SUPPLEMENT ARTICLE

Pathogenesis of Methicillin-Resistant Staphylococcus

aureus Infection
Rachel J. Gordon1 and Franklin D. Lowy1,2
1
Division of Infectious Diseases, Department of Medicine, and 2Department of Pathology, Columbia University College of Physicians
and Surgeons, New York, New York

Staphylococcus aureus is a versatile pathogen capable of causing a wide range of human diseases. However,
the role of different virulence factors in the development of staphylococcal infections remains incompletely

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understood. Some clonal types are well equipped to cause disease across the globe, whereas others are facile
at causing disease among community members. In this review, general aspects of staphylococcal pathogenesis
are addressed, with emphasis on methicillin-resistant strains. Although methicillin-resistant S. aureus (MRSA)
strains are not necessarily more virulent than methicillin-sensitive S. aureus strains, some MRSA strains contain
factors or genetic backgrounds that may enhance their virulence or may enable them to cause particular
clinical syndromes. We examine these pathogenic factors.

OVERVIEW OF THE PATHOGENESIS onized. However, numerous other sites may be

OF STAPHYLOCOCCUS AUREUS colonized, including the axillae, groin, and gastroin-
testinal tract. Colonization provides a reservoir from
This article summarizes the pathogenesis of S. aureus
which bacteria can be introduced when host defenses
disease and specifically addresses the pathogenesis of
are breached, whether by shaving, aspiration, insertion
infections caused by methicillin-resistant S. aureus
of an indwelling catheter, or surgery. Colonization
(MRSA) strains originating in health care settings (hos-
clearly increases the risk for subsequent infection [1,
pital-acquired MRSA [HA-MRSA]) and in the com-
2]. Those with S. aureus infections are generally infected
munity (community-acquired MRSA [CA-MRSA]). S.
with their colonizing strain [3]. In a study of bacter-
aureus pathogenesis is reviewed before the discussion
emia, blood isolates were identical to nasal isolates in
of the pathogenesis of MRSA, because MRSA virulence 82% of patients [4]. Colonization also allows S. aureus
factors are generally not unique to MRSA. Nonetheless, to be transmitted among individuals in both health care
certain MRSA strains appear to contain particular fac- and community settings. The basis for S. aureus col-
tors or genetic backgrounds that enhance their viru- onization is complex and incompletely understood but
lence or enable them to cause particular clinical appears to involve the host’s contact with S. aureus (e.g.,
syndromes. other carriers) and the ability of S. aureus to adhere to
Colonization and disease. S. aureus is both a com- host cells and to evade the immune response (reviewed
mensal organism and a pathogen. The anterior nares by Wertheim et al. [1]).
are the main ecological niche for S. aureus. Approxi- Virulence factors and disease. The armamentar-
mately 20% of individuals are persistently nasally col- ium of virulence factors of S. aureus is extensive, with
onized with S. aureus, and 30% are intermittently col- both structural and secreted products playing a role in
the pathogenesis of infection (figure 1). Selected ex-
amples of these factors are described in table 1. Two
Reprints or correspondence: Dr. Rachel J. Gordon, Dept. of Medicine, Div. of
noteworthy features of staphylococci are that a viru-
Infectious Diseases, Columbia University College of Physicians and Surgeons, 630
W. 168th St., Box 82, New York, NY 10032 (rj216@columbia.edu). lence factor may have several functions in pathogenesis
Clinical Infectious Diseases 2008; 46:S350–9 and that multiple virulence factors may perform the
 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4611S5-0004$15.00
same function. In establishing an infection, S. aureus
DOI: 10.1086/533591 has numerous surface proteins, called “microbial sur-

S350 • CID 2008:46 (Suppl 5) • Gordon and Lowy

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Figure 1. Pathogenic factors of Staphylococcus aureus, with structural and secreted products both playing roles as virulence factors. A, Surface
and secreted proteins. B and C, Cross-sections of the cell envelope. TSST-1, toxic shock syndrome toxin 1. Reprinted from [32], with permission from
the Massachusetts Medical Society. Copyright 1998 Massachusetts Medical Society. All rights reserved.

