Quorum Sensing and Toxin Production in Staphylococcus aureus Osteomyelitis: Pathogenesis and Paradox

Abstract

Staphylococcus aureus is a Gram-positive pathogen capable of infecting nearly every vertebrate organ. Among these tissues, invasive infection of bone (osteomyelitis) is particularly common and induces high morbidity. Treatment of osteomyelitis is notoriously difficult and often requires debridement of diseased bone in conjunction with prolonged antibiotic treatment to resolve infection. During osteomyelitis, S. aureus forms characteristic multicellular microcolonies in distinct niches within bone. Virulence and metabolic responses within these multicellular microcolonies are coordinated, in part, by quorum sensing via the accessory gene regulator (agr) locus, which allows staphylococcal populations to produce toxins and adapt in response to bacterial density. During osteomyelitis, the Agr system significantly contributes to dysregulation of skeletal homeostasis and disease severity but may also paradoxically inhibit persistence in the host. Moreover, the Agr system is subject to complex crosstalk with other S. aureus regulatory systems, including SaeRS and SrrAB, which can significantly impact the progression of osteomyelitis. The objective of this review is to highlight Agr regulation, its implications on toxin production, factors that affect Agr activation, and the potential paradoxical influences of Agr regulation on disease progression during osteomyelitis.

Mechanisms of Antibiotic Failure During Staphylococcus aureus Osteomyelitis

“…Key characteristics of osteomyelitis are severe inflammation, vascular impairment, and localized bone loss and destruction (2). The host responds to the presence of bacteria such as S. aureus by releasing inflammatory factors and degradative enzymes from immune cells, which contribute to the destruction of bone matrix and bone trabeculae (1,(5)(6)(7)(8)(9)(10). Many of the innate immune responses involved in antibacterial host defense also have significant impacts on bone homeostasis, and the release of inflammatory mediators at the infection site can result in decreased osteoblast-mediated bone formation and increased osteoclast activation and bone resorption, thereby promoting bone loss.…”

Pyranoanthocyanins Interfering with the Quorum Sensing of Pseudomonas aeruginosa and Staphylococcus aureus

“…In S. aureus, the agr quorum sensing system plays a major role in the regulation of virulence factors production [10]. The agr operon consists of four genes: agrB, agrD, agrC, and agrA.…”

“…RNAIII serves to enhance the expression of genes encoding toxins, such as α-hemolysin, while reducing the expression of genes encoding surface proteins. Although most of the QS regulation depends on RNAIII, it has been shown that AgrA, upon phosphorylation, is also directly responsible for the production of some virulence factors, such as phenol-soluble modulines (PSMs) [10]. It is believed that the agr system influences biofilms in vivo by upregulating PSMs expression, which are involved in the structure of biofilms by forming channels and promoting cell dispersal from the biofilm to further colonize the host [49,50].…”

“…Regarding the effect of carboxypyCy-3-glc in the gene expression of MDR isolates, sarA, RNAIII and hla were overexpressed in SA007, while agrA and hla were downexpressed in SA011. It has been demonstrated that AgrA negatively regulates the production of proteases that degrade several virulence factors, such as coagulases and PSMs [10,54,55]. Thus, the inhibition of AgrA in SA011 and consequent protease de-repression might be the reason why the biofilm structure is so deeply affected in the presence of either the extract or the compound.…”

Staphylococcus aureus Toxins: Promoter or Handicap during Infection?

“…The authors described a decrease in virulence and toxin genes that most likely reflect the bacterial adaptation process towards a persisting phenotype [ 34 ]. Additionally, in S. aureus osteomyelitis, the bacteria revealed adaptation strategies largely controlled by the accessory gene regulator ( agr ) locus, which is extensively reviewed by Butrico et al [ 35 ]. Finally, Wong Fok Lung et al display the S. aureus metabolic adaptation that is induced by the host immune response and results in bacterial strains adapted for chronicity [ 36 ].…”