Panton-Valentine Leukocidin in the Pa Tho Genesis

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REVIEW ARTICLE

Panton-Valentine Leukocidin in the Pathogenesisof Community-associated Methicillin-resistantStaphylococcus aureus Infection

Wen-Tsung Lo, Chih-Chien Wang*

Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Received Feb 25, 2010; received in revised form May 17, 2010; accepted Jun 22, 2010

Key Wordscommunity-associatedmethicillin-resistantStaphylococcus aureus;

Panton-Valentineleukocidin;pathogenesis;Taiwan

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that

causes serious infectious diseases and was endemic in hospitals by the late 1960s. Beginning

with its first report in the late 1990s, the rapid emergence of community-associated MRSA

(CA-MRSA) worldwide responsible for a wide spectrum of diseases ranging from minor skin

infections to fatal necrotizing pneumonia has been found in previously healthy individualswithout established risk factors for MRSA acquisition. Recently, various virulence determinants

unique to CA-MRSA have been uncovered, which explain how the pathogen spreads easily and

causes severe CA-MRSA infections among humans. However, the role of Panton-Valentine leu-kocidin (PVL) in the pathogenesis of CA-MRSA infection is currently a matter of much debate

because of conflicting data from epidemiologic studies of CA-MRSA infections and various

murine disease models. Identifying specialized pathogenic traits of CA-MRSA and the concerted

regulation of these factors remains a challenge that will foster development of vaccines and

therapies designed to control CA-MRSA infections. This review focuses on the current status

of molecular epidemiology associated with CA-MRSA in Taiwan and progresses toward under-

standing the enhanced virulence properties of CA-MRSA, with an emphasis on the role of Pan-

ton-Valentine leukocidin.

Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights

reserved.

* Corresponding author. Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2,Cheng-Kung Rd, Neihu, Taipei 114, Taiwan.

E-mail address: [email protected] (C.-C. Wang).

a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n a l h o m e p a g e : h t t p : / / w w w . p e d i a t r - n e o n a t o l . c o m

Pediatrics and Neonatology (2011) 52, 59e65

1875-9572/$36 Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.doi:10.1016/j.pedneo.2011.02.008

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1. Background

Staphylococcus aureus is a ubiquitous human pathogen anda leading cause of bacterial infections involving the blood-stream, lower respiratory tract, and skin and soft tissue.1

The high morbidity and mortality resulting from S aureus

were abated by penicillin in the 1940s, but this was short-lived, as penicillin-resistant S aureus (PRSA) producing

b-lactamase quickly emerged in the mid-1940s. The preva-lence of PRSA then increased dramatically within a fewyears.2À4 Methicillin, a b-lactamase-insensitive b-lactam,provided new treatment options for PRSA infections in thelate 1950s. However, after first being reported in 1961,methicillin-resistant S aureus (MRSA) that was cross-resistantto the entire b-lactam class of antibiotics, rapidly increasedand spread during the 1980s, primarily in health care envi-ronments.2,5,6 Since then, MRSA has become endemic inhospital settings in many developed countr ies and accountsfor most nosocomial S aureus infections.7e9 In Taiwan, MRSAwas first documented in the early 1980s and rapidlyincreased in the 1990s.10 In 2000, methicillin resistance was

identified in 53%e

83% of all S aureus isolates at the 12 major hospitals in Taiwan.11

2. Emergence of Community-associated MRSAClones

Historically, MRSA infections represent a considerableburden on health care; infected patients require prolongedhospital stays, entail high hospital costs, and have increasedin-hospital mortality.12 With few exceptions, MRSA wasa problem in most patients who had traditional risk factorsassociated with treatment in nosocomial settings.13,14

However, the traditional notion of MRSA as a pathogen that

is seemingly confined to the nosocomial arena was recentlychallenged with the recognition of community-associatedMRSA (CA-MRSA) among children and adults lacking tradi-tional risk factors.15e18

CA-MRSA was first reported in Western Australia in the1990s and, by the end of the 1990s, reports of serious andrapidly progressive fatal disease in children in Minnesotaand North Dakota in the USA because of virulent CA-MRSAwere the focus of attention.19,20 Since these early reports,CA-MRSA isolates have become globally pervasive andepidemiologically unassociated outbreaks of CA-MRSAhave been reported throughout the world, including inTaiwan.5,21e42 Two categories of MRSA are now recognized:health careeassociated (HA) MRSA, the leading cause of

HA infections worldwide, particularly in intensive careunits, and CA-MRSA.43 The isolates that cause CA-MRSAinfection are identified by using a definition advocated bythe Centers for Disease Control and Prevention in 2000.44

This definition states that a case of CA-MRSA infection isdiagnosed in an outpatient or within 48 hours of hospital-ization if the patient lacks the following traditional riskfactors for MRSA infection such as receipt of hemodialysis,surgery, residence in a long-term care facility, or hospi-talization during the previous year; the presence of anindwelling catheter or a percutaneous device at the timecultur e samples were obtained; or previous isolation ofMRSA.44,45