face components recognizing adhesive matrix molecules” zwitterionic capsule (both positively and negatively charged)
(MSCRAMMs), that mediate adherence to host tissues. can also induce abscess formation [17, 18]. The MSCRAMM
MSCRAMMs bind molecules such as collagen, fibronectin, and protein A binds the Fc portion of immunoglobulin [31] and,
fibrinogen, and different MSCRAMMs may adhere to the same as a result, may prevent opsonization. S. aureus may also secrete
host-tissue component. MSCRAMMs appear to play a key role chemotaxis inhibitory protein of staphylococci or the extra-
in initiation of endovascular infections, bone and joint infections, cellular adherence protein, which interfere with neutrophil ex-
and prosthetic-device infections. Different S. aureus strains may travasation and chemotaxis to the site of infection (reviewed
have different constellations of MSCRAMMs and so may be by Foster [16]). In addition, S. aureus produces leukocidins
predisposed to causing certain kinds of infections [5–8]. that cause leukocyte destruction by the formation of pores in
Once S. aureus adheres to host tissues or prosthetic materials, the cell membrane [19].
it is able to grow and persist in various ways. S. aureus can form During infection, S. aureus produces numerous enzymes, such
biofilms (slime) on host and prosthetic surfaces, enabling it to as proteases, lipases, and elastases, that enable it to invade and
persist by evading host defenses and antimicrobials [9]. The abil- destroy host tissues and metastasize to other sites. S. aureus is
ity to form and reside in biofilms is one reason why prosthetic- also capable of producing septic shock. It does this by interacting
device infections, for example, can be so difficult to eradicate with and activating the host immune system and coagulation
without removal of the device. In vitro, S. aureus can also invade pathways. Peptidoglycan, lipoteichoic acid, and a-toxin may all
and survive inside epithelial cells, including endothelial cells, play a role [22–24] (reviewed by Lowy [32]). In addition to
which theoretically may also allow it to escape host defenses, causing septic shock, some S. aureus strains produce superan-
particularly in endocarditis [10–12, 30]. S. aureus is also able to tigens, resulting in various toxinoses, such as food poisoning and
form small-colony variants (SCVs), which may contribute to toxic shock syndrome [25, 33]. Unlike the structural components
persistent and recurrent infection. In vitro, SCVs are able to noted earlier, these superantigens can produce a sepsis-like syn-
“hide” in host cells without causing significant host-cell damage drome by initiating a “cytokine storm.” Some strains also pro-
and are relatively protected from antibiotics and host defenses. duce epidermolysins or exfoliative toxins capable of causing
They can later revert to the more virulent wild-type phenotype, scalded skin syndrome or bullous impetigo [26].
possibly resulting in recurrent infection [13–15]. Regulation of expression of staphylococcal virulence factors
S. aureus has many other characteristics that help it evade plays a central role in pathogenesis. To reduce undue metabolic
the host immune system during an infection (reviewed by Fos- demands, expression occurs in a coordinated fashion—only
ter [16]). Its main defense is production of an antiphagocytic when required by the bacterium. Expression of MSCRAMMs
microcapsule (most clinical isolates produce type 5 or 8). The generally occurs during logarithmic growth (replication),

MRSA Pathogenesis • CID 2008:46 (Suppl 5) • S351

Table 1. Selected Staphylococcus aureus virulence factors.

a
Type of virulence factors Selected factors Genes Associated clinical syndromes Reference(s)
Involved in attachment MSCRAMMs (e.g., clumping factors, fibro- clfA, clfB, fnbA, fnbB, cna, sdr, bbp Endocarditis, osteomyelitis, septic arthritis, [5–8]
nectin-binding proteins, collagen, and and prosthetic-device and catheter
bone sialoprotein-binding proteins) infections
Involved in persistence Biofilm accumulation (e.g., polysaccharide ica locus, hemB mutation Relapsing infections, cystic fibrosis, and [9–15]
intercellular adhesion), small-colony vari- syndromes as described above for
ants, and intracellular persistence attachment
Involved in evading/destroying host Leukocidins (e.g., PVL and g-toxin), capsu- lukS-PV, lukF-PV, hlg, cap5 and 8 gene Invasive skin infections and necrotizing [16–20]
defenses lar polysaccharides (e.g., 5 and 8), pro- clusters, spa, chp, eap, psm-a gene pneumonia (CA-MRSA strains that cause
tein A, CHIPS, Eap, and phenol-soluble cluster these are often associated with PVL) ab-
modulins scesses (associated with capsular
polysaccharides)
Involved in tissue invasion/penetration Proteases, lipases, nucleases, hyaluronate V8, hysA, hla, plc, sepA Tissue destruction and metastatic [21]
lyase, phospholipase C, and metallopro- infections
teases (elastase)
Involved in toxin-mediated disease and/ Enterotoxins, toxic shock syndrome toxin- sea-q (no sef), tstH, eta, etb, hla Food poisoning, toxic shock syndrome, [22–26]
or sepsis 1, exfoliative toxins A and B, a-toxin, scalded skin syndrome, bullous impetigo,
peptidoglycan, and lipoteichoic acid and sepsis syndrome
With poorly defined role in virulence Coagulase, ACME, and bacteriocin arc cluster, opp-3 cluster, bsa [27, 28]

