The BvgASR virulence regulon of Bordetella pertussis
Authors: Scott Stibitz
Qing Chen
Journal: Current opinion in microbiology (2019)
Discipline: MICROBIOLOGY
Keywords: BvgAS two-component system; virulence genes; phosphodiesterase BvgR; c-di-GMP; RisA∼P
Affiliations: Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, United States., Center for Biologics Evaluation and Research, FDA, Silver Spring, MD, United States. Electronic address: .

Abstract:  The BvgAS two-component system of Bordetella pertussis directly activates the expression of a large number of virulence genes in an environmentally responsive manner. The Bvg+ mode also promotes the expression of the phosphodiesterase BvgR, which turns off the expression of another set of genes, the vrgs, by reducing levels of c-di-GMP. Increased levels of c-di-GMP in the Bvg- mode are required, together with the phosphorylated response regulator protein RisA∼P, to activate vrg expression. Phosphorylation of RisA requires RisK, a non-co-operonic sensor kinase, but not its co-operonic sensor kinase RisS which is truncated in B. pertussis but intact in the ancestral B. bronchiseptica. The loss of RisS during evolution of B. pertussis led to the ability to express the vrgs, potentially enhancing aerosol transmission of B. pertussis. 

Retracted: No

PubPeer comments:
 In this interesting review Qing Chen and Scott Stibitz summarized the current knowledge regarding *Bordetella spp * virulence factors regulation. Authors described how the locus bvgASR regulates virulence activated and repressed genes (vags and vrgs respectively). BvgASR role on regulating virulence activated genes is well documented in both* B. pertussis* and *B. bronchiseptica*. When activated, vags are expressed and bacteria is in virulent mode (Bvg+). Conversely, when inactivated vags are repressed, vrgs expressed and bacteria is in avirulent mode (Bvg--). BvgR-repressed genes or vrgs is a group of genes that are regulated at least by two proteins: BvgR as a negative regulator and RisA as an activator of those genes [2, 3, 4, 5]. Mechanisms involved in vrgs regulation by BvgR are unclear to the moment. Chen and Stibitz and other authors described that BvgR encodes a EAL domain, present in cyclic dimeric GMP (c-di-GMP) phosphodiesterases [6]. The second messenger c-di-GMP is almost ubiquitous among bacteria and mediate regulation of motility, biofilm formation and virulence [6]. While most EAL domain proteins contains additional domains, there is a family of proteins with stand-alone EAL domains. BvgR belongs to that family. Authors stated that BvgR with an EAL domain is capable of reduce c-di-GMP intracellular concentration. In coincidence with this, they proposed a working model where BvgR regulates c-di- GMP levels. Particularly they proposed that in the Bvg-- mode in *B. bronchiseptica* high levels of c-di- GMP and low levels of phosphorylated RisA allow the expression of flhC, flhD along with genes for flagella and chemotaxis. To our knowledge no evidences has been published supporting in vitro or in vivo phosphodiesterase activity for BvgR. Systematic alanine substitutions of conserved signature amino acids in EAL domains have given insights into the catalytic mechanism of EAL containing phosphodiesterases [7, 8]. The findings from this mutagenesis study enabled the differentiation of EAL domains in three classes: catalytically active (Class I), potentially catalytically active (Class II), and catalytically inactive EAL domains (Class III). Class III domains can be further divided in EAL domains that can bind c-di-GMP, thus serving as c-di-GMP receptors (Class IIIa), whereas others are unable to bind c-di-GMP (Class IIIb). According to this classification BvgR EAL domain, either form *B. pertussis* or *B. bronchiseptica*, are classified as Class IIIb EAL domains (FIgure). Hence we proposed that giving a phosphodiesterase role to BvgR without further evidence seems premature and may be detrimental to establish future statements about how vrgs are regulated in Bordetellae. Importantly, Chen and Stibitz proposed a working model where in Bvg-- mode in *B. bronchiseptica* with high c-di-GMP intracellular levels, flagella genes are expressed. This model is in contradiction to experimental results previously published by Sisti et al. [9]. Expression from a plasmid of an active diguanylate cyclase in* B. bronchiseptica* augments c-di-GMP levels and inhibits motility, in agreement to the proposed role for c-di-GMP in motility regulation in bacteria [10]. More over, results in recent paper demonstrated that high levels of c-di-GMP inhibits flaA gen expression encoding for flagella monomer [11]. Vags and vrgs regulation in Bordetellae has been extensively described. Without doubt bvgASR regulon is involved in virulent avirulent modulation and vags and vrgs regulation. Coordinated action of bvgASR locus with other regulators like RisAS K, c-di-GMP and small RNAs is definitely plausible. However, the role of these regulators and mechanisms involved still need further study. Insight into these mechanisms will allow to described precisely how Bordetella regulates transitions between different situations. Federico Sisti and Julieta Fernandez Instituto de Biotecnologu00eda y Biologu00eda Molecular (IBBM)-CCT-CONICET-La Plata, Departamento de Ciencias Biolu00f3gicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina References. 1. Cheng Q, Stibitz S: The BvgASR virulence regulon of Bordetella pertussis. Curr Opin Microbiol 2019, 47:74-81. 2. Merkel TJ, Stibitz S: Identification of a locus required for the regulation of bvg-repressed genes in Bordetella pertussis. J Bacteriol 1995, 177:2727-2736. 3. Fernu00e1ndez J, Sisti F, Bottero D, Gaillard ME, Hozbor D: Constitutive expression of bvgR-repressed factors is not detrimental to the Bordetella bronchiseptica-host interaction. Res Microbiol 2005, 156(8):843-50. 4. Stenson TH, Allen AG, Al-Meer JA, Maskell D, Peppler MS: Bordetella pertussis risA, but not risS, is required for maximal expression of Bvg-repressed genes. Infect Immun 2005, 73:5995-6004. 5. Croinin TO, Grippe VK, Merkel TJ: Activation of the vrg6 promoter of Bordetella pertussis by RisA. J Bacteriol 2005, 187:1648-1658. 6. 35. Romling U, Galperin MY, Gomelsky M: Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 2013, 77:1-52. 7. Rao F, Qi Y, Chong HS, Kotaka M, Li B, Li J, Lescar J, Tang K, Liang ZX: The functional role of a conserved loop in EAL domain-based cyclic di-GMP-specific phosphodiesterase. J Bacteriol 2009, 191:4722u2013 4731. 8. Rao F, Yang Y, Qi Y, Liang ZX: Catalytic mechanism of cyclic di-GMP-specific phosphodiesterase: a study of the EAL domain containing RocR from Pseudomonas aeruginosa. J Bacteriol 2008, 190:3622u20133631. 9. Sisti F, Ha DG, O Toole GA, Hozbor D, Fernu00e1ndez J: Cyclic-di-GMP signalling regulates motility and biofilm formation in Bordetella bronchiseptica. Microbiology, 2013 159:869-879. 10. Jenal U, Reinders A, Lori C: Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol, 2017 5:271-284. 11. Belhart K, Gutierrez MDLP, Zacca F, Ambrosis N, Cartelle Gestal M, Taylor D, Dahlstrom KM, Harvill ET, Ou2019Toole GA, Sisti F, Fernu00e1ndez J. 2019. Bordetella bronchiseptica diguanylate cyclase BdcA regulates motility and is important for the establishment of respiratory infection in mice. J Bacteriol 201:e00011-19. ![file] ,