CA-MRSA strains have unique microbiologic characteristicssuch as limited antibiotic resistance (except to b-lactamantimicrobial agents), different exotoxin gene profiles [e.g.,Panton-Valentine leukocidin (PVL)], and smaller staphylo-coccal cassette chromosome mec (SCCmec) variants: either SCCmec type IV or less frequently, type V.32 They havecommon pulsed gel electrophoresis patterns that are distinctfrom those of the major pandemic clones of HA isolates.46

Nowadays, the vast majority of CA-MRSA diseases world-wide result from strains belonging to at least five clonallineages such as sequence types (ST)1, ST8, ST30, ST59, andST80. Evidently, CA-MRSA clones appear to be epidemiolog-ically successful, fit, and well adapted for disseminationin the community, and predominate over methicillin-susceptible S aureus in certain populations.5,47À51 Further-more, the virulence of CA-MRSA seems to parallel itsepidemiologic success.

3. CA-MRSA Epidemiology and ClinicalManifestations in Taiwan

CA-MRSA causes a wide range of diseases, ranging frominfection of skin or soft tissue to severe invasive diseases,such as severe sepsis, necrotizing pneumonia, necrotizingfasciitis, and disseminated invasive osteomyelitis.34,52À54 InTaiwan, CA-MRSA infections have been increasingly repor-ted in pediatric patients since 2002.55,56 After pooling thedata from different retrospective studies with similar designs between 1997 and 2001, the MRSA rate is estimatedto be 44% in pediatric cases of community-associatedS aureus infections.57À59 However, a substantial proportion(41%e65%) of the pediatric cases with CA-MRSA infectionhad identified risk factors, although the definition of healthcareeassociated risks varied among different studies.60

Currently, the characteristics of CA-MRSA infectingstrains in Taiwan can be demonstrated in three differentways. First, they are characterized by multiple antibioticresistance [including clindamycin (93%e100%), erythro-mycin (94%e100%), and chloramphenicol (57%e65%)], whichdiffers from that in the United States. Additionally, theyare less resistant to gentamicin (11%e34%), ciprofloxacin(0%), fusidic acid (0%), trimethoprim-sulfamethoxazole(0%e9%), and minocycline (7%) than are health careeassociated MRSA.27,57,58 Second, although skin andsuperficial soft tissue infections are the major clinicalmanifestations, significant morbidity and mortality becauseof CA-MRSA infections in pediatric cases are increasinglyreported.56,61À64 Third, they have a common genotype

(e.g., ST59/USA1000) that differ from those of the major pandemic clones of nosocomial MRSA isolates, possess PVL,staphylococcal enterotoxin B, and smaller SCCmec variants:either SCCmec type VT (now designated type VII), or lessfrequently, type IV.27,29,60,65,66

In addition to the hospital-based studies, severalcommunity-based colonization studies and the latestisland-wide survey were conducted to estimate the extentof MRSA in community children.29,61,65,67À70 These studiesindicated that the prevalence of the nasal MRSA coloniza-tion in Taiwan increased significantly during the period of2005e2006 compared with those during the period of2001e2002 (from 1.9% to 9.5% for northern Taiwan and from

60 W.-T. Lo, C.-C. Wang



3.3% to 6.7% for southern Taiwan).68 This increasing prev-alence trend of community MRSA colonization prevalencecould account for the emergence of CA-MRSA disease inTaiwan.71

4. PVL in CA-MRSA Virulence and Pathogenesis

In 1894, van de Velde identified a substance named“substance leukocide” or leukocidin, which is a moleculeproduced by S aureus that lyses leukocytes.72 Panton andValentine then discovered a leukocidin clearly distinct froma hemolytic toxin that was nonlethal for rabbits.73

However, they showed a correlation between presence ofthis nonlethal leukocidin (later named PVL) and severe skininfections, especially carbuncles (large abscesses), some ofwhich were ultimately fatal in the absence of antibiotics.73

PVL is a two-component cytotoxin that targets humanand rabbit polymorphonuclear neutrophils, and monocytesor macrophages, or both.74 The products of pvl genes (LukS-PV and LukF-PV), which are encoded by contiguouslylocated cotranscribed genes (lukS-PV and lukF-PV ) within

specific bacteriophages assemble as heterooligomers andsynergistically exert cytolytic pore-forming activity on thesurface of susceptible host cells, although the plasmamembrane binding site and/or receptor is unknown.74À76

Notably, in vitro studies with recombinant PVL demon-strated a concentration-dependent effect leading to either apoptosis or necrosis in neutrophils exposed to differenttoxin concentrations, with Bax-independent apoptosisoccurring by means of a novel pathway that presumablyinvolved PVL-mediated pore formation in the mitochondriamembranes.1,77,78 Sublytic concentrations of PVL trigger apoptosis of human neutrophils within 6 hours of treat-ment, whereas higher toxin concentrations cause cell lysiswithin 1 hour.1,78 In addition to its ability to form pores in

membranes of target leukocytes, PVL is also a poly-morphonuclear neutrophils priming agent.77,79e81 Morerecently, the signal peptide of PVL has been implicated asa S aureus adherence molecule; these findings are consis-tent with earlier studies by de Bentzmann et al. and Tristanet al.,82,83 who reported that PVL-positive S aureus isolatesassociated with necrotizing pneumonia have strong affinityfor host extracellular matrix proteins.