NOTE. ACME, arginine catabolic mobile element; CA-MRSA, community-acquired methicillin-resistant S. aureus; CHIPS, chemotaxis inhibitory protein of staphylococci; Eap, extracellular adherence protein;
MSCRAMMs, microbial surface components recognizing adhesive matrix molecules; PVL, Panton-Valentine leukocidin. Adapted from Projan and Novick [21] and Archer [29].
a
Several factors may have 11 role in S. aureus pathogenesis.

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whereas secreted proteins, such as toxins, are produced during reus (MSSA) clones. Using multilocus sequence typing (com-
the stationary phase. During infection, the early expression of paring the internal sequences of 7 housekeeping genes), Enright
the MSCRAMM proteins facilitates initial colonization of tissue et al. [49] demonstrated that MRSA clones evolved from 5 dif-
sites, whereas the later elaboration of toxins facilitates spread. ferent groups of related genotypes or clonal complexes, each
The accessory gene regulator (agr) is a quorum-sensing system arising from a distinct ancestral genotype. The earliest MRSA
that plays a critical role in the regulation of staphylococcal isolates evolved from sequence type (ST) 8-MSSA, which, after
virulence. It has been studied extensively and has been reviewed a point mutation, evolved into ST250-MSSA. This MSSA was
by Yarwood and Schlievert [34] and Novick [35], among others. likely the first recipient of SCCmec (specifically, type I) to yield
The agr mutants appear to have diminished virulence, and the first MRSA, labeled ST250-MRSA-I [49]. As in the work of
certain agr types are associated with particular clinical syn- Enright et al. [49], Crisóstomo et al. [50] identified probable
dromes [36]. Other important regulators include the staphy- recipient MSSA strains for early MRSA strains in another col-
lococcal accessory regulator [37], ArlR and ArlS [38], SaeRS lection of isolates. Select MRSA clones are described in table 2.
[39, 40], Rot [41], and mgr [42]. HA-MRSA infections historically have been caused by in-
Host factors may also affect susceptibility to staphylococcal ternationally disseminated clones, including 5 major clones (the
disease but, in general, are poorly characterized. In one large Iberian, Brazilian, Hungarian, New York/Japan, and Pediatric
study, S. aureus nasal carriage and subsequent development of clones) that have been described in several ways (e.g., by mul-
S. aureus bacteremia and mortality were assessed in nonsurgical, tilocus sequence typing and PFGE) with the use of different

