INTRODUCTION — The virulence and rapid transmission of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections have raised interest in understanding the pathogenesis of this organism [1,2]. The most prevalent CA-MRSA strain in the United States, USA300, is now among the most common causes of skin and soft tissue infections in urban emergency departments across the United States [3,4]. Up to 10 percent of these infections are invasive infections such as sepsis, meningitis, osteomyelitis, and necrotizing pneumonia [5,6].
Issues related to evolution and virulence determinants that appear to be specific to the emergence of these epidemic CA-MRSA clones will be reviewed here. Issues related to the microbiology of MRSA are discussed in detail separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology".)
EVOLUTION OF CA-MRSA
Overview — Several of the emergent community-acquired methicillin-resistant S. aureus (CA-MRSA) strain sequences demonstrate striking similarity to other clonal MRSA strains [7,8]. The genetic persistence of these strains over time suggests they have core genomic determinants that facilitate their survival and virulence. A limited number of clones are responsible for most MRSA infections. The original methicillin-resistant isolate is strikingly similar in nucleotide sequence to the epidemic strain USA300 [7]. USA300 appears to have originated in Europe as a methicillin-susceptible sequence type 8 strain. It acquired the gene for methicillin resistance, and the PVL and ACME genes following its transport to the United States in the early 20th century [9]. Another CA-MRSA strain, the southwest Pacific strain that has caused infections in Australia and other countries in the region is a descendent of the phage 80/81 strain that has caused outbreaks in newborn nurseries in the 1960s [8].
As noted above, the genetic sequence of USA300 revealed that these strains contained a unique mobile element that includes the methicillin-resistance gene staphylococcal cassette chromosome mec (SCCmec) IVa, the arginine catabolic mobile element, enterotoxins Seq and Sek, and a prophage containing the leukocidin, Panton-Valentine leukocidin [7].
Clonal spread — The successful spread of CA-MRSA clones is associated with evolutionary changes of these clones that facilitate their success:
●A paper describing CA-MRSA transmission in Brooklyn noted an association between virulence and likelihood of spread [10]. The sequential evolutionary changes included acquisition of a prophage affecting pyrimidine nucleotide biosynthesis that enhanced fitness and promoted abscess formation and colonization potential. A second change was the acquisition of a plasmid encoding genes for topical biocide resistance.
●Another study also demonstrated the importance of antimicrobial resistance in the success of a CA-MRSA clone [11]. In it, spread of USA300 in Manhattan was associated with the emergence of a clone that was fluoroquinolone resistant.
Both of these studies illustrate that, in addition to the virulence factors described above, antimicrobial resistance also plays a critical role in the successful transmission of these strains.
VIRULENCE DETERMINANTS AND THEIR REGULATION — The enhanced virulence of the community-acquired methicillin-resistant S. aureus (CA-MRSA) strains is not fully understood but appears to result from several contributing factors (figure 1), including:
●The presence of the antibiotic resistance gene for methicillin
●The more rapid growth rate of these strains
●Virulence determinants unique to these strains
●Regulatory genes that modulate expression of the virulence determinants
●The host response to infection by these strains
●Factors facilitating transmission and survival of these strains in the environment [12,13]
Panton-Valentine leukocidin — Panton-Valentine leukocidin (PVL) was among the staphylococcal toxins first described in the 1930s by investigators seeking targets for development of antisera in an era prior to therapeutic antimicrobials [14,15]. These toxins included leukocidins (destructive for phagocytes), hemolysins, necrotoxins (necrotic when injected subcutaneously), and lethal toxin (fatal for rabbits after intravenous injection) [14].
PVL is a cytotoxin that causes leukocyte destruction and tissue necrosis; it is encoded by the genes lukS-PV and lukF-PV (together, the two components are referred to as lukSF-PV) [16]. PVL is often found in strains with mobile genetic elements, SCCmec type IV and V, that carry the methicillin-resistance gene. They are seldom present among SCCmec types I, II, and III (health care-associated MRSA strains) [17-25]. Although uncommon, PVL is also present in some methicillin-susceptible strains of S. aureus. PVL-containing S. aureus have been most frequently associated with skin and soft tissue (SSTIs) infections and necrotizing pneumonias [3,26-31].
