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.

Keywords: Staphylococcus aureus; accessory gene regulator; bone; infectious; osteomyelitis; pathogenesis; quorum; toxin; virulence.

Figure 1

Accessory gene regulator (Agr) signals through self-regulation and crosstalk with other two-component systems. Quorum-mediated Agr signaling is influenced by regulatory proteins, staphylococcal accessory regulator A (SarA), carbon catabolite control protein A (CcpA), and CodY and two-component systems, staphylococcal respiratory response AB (SrrAB) and Staphylococcus aureus exoprotein expression response regulator (SaeRS), which are responsive to oxygen (SrrAB) and nutrient availability (SaeRS), as well as host immune stress. AgrB facilitates the formation of extracellular AIP from the AgrD precursor. Agr signaling occurs through AIP-mediated signal transduction at a threshold concentration that activates AgrC phosphotransferase activity to phosphorylate AgrA. AgrA activates the transcription of RNAIII via P3 to produce virulence factors implicated in S. aureus acute osteomyelitis. AgrA binding to P2 results in transcription of RNAII, leading to additional agrA, agrC, agrD, and agrB mRNA. Phosphorylated AgrA also enhances the transcription of phenol-soluble modulins (PSMs) directly. SarA and activated SaeR indirectly augment PSM production via inhibition of the protease Aureolysin (Aur).

Figure 2

Paradoxical benefits of agr expression and inhibition/mutation on S. aureus fitness during osteomyelitis. S. aureus strains produce virulence factors including cytotoxic proteins, such as phenol-soluble modulins (PSMs) and Panton–Valentine leucocidin (PVL) that insert into the membranes of neutrophils and bone cells to induce cell death in an Agr-dependent manner. S. aureus strains with high agr expression also produce alpha-toxin (Hla), which induces pro-inflammatory cytokine production and enhances bone resorption. Additionally, the production of MHC class II analog protein (Map) results in suppression of T cell immunity. S. aureus strains with mutations in agr are commonly isolated from chronic infections, whereby the bacteria exhibit characteristics that enable persistent colonization. Coagulase (Coa) and von Willebrand factor-binding protein (vWbp) contribute to formation of fibrin matrices that facilitate bacterial attachment. Staphylococcal protein A (SpA) increases in abundance in the absence of RNAIII as well and has a number of immunomodulatory functions.