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hospitalized patients. Among those who developed S. aureus nomenclature. Subsequently, these multidrug-resistant clones
bacteremia, noncarriers had mortality higher than that among were disseminated globally and accounted for the majority of
carriers. Because most infections among carriers occurred with HA-MRSA infections in several regions. For example, the Bra-
their colonizing strains, colonization may confer some protec- zilian clone spread to Portugal, Argentina, Uruguay, Chile, and
tive immunity if staphylococcal infection develops [43]. An- the Czech Republic [55]. It remains unclear why particular
tibodies also appear to protect against the development of toxic clones are so transmissible and are able to become the “estab-
shock syndrome, which occurs almost exclusively in those who lished” HA-MRSA strains in certain regions. Certainly, resis-
lack antibodies to the implicated toxin at the time of acute tance to multiple antibiotics plays a role in establishing dom-
illness [33]. inance in hospital settings. However, investigators have also
As described, S. aureus has numerous mechanisms to pro- postulated that these clones have enhanced virulence, as de-
duce disease and to evade host defenses. However, it is im- noted by their increased transmissibility or ability to colonize
portant to note that not all S. aureus strains are created equal. hosts.
Different strains may contain different adhesins or toxins or
One example of a successful clonal type is phage type 80/81,
may differ in their ability to produce biofilms and resist phago-
which was responsible for pandemic S. aureus nosocomial and
cytosis. The distribution of some virulence factors is related to
community-acquired infections throughout the 1950s. Its prev-
clonal type, whereas the presence of others is unrelated to ge-
alence began to fade in the 1960s after methicillin became avail-
netic background [44]. In this regard, it is important to note
able. Phage type 80/81 is ST30 and contains the Panton-Valentine
that there is limited information on the expression of these
leukocidin (PVL) gene. This highly successful clone is related to
genes during infection.
the southwest Pacific (SWP) clone, a CA-MRSA clone that is
also ST30 and contains SCCmec IV as well as PVL. Given the
PATHOGENESIS OF HA-MRSA
similar genetic backgrounds of these strains and the previous
History of MRSA. Methicillin was first introduced in 1959– epidemicity of phage type 80/81, one would expect the SWP
1960, and, within a year, methicillin-resistant isolates were re- clone to have great potential to cause widespread disease. Of
ported [45]. Methicillin resistance is conferred by the mecA note, this clone has already appeared in the United Kingdom.
gene, which encodes a penicillin-binding protein (PBP2A) with Phage type 80/81 also is a likely close relative of the hospital-
decreased affinity for b-lactam antibiotics. mecA is part of a acquired, epidemic MRSA-16 strain (ST36-MRSA-II) [56].
mobile genetic element called the “staphylococcal cassette chro- HA-MRSA virulence: the Brazilian clone. The Brazilian
mosome (SCC) mec.” SCCmec is flanked by cassette chro- clone (also known as Brazilian epidemic clonal complex
mosome recombinase genes (ccrA/ccrB or ccrC) that permit [BECC]), PFGE type A1, became the major cause of invasive
intra- and interspecies horizontal transmission of SCCmec. The staphylococcal infections at João Barros Barreto University
initial reservoir of SCCmec is unclear but may have been a Hospital (Belém, Brazil) in the 1990s. In 1995, it accounted for
coagulase-negative staphylococcal species [46–48]. 38% of S. aureus isolates and, by 1998, 79% of isolates. In-
A limited number of MRSA lineages has emerged from the vestigators compared BECC A1 strains to MSSA and sporadic
transfer of SCCmec into successful methicillin-susceptible S. au- MRSA strains (rarely detected in hospitals) in several in vitro

MRSA Pathogenesis • CID 2008:46 (Suppl 5) • S353

 Table 2. Details of select important methicillin-resistant Staphylococcus aureus
(MRSA) clones and their clonal complexes.

Clonal
a b
Clone name complex Other names of clone
ST1-MRSA-IV 1 USA400, MW2
ST5-MRSA-I 5 UK EMRSA-3
ST5-MRSA-II 5 New York/Japanese, GISA, and USA100
ST5-MRSA-IV 5 USA800 and Pediatric
ST228-MRSA-I 5 Southern Germany
ST8-MRSA-II 8 Irish-1
ST8-MRSA-IV 8 UK EMRSA-2, -6, USA300, and USA500
ST239-MRSA-III 8 UK EMRSA-1, -4, -11, Portuguese, Brazilian, and Viennese
ST247-MRSA-I 8 UK EMRSA-5, -17, and Iberian
ST250-MRSA-I 8 First MRSA and Archaic
ST22-MRSA-IV 22 UK EMRSA-15 and Barnim
ST36-MRSA-II 30 UK EMRSA-16 and USA200
ST30-MRSA-IV 30 Southwest Pacific

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ST45-MRSA-IV 45 Berlin and USA600
ST72-MRSA-IV … USA700

NOTE. EMRSA, epidemic MRSA; GISA, glycopeptide-intermediate S. aureus. Adapted from [51],
with permission from Elsevier.
a
The clone name is comprised of the sequence type (ST), which is the multilocus sequence type
based on the sequences of 7 housekeeping genes, and the MRSA staphylococcal cassette chromosome
(SCC) mec type.
b
Only select “other names” are included. Additional sources: Enright et al. [49], McDougal et al.
[52], Tenover et al. [53], and Melles et al. [54].