There is a strong epidemiologic association between SSTIs and PVL production by the MRSA strain USA300 [28]. USA300 refers to the strain's pulse field gel electrophoresis pattern; this pattern is the most common among United States MRSA isolates [32]. In addition, USA300 contains staphylococcal cassette chromosome mec (SCCmec) type IV, which is relatively short (about 20 kb), and, as a result, is capable of rapid horizontal spread among strains of staphylococci.
Among 320 patients with SSTIs presenting to emergency departments in 11 United States cities in 2004, MRSA was the predominant pathogen (78 percent of isolates), and 98 percent of these were USA300 [3]. Nearly all of the USA300 isolates contained SCCmec type IV and the lukSF-PV genes encoding PVL, whereas genes for common staphylococcal enterotoxins and toxic shock syndrome were seldom present. Subsequently, both MRSA and methicillin-susceptible S. aureus (MSSA) USA300 PVL-positive strains were noted among 843 patients admitted to a large public hospital in Los Angeles in 2005, but there were no reliable epidemiologic factors to distinguish those with CA-MRSA from those with CA-MSSA [33]. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology".)
Inevitably, MRSA isolates elaborating PVL have also spread to hospitalized patients causing nosocomial infections. Among 37 clinical MRSA isolates at a veteran's hospital, for example, 60 percent were USA300 PVL positive [34]. The strain has also spread to several countries on various continents [18,35].
Although PVL has a strong epidemiologic association with CA-MRSA infections, its role in the pathogenesis and spread of infection is controversial [19,36-40]. The most compelling clinical data have been the association of PVL with necrotizing pneumonia, particularly in the setting of post-influenza respiratory infections [21,22]. A rabbit model of necrotizing pneumonia demonstrated that PVL plays a critical role in infection [41]. The authors hypothesized that, in the presence of a sufficient number of bacteria, PVL is produced, resulting in the activation of polymorphonuclear leukocytes (PMNs) and macrophages with the consequent release of inflammatory cytokines. In addition, the PVL lyses PMNs, causing the release of granules and proteolytic enzymes.
In other settings, the presence of PVL may not be as important. Among 109 patients with MRSA hospital-acquired pneumonia and ventilator-acquired pneumonia (including PVL+ strains in 27 percent of cases), the severity of disease and clinical outcome was not influenced by the presence of the PVL gene [42]. The PVL gene may be variably expressed in different settings. This was illustrated in an analysis of 31 S. aureus strains collected from patients with infections of varying severity; the quantity of PVL produced in vitro did not correlate with severity of infection [40].
Alpha-hemolysin — Alpha-hemolysin is a well-characterized toxin capable of forming pores in selected host cells, including erythrocytes, macrophages, and lymphocytes; it appears to play a critical role in the pathogenesis of infection in a mouse model [43]. In mice infected with isogenic strains of USA300, alpha-hemolysin was essential for development of pneumonia, but PVL was not [38]. Subsequent studies demonstrated vaccination with the toxin protected mice from infection [44]. More recently, studies using rabbit models of pneumonia and also of skin and soft tissue infections have also demonstrated the important role of alpha-toxin in the pathogenesis of these infections as well as the ability anti-alpha-toxin antibodies to protect against these infections [45,46].
Phenol soluble modulins (PSMs) — PSMs are small cytolytic peptides that are secreted in greater quantities by CA-MRSA than traditional isolates. These peptides are capable of attracting and lysing both red blood cells and polymorphonuclear leukocytes, have proinflammatory effects, and impair the host defense against staphylococcal infection. They also have a role in forming biofilms [47,48].
