Accessory gene regulator (agr) is a complex 5 gene locus that is a global regulator of virulence in Staphylococcus aureus.[1][2][3] It encodes a two-component transcriptional quorum-sensing (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP).[4]

Agr occurs in 4 allelic subtypes that have an important role in staphylococcal evolution.[5][6] The corresponding AIPs are mutually cross-inhibitory, which may enhance the evolutionary separation of the 4 groups.[6][7] The agr receptor, AgrC, is a model histidine phosphokinase (HPK) that has been used to decipher the molecular mechanism of signal transduction.[8] AIP binding to the extracellular domain of AgrC causes twisting of the intracellular a-helical domain so as to enable trans-phosphorylation of the active site histidine;  the inhibitory AIPs cause the α-helical domain to twist in the opposite direction, preventing trans-phosphorylation.[8] The agr QS circuit autoactivates transcription of agrA which, in turn upregulates the phenol-souble modulins.[9] More importantly, it activates transcription of a divergently oriented promoter whose transcript, known as RNAIII,[10] is a 514 nt regulatory RNA that encodes δ-hemolysin and is the major effector of the agr regulon.[10] RNAIII acts by antisense inhibition or activation of target gene translation. In vitro, early in growth, genes encoding surface proteins important for adhesion and immune evasion (such as spa – encoding proteinA[11]) are expressed, enabling the organism to gain a foothold. Later in growth, these genes are down-regulated by RNAIII and those encoding toxins, hemolysins and other virulence-related proteins, are turned on, enabling the organism to establish and promulgate its pathological programs, such as abscess formation.[12] It is assumed that this program operates in vivo as well. As agr is essential for staphylococcal contagion,[13] agr-defective mutants are not contagious, but enable the organism's long-term survival in chronic conditions such as surgical implant infections, osteomyelitis or the infected lung in cystic fibrosis. In keeping with this behavior, mutations inactivating agr function enhance the stability of biofilms,[14] which are key to the maintenance of chronic infections.

Agr is widely conserved among Bacillota[15] and has a well-defined role in virulence regulation in several genera, especially Listeria and Clostridia.

References

  1. ^ Recsei P, Kreiswirth B, O'Reilly M, Schlievert P, Gruss A, Novick RP (January 1986). "Regulation of exoprotein gene expression in Staphylococcus aureus by agar". Molecular & General Genetics. 202 (1): 58–61. doi:10.1007/BF00330517. PMID 3007938. S2CID 8592594.
  2. ^ Gomes-Fernandes M, Laabei M, Pagan N, Hidalgo J, Molinos S, Villar Hernandez R, et al. (2017-04-14). "Accessory gene regulator (Agr) functionality in Staphylococcus aureus derived from lower respiratory tract infections". PLOS ONE. 12 (4): e0175552. Bibcode:2017PLoSO..1275552G. doi:10.1371/journal.pone.0175552. PMC 5391941. PMID 28410390.
  3. ^ Tan L, Li SR, Jiang B, Hu XM, Li S (2018). "Therapeutic Targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) System". Frontiers in Microbiology. 9: 55. doi:10.3389/fmicb.2018.00055. PMC 5789755. PMID 29422887.
  4. ^ Ji G, Beavis RC, Novick RP (December 1995). "Cell density control of staphylococcal virulence mediated by an octapeptide pheromone". Proceedings of the National Academy of Sciences of the United States of America. 92 (26): 12055–9. Bibcode:1995PNAS...9212055J. doi:10.1073/pnas.92.26.12055. PMC 40295. PMID 8618843.
  5. ^ Wright JS, Traber KE, Corrigan R, Benson SA, Musser JM, Novick RP (August 2005). "The agr radiation: an early event in the evolution of staphylococci". Journal of Bacteriology. 187 (16): 5585–94. doi:10.1128/JB.187.16.5585-5594.2005. PMC 1196086. PMID 16077103.
  6. ^ a b Jarraud S, Lyon GJ, Figueiredo AM, Lina G, Gérard L, Vandenesch F, et al. (November 2000). "Exfoliatin-producing strains define a fourth agr specificity group in Staphylococcus aureus". Journal of Bacteriology. 182 (22): 6517–22. doi:10.1128/jb.182.22.6517-6522.2000. PMC 94802. PMID 11053400.
  7. ^ Ji G, Beavis R, Novick RP (June 1997). "Bacterial interference caused by autoinducing peptide variants". Science. 276 (5321): 2027–30. doi:10.1126/science.276.5321.2027. PMID 9197262.
  8. ^ a b Wang B, Zhao A, Xie Q, Olinares PD, Chait BT, Novick RP, Muir TW (January 2017). "Functional Plasticity of the AgrC Receptor Histidine Kinase Required for Staphylococcal Virulence". Cell Chemical Biology. 24 (1): 76–86. doi:10.1016/j.chembiol.2016.12.008. PMC 5697745. PMID 28065658.
  9. ^ Chatterjee SS, Chen L, Joo HS, Cheung GY, Kreiswirth BN, Otto M (2011-12-12). Horsburgh MJ (ed.). "Distribution and regulation of the mobile genetic element-encoded phenol-soluble modulin PSM-mec in methicillin-resistant Staphylococcus aureus". PLOS ONE. 6 (12): e28781. Bibcode:2011PLoSO...628781C. doi:10.1371/journal.pone.0028781. PMC 3236207. PMID 22174895.
  10. ^ a b Novick RP, Ross HF, Projan SJ, Kornblum J, Kreiswirth B, Moghazeh S (October 1993). "Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule". The EMBO Journal. 12 (10): 3967–75. doi:10.1002/j.1460-2075.1993.tb06074.x. PMC 413679. PMID 7691599.
  11. ^ Benito Y, Kolb FA, Romby P, Lina G, Etienne J, Vandenesch F (May 2000). "Probing the structure of RNAIII, the Staphylococcus aureus agr regulatory RNA, and identification of the RNA domain involved in repression of protein A expression". RNA. 6 (5): 668–79. doi:10.1017/S1355838200992550. PMC 1369947. PMID 10836788.
  12. ^ Novick RP (June 2003). "Autoinduction and signal transduction in the regulation of staphylococcal virulence". Molecular Microbiology. 48 (6): 1429–49. doi:10.1046/j.1365-2958.2003.03526.x. PMID 12791129. S2CID 6847208.
  13. ^ Shopsin B, Eaton C, Wasserman GA, Mathema B, Adhikari RP, Agolory S, et al. (November 2010). "Mutations in agr do not persist in natural populations of methicillin-resistant Staphylococcus aureus". The Journal of Infectious Diseases. 202 (10): 1593–9. doi:10.1086/656915. PMID 20942648.
  14. ^ Kong KF, Vuong C, Otto M (April 2006). "Staphylococcus quorum sensing in biofilm formation and infection". International Journal of Medical Microbiology. 296 (2–3): 133–9. doi:10.1016/j.ijmm.2006.01.042. PMID 16487744.
  15. ^ Wuster A, Babu MM (January 2008). "Conservation and evolutionary dynamics of the agr cell-to-cell communication system across firmicutes". Journal of Bacteriology. 190 (2): 743–6. doi:10.1128/JB.01135-07. PMC 2223712. PMID 17933897.
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