experiments. BECC A1 strains produced significantly more bio- as the MW2 strain) [52]. Subsequently, clonal outbreaks of skin
film than did the other strains. They also had higher adhesion and soft-tissue infection caused by CA-MRSA were also re-
to polystyrene, as well as to bronchial epithelial cells, and were ported among prison inmates, men who have sex with men,
more likely to invade these cells. The presence of accessible soldiers, and athletes, particularly football players [61–64]. The
fibronectin-binding domains appeared to be necessary for a strain responsible for these infections was ST8 and PFGE type
high level of invasion. These in vitro studies suggest that this USA300 [53]. Cases of CA-MRSA skin infection and necrotiz-
particular clone may be successful because it has an enhanced ing pneumonia were reported internationally as well [65, 66].
ability to bind, persist, and invade [57]. Whether these attri- In addition to causing necrotizing pneumonia, CA-MRSA
butes are present in other HA-MRSA epidemic clones is has recently been reported to cause infections or infectious
unknown. complications in situations in which S. aureus or MRSA is an
unusual pathogen. These have included cases of necrotizing
PATHOGENESIS OF CA-MRSA INFECTION fasciitis caused by PFGE type USA300 [67], as well as cases of
Until the 1990s, MRSA rarely caused infections among com- pyomyositis [68, 69], purpura fulminans with toxic shock syn-
munity members without exposure to the health care setting drome [70], and Waterhouse-Friderichsen syndrome [71].
(one exception is injection drug users). An outbreak of CA- The number of CA-MRSA infections appears to be increas-
MRSA infections occurred between 1989 and 1991 among in- ing, and the strains responsible for these infections have now
digenous Australians in western Australia without health care entered the health care setting, blurring the line between “com-
contact [58]. CA-MRSA infections were also reported in people munity” and “hospital” strains [72, 73]. The strains that cause
from neighboring regions [59]. In the late 1990s, several cases these virulent infections carry SCCmecIV (sometimes
of aggressive MRSA infection also occurred among individuals SCCmecV), the smallest of the SCCs that confer methicillin
in the United States without established risk factors for MRSA. resistance, and are generally susceptible to several non–b-lactam
Four children died of CA-MRSA infections in Minnesota and antibiotics. This is in contrast to the multidrug-resistant nos-
North Dakota from 1997 to 1999. All the cases were rapidly ocomial MRSA strains that carry larger SCCmec types [74, 75].
fatal and were associated with necrotizing pneumonia or pul- CA-MRSA strains may also have a growth advantage over HA-
monary abscesses and sepsis [60]. The strain responsible for MRSA strains [27, 76].
these infections was ST1 and PFGE type USA400 (also known Although SCCmecIV has appeared in several different genetic

S354 • CID 2008:46 (Suppl 5) • Gordon and Lowy

backgrounds [55], PFGE types USA300 (ST8) and USA400 rationale for this association. Staphylococcal leukotoxins, in-
(ST1)—both agr type III—accounted for the vast majority of cluding PVL, are secreted as bicomponent toxins consisting of
CA-MRSA infections in individuals without the usual MRSA S and F proteins [16, 84]. Depending on the combination of
risk factors or health care contact in the United States [52, 77]. particular S and F proteins, a toxin is formed with varying
USA300 is now the predominant strain. Of interest, some of leukocytolytic, erythrocytolytic, and dermonecrotic properties
these USA300 isolates that cause infections are PVL positive [84, 85]. PVL consists of LukS-PV and LukF-PV and 4 units
but methicillin susceptible [78]. of each form of octameric b-barrel pores in leukocyte mem-
Worldwide, there are other prevalent CA-MRSA strains, such branes in vitro, resulting in cell lysis [19, 86–88]. This may
as ST80 (France-Switzerland), ST30 (SWP clone), and ST93 cause cells such as neutrophils to release inflammatory enzymes
(Australia Queensland clone) [65]. Said-Salim et al. [77] iden- and cytokines (sublytic concentrations of PVL also appear to
tified additional “community-acquired strains” (CA-MRSA induce the release of these substances) [88–90]. PVL also ap-
strains defined as containing SCCmecIV); however, these were pears to induce apoptosis of neutrophils via a mitrochondrial
in individuals with MRSA risk factors or health care contact. pathway at lower concentrations, whereas, at higher concen-
The basis for the apparent increased virulence of CA-MRSA trations, PVL induces necrosis [91]. In vivo, PVL causes der-
strains is incompletely understood. Numerous factors have been monecrosis when injected intradermally in rabbits [92].
proposed, such as increased fitness, improved evasion of the host Given this evidence and the strong epidemiological associ-
immune system, and unique toxin production. The genes and ation between PVL-containing CA-MRSA strains and necro-