Arginine catabolic mobile element (ACME) — ACME is a pathogenicity island identified in USA300; it is rarely found in other strains of S. aureus, and its role in virulence is still uncertain [49]. ACME is usually linked to SCCmec and inserts into the same region, orfX. The gene cluster in ACME consists of arc and opp-3. The arc gene encodes the arginine deiminase system; depletion of arginine may reduce nitric oxide production. ACME facilitates staphylococcal survival in acidic environments and, as a result, may enhance its ability to survive on skin surfaces [50,51]. The presence of SpeG, a gene that detoxifies polyamines that are found in the skin, may increase bacterial burden in abscesses [51,52].
Two-component regulatory systems — There are numerous two-component regulatory systems (TCRSs) responsible for regulation of S. aureus virulence gene expression.
One TCRS, the accessory gene regulator (agr), is a regulatory gene that can control expression of virulent genes; it has several polymorphisms (I to IV), and strains can be grouped based on these polymorphisms [53,54]. In one study of CA-MRSA virulence in a rat pneumonia model using USA300 and USA400 strains, higher levels of regulatory genes including agr were produced by USA300 in vitro, suggesting one potential mechanism for its apparent enhanced virulence [55]. The role of agr and other regulatory genes in CA-MRSA infections is not fully understood; however, in the CA-MRSA strain, USA300 agr appears to enhance expression of surface adhesins, toxins, and exoenzymes, all of which may contribute to enhanced virulence [56].
A second TCRS, SaeR/S, has been shown to regulate expression of the promoters of extracellular virulence genes containing a consensus sequence. Its role has been demonstrated in murine sepsis and soft tissue infection models [57].
Serologic response to infection — In one study including 235 children with S. aureus colonization, those with invasive staphylococcal infections had the lowest alpha-hemolysin and Panton-Valentine leukocidin (LukF and LukS subunits) antibody titers; those with cutaneous S. aureus infection did not achieve a lasting immune response following infection. Patients with higher convalescent alpha-hemolysin antibody titers had longer duration of protection against recurrent infection over one year [58].
Environmental transmission — The CA-MRSA epidemic clones may be more efficient than other strains at colonizing multiple body sites and surviving on environmental surfaces [59-62]. These factors may contribute to an enhanced risk of reinfections in community reservoirs [63].
SUMMARY
●USA300 is the most prevalent strain of methicillin-resistant Staphylococcus aureus (MRSA) and is among the most common causes of skin and soft tissue infections in the United States and other countries. (See 'Introduction' above.)
●The acquisition of genes that confer antimicrobial resistance contributes to the success of community-acquired (CA-)MRSA clones. (See 'Clonal spread' above.)
●The virulence and rapid transmission of CA-MRSA have raised interest in understanding the pathogenesis of this organism. The enhanced virulence of the CA-MRSA strains is not fully understood but appears to result from several contributing factors. (See 'Virulence determinants and their regulation' above.)
●Several of the emergent CA-MRSA strain sequences demonstrate striking similarity to other clonal MRSA strains. The genetic persistence of these strains over time suggests they have core genomic determinants that facilitate their survival and virulence. (See 'Evolution of CA-MRSA' above.)
●Bacterial virulence determinants include Panton-Valentine leukocidin, alpha-hemolysin, phenol soluble modulins, and arginine catabolic mobile element. The accessory gene regulator and other regulatory genes in S. aureus can control expression of virulence genes. (See 'Virulence determinants and their regulation' above.)
1 : Case definition for community-associated methicillin-resistant Staphylococcus aureus.
2 : Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus.
3 : Methicillin-resistant S. aureus infections among patients in the emergency department.
4 : Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.
5 : Methicillin-resistant Staphylococcus aureus disease in three communities.
6 : Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat.
7 : Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus.
8 : Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone.
9 : Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8.
10 : Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus.
11 : Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community.
12 : The role of virulence determinants in community-associated MRSA pathogenesis.
13 : Secrets of a superbug.
14 : Staphylococcal toxin
15 : Staphylococcal infection and antitoxin treatment
16 : Clones and drones: do variants of Panton-Valentine leukocidin extend the reach of community-associated methicillin-resistant Staphylococcus aureus?
17 : Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection.
