Trends in Microbiology
OpinionThe role of virulence determinants in community-associated MRSA pathogenesis
Section snippets
Emergence of community-associated clones
Staphylococcus aureus is a major human pathogen and the leading cause of hospital-associated infections. S. aureus strains have developed resistance to almost all antibiotics, thereby complicating disease management. After first being reported in 1961, methicillin-resistant S. aureus (MRSA) has become endemic in hospitals worldwide, rendering the entire β-lactam class of antibiotics ineffective. Until recently, feral descendants of hospital-associated MRSA (HA-MRSA) were the most common cause
Unique genomic contents
Based on clonal analysis (Figure 1), two prevalent CA-MRSA strains from the USA were selected for further characterization to elucidate the molecular basis for inter-strain variations in epidemiological characters, disease frequencies and disease severity. Genome sequencing of two CA-MRSA strains, the Midwest Clone MW2 (USA400) and the pandemic clone USA300 6, 8, 9, 10, 24, 25, revealed that ∼20% of the unique genomic contents of CA-MRSA strains are a result of the horizontal acquisition of
Is PVL the major virulence determinant of CA-MRSA?
The epidemiological association among genetically diverse S. aureus strains carrying the pvl genes and fatal necrotizing pneumonia has renewed and intensified interest in understanding the biological role of PVL [34]. A PubMed search for articles on PVL published during the period 2002–2007 identified >250 articles noting an association between PVL and CA-MRSA disease outbreaks. Although compelling, epidemiological data alone are insufficient to establish whether PVL directly contributes to
PVL and its effects as purified toxin
PVL belongs to a family of similar bi-component leukocidal toxins (synergohymenotropic toxins) produced by staphylococci, with one component belonging to the F and one to the S class [41]. PVL is encoded by the lukPV operon that encodes the LukF-PV and LukS-PV components on the ϕSLT, ϕPVL, ϕSA2MW or ϕSA2usa phages 25, 41. These β-barrel structured toxins form pores almost exclusively in leukocytes, through a mechanism similar to that used by α-hemolysin (α-toxin) [42]. In contrast to PVL,
Isogenic PVL+/PVL− CA-MRSA strains in abscess and sepsis models
The effects of deleting the lukPV operon in MW2 and USA300 genetic backgrounds were tested in a mouse abscess model, to reproduce the most common clinical disease associated with PVL-positive CA-MRSA disease [18]. No significant difference in weight loss, abscess size or bacteria colony-forming units per abscess were detected when using Crl:SKH1-hrBR hairless and BALB/c mice to compare the following isogenic strain pairs: (i) MW2Δpvl mutant, in which the lukPV operon was deleted by allelic
PVL in experimental pneumonia: an exception?
Among infections caused by CA-MRSA, pneumonia is a rare but serious complication 17, 23. Using purified toxin or a laboratory strain of S. aureus that overproduced PVL through a multicopy plasmid, PVL was shown to impact mouse survival in a model of pneumonia using BALB/c mice [46]. It is of interest that, when comparing isogenic S. aureus strains lysogenized with either wild-type ϕSLT or mutated ϕSLT in which the lukPV operon was deleted, no difference in mouse survival was found [46],
Isogenic PVL+/PVL− CA-MRSA strain interactions with human neutrophils
Neutrophils are the main human leukocyte type to eliminate invading bacteria and are the main cellular target of PVL [41]. Because animal models can only reproduce partially how pathogens cause disease in humans, the null effect of PVL in the mouse and rabbit models might be due to a specific interaction of PVL with human neutrophils. Surprisingly, culture supernatants prepared from MW2 and USA300 clinical strains and their Δpvl isogenic mutants did not exhibit differences in capacity for pore
Does PVL have a gene-regulatory effect?
Recently, a pronounced global gene-regulatory effect has been ascribed to PVL [46], with the regulatory changes reminiscent of disrupting the accessory gene regulator agr[52]. For example, expression of PVL in a laboratory S. aureus strain background lysogenized with ϕSLT seemed to result in a strong up-regulation of protein A compared with the isogenic strain lysogenized with a mutated ϕSLT in which the lukPV operon was deleted, indicating that PVL regulates the expression of protein A by an
SCCmec and ACME linkage
MRSA strains contain distinct allotypes of the SCCmec element. In the absence of antibiotic-selection pressure, SCCmec is thought to reduce the biological fitness of MRSA. The type IV SCCmec element found in CA-MRSA strains is smaller in size than the type I–III SCCmec elements found in HA-MRSA strains. Thus, it might impose only a slight cost to fitness because it does not encode resistance determinants other than mecA. When comparing isogenic strains with different allotypes of the SCCmec
Phenol-soluble modulins and other toxins
Although S. aureus produces many molecules with the capacity to lyse human leukocytes, it has remained obscure which molecules are mainly responsible for neutrophil lysis in vivo and the pronounced lytic activity seen in CA-MRSA. Recently, novel cytolytic peptides have been found in S. aureus: α-type phenol-soluble modulins (PSMs), which are encoded in an operon on the genomes of all sequenced S. aureus strains (Figure 3a). The α-helical and amphipathic α-type PSMs are secreted in a yet
Concluding remarks and future directions
In recent years, perhaps no infectious disease problem has generated as much interest as the epidemic spread of CA-MRSA strains. In 2005, 18 650 deaths were estimated in patients with invasive MRSA disease in the USA, which was comparable with the number of deaths attributed to HIV/AIDS 23, 64. The pandemic clone USA300 has contributed more than any other strain to the dramatic increase in MRSA disease because it is unusually virulent and especially well adapted for transmission in the
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