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mechanisms by which CA-MRSA strains may cause aggressive tizing pneumonia and skin and soft-tissue infections, it is plau-
disease are discussed in the sections that follow. Because these sible that PVL is partly responsible for the enhanced virulence
strains usually contain PVL, which is usually absent in HA-MRSA of CA-MRSA (other leukocidins may also play a role). However,
strains, some researchers postulate that this protein, with leu- recent studies comparing the virulence of PVL-positive and
kocytolytic and dermonecrotic activity, is responsible. PVL-negative strains have had conflicting results.
The role of PVL versus other virulence determinants. Saı̈d-Salim et al. [77] compared human polymorphonuclear
There is a strong epidemiological association between PVL and cell lysis among PVL-positive and PVL-negative CA-MRSA
the emergence of CA-MRSA infections. PVL is uncommonly strains with similar genetic backgrounds and found no differ-
found in MSSA and HA-MRSA isolates [79–83]. In a study of ence in polymorphonuclear lysis. Voyich et al. [93] compared
593 S. aureus isolates in France, PVL was absent in HA-MRSA PVL-positive strains and PVL-negative strains with similar ge-
isolates but was associated with all CA-MRSA strains [83]. In netic backgrounds in mouse sepsis and abscess models, as well
another study, PVL was ubiquitous in a large sample of CA- as PVL knockouts created for the USA300 and USA400 strains.
MRSA isolates collected from across the globe [65]. It is usually There was no difference in survival in the mouse sepsis model.
present in USA300 and USA400 [27, 53, 77] and is often har- In the abscess model, PVL-negative strains unexpectedly caused
bored by other SCCmecIV-containing strains [77]. The out- slightly larger abscesses than did the PVL-positive strains. Iso-
breaks of skin and soft-tissue infections and necrotizing pneu- genic pvl strains of USA300 and USA400 showed no difference
monia mentioned above were caused by PVL-positive strains. in the ability to cause polymorphonuclear lysis in vitro. The
Lina et al. [66] determined the presence of lukS-PV and lukF- authors concluded that the PVL “…toxin is not the major
PV (the cotranscribed genes for PVL) in 172 S. aureus strains determinant of disease caused by these prominent CA-MRSA
collected from patients with a variety of clinical syndromes. strains” [93, p. 1769]. It is possible that the mouse models used
PVL was significantly associated with community-acquired in this study were not optimal to assess the in vivo effects of
pneumonia (85% of strains), compared with hospital-acquired PVL, or, as the authors suggested, that PVL either is a marker
pneumonia (0%). PVL was also significantly associated with for other virulence factors present in these strains or is one of
strains causing invasive skin infections such as furunculosis many factors causing the enhanced virulence of particular CA-
(93%) and cutaneous abscess (50%), compared with superficial MRSA strains.
folliculitis (0%). PVL was not observed in strains associated PVL was investigated in a mouse pneumonia model by La-
with infective endocarditis, urinary tract infections, toxic shock bandeira-Rey et al. [94]. Mice were infected with isogenic PVL-
syndrome, or mediastinitis, although few strains were tested positive and PVL-negative (non–CA-MRSA) strains. PVL-pos-
[66]. Diep et al. [80] reported a similar association of PVL and itive strains caused necrotizing pneumonia similar to that seen
skin and soft-tissue infections caused by MRSA isolated from in humans, whereas PVL-negative strains showed only some
inpatients and outpatients from San Francisco General Hospital leukocytic invasion. When PVL-negative mutants were com-
and inmates in county jails. plemented with plasmids containing the PVL operon, massive
In addition to the epidemiological evidence suggesting that tissue damage and mortality resulted. In mice, exposure to
PVL may be a virulence factor in CA-MRSA, there is a scientific LukS-PV and LukF-PV toxin was sufficient to cause lung dam-