Both epidemiologic and clinical data provide compellingevidence that the high virulence potential of CA-MRSAoriginates from PVL.32,84,85 For example, Lina et al.85 andGillet et al.84 reported a link between PVL-positive S aureus

and severe skin infections and necrotizing pneumonia.

Moreover, despite the large repertoire of transferable toxingenes among S aureus strains, pvl is the most consistentlypresent transferable toxin locus among CA-MRSA strains andis considered a stable marker of CA-MRSA strains worldwide(e.g., 100% for the US clone, the Southwest Pacific clone,the Europe clone, and 73.3%e100% for the Taiwanclone).27,32,34,63,86,87 Although compelling, epidemiologicdata alone are not sufficient to establish a direct role for PVL in S aureus pathogenesis or whether it directlycontributes to widespread dissemination of CA-MRSAclones.88,89

To test directly the role of PVL in the pathogenesis ofCA-MRSA infection, Voyich et al. compared USA300 and

USA400 wild-type and isogenic PVL-deletion strains inmurine abscess and sepsis models of infection.90 However,regardless of strains used, they found that the course ofinfection was virtually identical in both models and PVLhad no effect on neutrophil phagocytosis or lysis after uptake. Conversely, Varshney et al.91 reported thatmethicillin-susceptible S aureus and MRSA strains thatproduced high levels of PVL caused larger skin abscesses,

higher bacterial burdens, and more tissue inflammationthan did low-PVL producing strains in a mouse model ofskin infection. Furthermore, on the basis of the resultsreported by Labanderia-Rey et al.,92 they suggesteda potential role of PVL in a murine model of staphylo-coccal pneumonia by use of laboratory strains transducedto express the leukocidin and proposed a model in whichPVL functioned as a global regulator of gene expression.Furthermore, as shown in a recent study on gene expres-sion directly in human tissue, PVL, together with other secreted toxins, had a high level of expression duringsuperficial and invasive CA-MRSA infections.93 However, incontrast to the observation of Labanderia-Rey et al.,subsequent microarray-based and proteomics-based

studies demonstrated that PVL has no impact on gene or protein expression in either USA300 or USA400 strains in

vitro or in vivo.94,95 Thus, although the involvement ofPVL in CA-MRSA virulence is a topic of high interest and isunder intense investigation, conflicting results have beenreported in the potential role of PVL using diverse animalmodels for CA-MRSA disease.96À100

The reason for the discrepancy between studies remainsunclear, but collectively, most mouse models of CA-MRSApathogenesis support either no role or a limited transientrole for PVL in promoting disease.94 It is possible thatcontribution of PVL to CA-MRSA disease is limited toa specific host genetic background or susceptibility factor

(e.g., antecedent influenza), or is either too subtle to detectin current models of pathogenesis or the models do notaccurately r eflect human disease, as suggested by Kobayashiand DeLeo.77 Very recently, a study by Loffler et al.101

provided a definite explanation for these conflictingresults. They demonstrated that PVL induces rapid activa-tion and cell death in human and rabbit neutrophils, but notin murine or simian cells. Therefore, they questioned thevalue of infection models in mice and nonhuman primates toelucidate the impact of PVL and suggested that PVL has animportant cytotoxic role in human neutrophils, which hasmajor implications for the pathogenesis of CA-MRSA infec-tions. In further support of this notion, series of studiesindicate that the clinical sequelae of pvl-positive S aureus

infections tend to be more severe than infections with pvl-negative S aureus.54,84,102 Currently, the state ofknowledge regarding pathogenesis of CA-MRSA infection isalso focusing on additional factors beside PVL, such as thetype I arginine catabolic mobile element and a-type phenol-soluble modulins, in the prototypical strains MW2 andUSA300.103,104

5. Conclusion

CA-MRSA virulence and pathogenesis seems complex, andthere are likely multiple factors involved in transmission

PVL in the pathogenesis of CA-MRSA infection 61



and establishment of CA-MRSA disease. Further under-standing will be gained by continued identification ofspecific pathogenic traits of prevalent CA-MRSA strains,including ST59, to yield new diagnostic tools and thera-peutic targets for further drug and vaccine development.

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Panton-Valentine Leukocidin in the Pa Tho Genesis

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