Accessory gene regulator (agr) is a complex 5

gene locus In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total ...

that is a global regulator of

virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ...

in ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posit ...

''. It encodes a two-component transcriptional

quorum-sensing In biology, quorum sensing or quorum signalling (QS) is the ability to detect and respond to cell population density by gene regulation. As one example, QS enables bacteria to restrict the expression of specific genes to the high cell densities at ...

(QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP). Agr occurs in 4 allelic subtypes that have an important role in staphylococcal evolution. The corresponding AIPs are mutually cross-inhibitory, which may enhance the evolutionary separation of the 4 groups. The ''agr'' receptor, AgrC, is a model histidine phosphokinase (HPK) that has been used to decipher the molecular mechanism of

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...

. 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. The ''agr'' QS circuit autoactivates transcription of ''agrA'' which, in turn upregulates the phenol-souble modulins. More importantly, it activates transcription of a divergently oriented promoter whose transcript, known as

RNAIII RNAIII is a stable 514 nt regulatory RNA transcribed by the P3 promoter of the ''Staphylococcus aureus'' quorum-sensing '' agr'' system ). It is the major effector of the ''agr'' regulon, which controls the expression of many '' S. aureus'' gene ...

, is a 514 nt regulatory RNA that encodes δ-hemolysin and is the major effector of the ''agr'' regulon.

acts by

antisense In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...

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 protein''A'') are expressed, enabling the organism to gain a foothold. Later in growth, these genes are down-regulated by

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. It is assumed that this program operates in vivo as well. As ''agr'' is essential for staphylococcal contagion, ''agr-''defective mutants are not contagious, but enable the organism’s long-term survival in chronic conditions such as surgical implant infections,

osteomyelitis Osteomyelitis (OM) is an infection of bone. Symptoms may include pain in a specific bone with overlying redness, fever, and weakness. The long bones of the arms and legs are most commonly involved in children e.g. the femur and humerus, while the ...

or the infected lung in

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. ...

. In keeping with this behavior, mutations inactivating ''agr'' function enhance the stability of

biofilms A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular po ...

, which are key to the maintenance of chronic infections. ''Agr'' is widely conserved among

Bacillota The Bacillota (synonym Firmicutes) are a phylum of bacteria, most of which have gram-positive cell wall structure. The renaming of phyla such as Firmicutes in 2021 remains controversial among microbiologists, many of whom continue to use the ea ...

and has a well-defined role in virulence regulation in several genera, especially ''

Listeria ''Listeria'' is a genus of bacteria that acts as an intracellular parasite in mammals. Until 1992, 17 species were known, each containing two subspecies. By 2020, 21 species had been identified. The genus is named in honour of the British pi ...

'' and ''

Clostridia The Clostridia are a highly polyphyletic class of Bacillota, including '' Clostridium'' and other similar genera. They are distinguished from the Bacilli by lacking aerobic respiration. They are obligate anaerobes and oxygen is toxic to them. S ...

''.

References

{{Reflist Gene expression Genetics Virology