MRSA Pathogenesis • CID 2008:46 (Suppl 5) • S355

age, weight loss, and increased mortality in a concentration- eron, USA300 contained homologues closely related to staph-
dependent fashion [94]. In these studies, however, a single non– ylococcal enterotoxins Q and K, designated SEQ2 and SEK2.
CA-MRSA strain was used. Like COL and USA400, USA300 also has a genome that includes
In contrast, Bubeck Wardenburg et al. [95] recently reported a bacteriocin gene cluster. Most notably, USA300 contains a
conflicting results. They demonstrated that a-hemolysin and genomic island, termed “arginine catabolic mobile element”
not PVL was responsible for mortality in a mouse pneumonia (ACME), which encodes an arginine deaminase pathway that
model, using USA300 and USA400 CA-MRSA strains. converts l-arginine to carbon dioxide, adenosine triphosphate,
These studies suggest that the association of PVL with en- and ammonia. Arginine deaminase, a known virulence factor
hanced S. aureus virulence is complex and controversial and in other pathogens, may enhance the virulence of USA300 by
warrants further investigation. Furthermore, Wang et al. [20] enabling it to (1) survive more easily on acidic, human skin;
recently discovered that phenol-soluble modulins, a previously (2) proliferate more easily in conditions low in oxygen, such
unrecognized class of secreted S. aureus peptides, are up-reg- as abscesses; and (3) evade host defenses by inhibiting pro-
ulated in CA-MRSA strains, compared with the level in HA- duction of nitric oxide and mononuclear cell proliferation as
MRSA strains; cause inflammation; destroy neutrophils; and in Streptococcus pyogenes [28, 97]. Further investigation of
are responsible for virulence in mouse abscess and bacteremia ACME may help elucidate the remarkable success and virulence
models. Other toxins, such as the enterotoxins, may also play of the USA300 strain.
an important role in these infections. Colonization and CA-MRSA. As discussed above, the an-

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Virulence of USA400. USA400 (or MW2) is a highly vir- terior nares are the classic reservoir for nosocomial S. aureus
ulent CA-MRSA strain. This is apparent not only in human infections, including HA-MRSA. However, data suggest that
disease but also in animal models [27, 93]. Initially, its only other sites of colonization or modes of transmission play an
resistance genes were mec and blaZ, which encodes penicillin- important and underappreciated role in the development of
ase. Researchers sequenced USA400 and compared its sequence CA-MRSA infection. Heterosexual contact was recently iden-
with the sequences of 5 other strains (N315, a Japanese MRSA; tified as a mode of transmission of CA-MRSA. Most cases had
Mu50, a vancomycin-resistant MRSA; E-MRSA-16, an epi- genital CA-MRSA colonization without nasal colonization [98].
demic MRSA in the United Kingdom; COL, a MRSA strain; In an outbreak investigation of CA-MRSA abscesses among St.
and NCTC8325, a widely used reference strain) to identify po- Louis Rams football players, no MRSA was isolated from nasal
tential virulence factors associated with this strain. USA400 was or environmental samples. Perhaps other sites of colonization,
the only strain to contain the PVL operon. In addition, it con- shared items, or an unsampled environmental site played a role
in transmission [64]. Future epidemiological investigations of
tained 16 unique superantigen genes, including 11 exotoxin
CA-MRSA should include sampling of several environmental
genes and 5 enterotoxin genes. These genes had at least a 2%
and body sites in addition to the anterior nares.
difference in their amino acids, compared with their homo-
logues. One exception was staphylococcal enterotoxin H (seh),
which was unique to USA400 [27] and can cause a toxic-shock– IS MRSA MORE VIRULENT THAN MSSA?
like syndrome [96]. USA400 also contained a novel gene cluster There is an active debate as to whether MRSA is more virulent
dubbed “bacteriocin of S. aureus” (bsa). bsa encodes a potential than MSSA. Some epidemiologic studies, including a meta-
bacteriocin, or antibacterial agent. This bacteriocin could help analysis, found increased morbidity and/or mortality from nos-
USA400 compete with other colonizing flora and increase the ocomial MRSA (e.g., bloodstream infections, surgical-site in-
chance of infection with this strain [27]. These data suggest fections, and pneumonia), compared with those from MSSA
that there are several factors that may contribute to the viru- [99–102]; however, these studies may be confounded because
lence of USA400 and that these factors are ripe for future not all accounted for important factors such as time to initi-
investigation. ation of appropriate therapy or patient comorbidities. A recent
Virulence of USA300. Like USA400, USA300 is associated retrospective review found increased mortality for MRSA bac-
with virulent disease [93]; however, USA300 causes far more teremia but not MRSA pneumonia [103]. Other studies did
incident cases of CA-MRSA infection and is becoming resistant not demonstrate increased mortality associated with nosoco-
to several non–b-lactam antibiotics [28]. The genome of mial MRSA bacteremia [104] or ventilator-associated pneu-
USA300 was sequenced by Diep et al. [28] and compared with monia [105], compared with MSSA infections. An investigation
10 previously sequenced S. aureus strains as well as 4 coagulase- that compared CA-MRSA skin infections and CA-MSSA skin
negative strains to identify factors potentially associated with infections did not find more serious outcomes for the CA-
its high virulence. Of interest, there were minimal differences MRSA infections [106]. To date, there is no compelling evidence
between the core sequences of USA300 and COL, an early that MRSA, in general, is more virulent than MSSA. Although
MRSA. In addition to harboring SCCmecIV and the PVL op- this issue remains unresolved, invasive MRSA infection is as-