18 : Epidemiology of European community-associated methicillin-resistant Staphylococcus aureus clonal complex 80 type IV strains isolated in Denmark from 1993 to 2004.
19 : Community-acquired methicillin-resistant Staphylococcus aureus: the role of Panton-Valentine leukocidin.
20 : Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients.
21 : Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes.
22 : Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season.
23 : Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza--Louisiana and Georgia, December 2006-January 2007.
24 : Successful termination of a furunculosis outbreak due to lukS-lukF-positive, methicillin-susceptible Staphylococcus aureus in a German village by stringent decolonization, 2002-2005.
25 : High frequency of Panton-Valentine leukocidin genes in invasive methicillin-susceptible Staphylococcus aureus strains and the relationship with methicillin-resistant Staphylococcus aureus in Córdoba, Argentina.
26 : Unusually high prevalence of nosocomial Panton-Valentine leukocidin-positive Staphylococcus aureus isolates in Cape Verde Islands.
27 : Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children.
28 : Epidemiology and outcomes of community-associated methicillin-resistant Staphylococcus aureus infection.
29 : Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia.
30 : Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia.
31 : Factors predicting mortality in necrotizing community-acquired pneumonia caused by Staphylococcus aureus containing Panton-Valentine leukocidin.
32 : Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database.
33 : Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles.
34 : Community-associated strains of methicillin-resistant Staphylococccus aureus as the cause of healthcare-associated infection.
35 : Global distribution of Panton-Valentine leukocidin--positive methicillin-resistant Staphylococcus aureus, 2006.
36 : Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?
37 : Coexistence of Panton-Valentine leukocidin-positive and -negative community-associated methicillin-resistant Staphylococcus aureus USA400 sibling strains in a large Canadian health-care region.
38 : Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia.
39 : Widespread skin and soft-tissue infections due to two methicillin-resistant Staphylococcus aureus strains harboring the genes for Panton-Valentine leucocidin.
40 : In vitro production of panton-valentine leukocidin among strains of methicillin-resistant Staphylococcus aureus causing diverse infections.
41 : Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury.
42 : Severity of disease and clinical outcomes in patients with hospital-acquired pneumonia due to methicillin-resistant Staphylococcus aureus strains not influenced by the presence of the Panton-Valentine leukocidin gene.
43 : Staphylococcus aureusα-toxin: nearly a century of intrigue.
44 : Vaccine protection against Staphylococcus aureus pneumonia.
45 : IVIG-mediated protection against necrotizing pneumonia caused by MRSA.
46 : Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections.
47 : Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA.
48 : Phenol-soluble modulins and staphylococcal infection.
49 : The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus.
50 : The arginine catabolic mobile element is not associated with enhanced virulence in experimental invasive disease caused by the community-associated methicillin-resistant Staphylococcus aureus USA300 genetic background.
51 : Functional modularity of the arginine catabolic mobile element contributes to the success of USA300 methicillin-resistant Staphylococcus aureus.
52 : Arginine catabolic mobile element encoded speG abrogates the unique hypersensitivity of Staphylococcus aureus to exogenous polyamines.
53 : Diminished virulence of a sar-/agr- mutant of Staphylococcus aureus in the rabbit model of endocarditis.
54 : Quorum sensing in staphylococci.
55 : Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia.
56 : Role of the accessory gene regulator agr in community-associated methicillin-resistant Staphylococcus aureus pathogenesis.
57 : SaeR binds a consensus sequence within virulence gene promoters to advance USA300 pathogenesis.
58 : A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection.
59 : Clinical practice: colonization, fomites, and virulence: rethinking the pathogenesis of community-associated methicillin-resistant Staphylococcus aureus infection.
60 : Body site colonization in patients with community-associated methicillin-resistant Staphylococcus aureus and other types of S. aureus skin infections.
61 : Survival and transmission of community-associated methicillin-resistant Staphylococcus aureus from fomites.
62 : Staphylococcus aureus infections: transmission within households and the community.
63 : The environment as an unrecognized reservoir for community-associated methicillin resistant Staphylococcus aureus USA300: a case-control study.