cholerae_[57]. MshH directly interacts with the EIIA\({}^{\rm Glc}\) enzyme from the PTS system (phosphoenolpyruvate:carbohydrate phosphotransferase system) to positively control biofilm formation in a CsrA-independent manner. Connections between the Csr network and metabolism are also described in _S. typhimurium_ through the BarA/SirA TCS. The UvrY orthologue (SirA) is positively regulated by catabolite repression or directly phosphorylated by acetyl-phosphate, a product generated by acetate metabolism [58; 59; 60; 61]. Connections between the Csr network and motility are also mediated through the UvrY orthologue in specific species, such as in _P. carootovorum_. Expression of _gacA_ (homolog to _uvrY_) is positively regulated by FlhDC [62]. This regulator acts positively on the _csrB_ orthologue _rsmB_ via HexA, a LysR-like regulator known to control exoenzymes production, further linking the Csr network to virulence [62; 63]. In _P. aeruginosa_ and _P. fluorescens_, another layer of complexity is added.