S356 • CID 2008:46 (Suppl 5) • Gordon and Lowy

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RD. Persistent and relapsing infections associated with small-colony
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16. Foster TJ. Immune evasion by staphylococci. Nat Rev Microbiol
We thank Linda K. McDougal for her assistance with table 2. Dr. David 2005; 3:948–58.
DeVellis and Hilary Selby Polk provided assistance in editing the 17. O’Riordan K, Lee JC. Staphylococcus aureus capsular polysaccharides.
manuscript. Clin Microbiol Rev 2004; 17:218–34.
Financial support. R.J.G. was supported by National Institutes of 18. Tzianabos AO, Wang JY, Lee JC. Structural rationale for the modu-
Health (NIH) grant 1K08AI072043-01A1. F.D.L. was supported by Centers lation of abscess formation by Staphylococcus aureus capsular poly-
for Disease Control and Prevention grant CCR223380; NIH grants DA- saccharides. Proc Natl Acad Sci USA 2001; 98:9365–70.
15018 and HL077096-01 from the National Heart, Lung, and Blood In- 19. Gladstone GP, VanHeyningen WE. Staphylococcal leucocidins. Br J Exp
stitute, NIH-Specialized Center for Clinically Oriented Research; and grant Pathol 1957; 38:123–37.
P20 RR020616 from the National Center for Research Resources, NIH, 20. Wang R, Braughton KR, Kretschmer D, et al. Identification of novel
which supports the Center for Interdisciplinary Research on Antimicrobial cytolytic peptides as key virulence determinants for community-as-
Resistance. sociated MRSA. Nat Med 2007; 13:1510–4.
Supplement sponsorship. This article was published as part of a sup- 21. Projan SJ, Novick RP. The molecular basis of pathogenicity. In: Cros-
plement entitled “Methicillin-Resistant Staphylococcus aureus: An Evolving sley KB, Archer GL, eds. The staphylococci in human disease. New
Clinical Challenge,” sponsored by the Boston University School of Medicine York: Churchill Livingstone, 1997:55–81.
and supported by an unrestricted educational grant from Cubist Phar- 22. Timmerman CP, Mattsson E, Martinez-Martinez L, et al. Induction
maceuticals, Inc. of release of tumor necrosis factor from human monocytes by staph-
Potential conflicts of interests. F.D.L. has received research support ylococci and staphylococcal peptidoglycans. Infect Immun 1993; 61:
from Cubist Pharmaceuticals, GlaxoSmithKline, and Pfizer and has been 4167–72.
on advisory panels for Pfizer, Nabi Biopharmaceuticals, and Wyeth. R.J.G.: 23. Heumann D, Barras C, Severin A, Glauser MP, Tomasz A. Gram-
no conflicts. positive cell walls stimulate synthesis of tumor necrosis factor alpha
and interleukin-6 by human monocytes. Infect Immun 1994; 62:
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