The American Journal of Pathology, Vol. 185, No.

6, June 2015

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Infectious Disease Theme Issue 74
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Pathogenesis of Staphylococcus aureus Abscesses 77
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Q11 Scott D. Kobayashi, Natalia Malachowa, and Frank R. DeLeo 80
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20 From the Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National 82
21 Institutes of Health, Hamilton, Montana 83
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Accepted for publication
24 Staphylococcus aureus causes many types of human infections and syndromesdmost notably skin and 86
November 21, 2014.
25 soft tissue infections. Abscesses are a frequent manifestation of S. aureus skin and soft tissue infections 87
26 Address correspondence to 88
Frank R. DeLeo, Ph.D., and are formed, in part, to contain the nidus of infection. Polymorphonuclear leukocytes (neutrophils)
27 are the primary cellular host defense against S. aureus infections and a major component of S. aureus 89
Laboratory of Human Bacterial
28 abscesses. These host cells contain and produce many antimicrobial agents that are effective at killing 90
Pathogenesis, Rocky Mountain
29 bacteria, but can also cause non-specific damage to host tissues and contribute to the formation of 91
Laboratories, National Institute
30 of Allergy and Infectious abscesses. By comparison, S. aureus produces several molecules that also contribute to the formation of 92
31 Diseases, NIH, 903 S Fourth St, abscesses. Such molecules include those that recruit neutrophils, cause host cell lysis, and are involved 93
32 Hamilton, MT 59840. E-mail: in the formation of the fibrin capsule surrounding the abscess. Herein, we review our current knowledge 94
33 [email protected]. of the mechanisms and processes underlying the formation of S. aureus abscesses, including the 95
34 involvement of polymorphonuclear leukocytes, and provide a brief overview of therapeutic approaches. 96
35 (Am J Pathol 2015, 185: 1e10; http://dx.doi.org/10.1016/j.ajpath.2014.11.030) 97
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38 Q2 Staphylococcus aureus is a widespread commensal bacte- treatment of infections. Methicillin-resistant S. aureus 100
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rium and pathogen. Approximately 50% to 60% of in- (MRSA) was reported in the early 1960s and then ultimately
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dividuals are intermittently or permanently colonized with spread worldwide over the next several decades. MRSA is 103
42 S. aureus and, thus, there is relatively high potential for now endemic in health care facilities in virtually all industri- 104
43 infections.1,2 Indeed, S. aureus is among the most promi- alized countries, although recent data indicate a decrease in 105
44 nent causes of bacterial infections in the United States and the number of invasive MRSA infections in US health 106
45 other industrialized countries.3,4 For example, S. aureus care facilities.8 Community-associated MRSA (CA-MRSA) 107
46 was the most frequently recovered bacterium from in- appeared inexplicably in the 1990s and is currently a major 108
47 patients among 300 clinical microbiology laboratories in the problem in many countries worldwide, including the United 109
48 United States from 1998 to 2005.5 Staphylococcus aureus States.8,9 Unlike health careeassociated MRSA infections, 110
49 ranked second (after Escherichia coli) among bacterial which occur in individuals with predisposing risk factors, 111
50 isolates recovered from bacteremias in Europe in 2008, and CA-MRSA typically causes disease in otherwise healthy in- 112
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the prevalence of S. aureus bacteremias increased from dividuals. Although resistance to b-lactam antibiotics is
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2002 to 2008.4 Recently, S. aureus has been reported to be arguably the greatest problem for treatment of S. aureus in- 115
54 second only to Clostridium difficile as a cause of health fections, the pathogen can develop resistance to multiple 116
55 careeassociated infections in the United States.6 antibiotics beyond b-lactams, including vancomycin, an 117
56 In addition to its high prevalence, S. aureus is well known important therapeutic agent for severe MRSA infections.9 118
57 for its ability to acquire resistance to antibiotics. Notably, 119
58 antibiotic resistance in S. aureus has occurred in epidemic 120
Supported by the National Institute of Allergy and Infectious Diseases,
59 waves.7 Penicillin-resistant S. aureus emerged in the late NIH, Intramural Research Program (S.D.K., N.M., and F.R.D.). Q1
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60 1940s, and by the mid-1950s, penicillin resistance was so Disclosures: None declared.
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61 prevalent that the antibiotic was no longer effective for This article is part of a review series on infectious disease. 123
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Published by Elsevier Inc. on behalf of
the American Society for Investigative Pathology.
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174 Figure 1 Staphylococcus aureus skin abscesses. A: Formation of a S. aureus skin abscess. B: Representative histopathological section of a typical rabbit skin 236
175 abscess at day 14 after infection. C: Increased magnification of the boxed area shown in B. D and E: Gram stains of histological sections of a rabbit abscess. 237
Arrows in D indicate S. aureus. The dark area is a colony of S. aureus. Arrows in E indicate S. aureus associated with leukocytes within the abscess. These studies
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conformed to the guidelines set forth by the NIH and were approved by the Institutional Animal Care and Use Committee at Rocky Mountain Laboratories, National
177 Institute of Allergy and Infectious Diseases (Hamilton, Montana). PBS, phosphate-buffered saline; PMN, polymorphonuclear leukocyte.
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179 241
180 Taking these attributes collectively, it is not surprising that osteomyelitis, most community-associated infections in the 242
181 there is a high prevalence of S. aureus infections globally or United States are those that affect skin and soft tissues.9,11,12 243
182 that it remains a leading cause of pathogen-associated Of all military personnel, 4% to 6% ultimately acquire a skin 244
183 morbidity and mortality in the United States.6,8,10,11 and soft tissue infection (SSTI), and 91% of these infections 245
184 Although S. aureus causes a wide range of diseases and are caused by S. aureus (70% are MRSA).10 A CA-MRSA 246
185 syndromes, including bacteremia, pneumonia, cellulitis, and strain known as pulsed-field type USA300 (referred to 247
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249 herein as USA300) was the most frequently recovered bac- et al20 found a large mass of replicating S. aureus at the 311
250 terial isolate from community-associated SSTIs in the early- center of the kidney abscess that was surrounded by an 312
251 to-mid 2000s.3,13 This particular S. aureus strain gained eosinophilic pseudocapsuleda feature not observed in 313
252 314
additional notoriety after it caused skin abscesses in several rabbit skin abscesses.18 Inasmuch as S. aureus can produce
253 315
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US professional football players.14 USA300 has remained molecules that promote abscess formation (see below), it is 316
255 the most frequent organism recovered from individuals possible there is species and tissue specificity conferred by 317
256 reporting to hospital emergency departments for purulent these molecules. 318
257 SSTIs,11 with infections classified as abscesses in 85% of The pyogenic abscess begins as a localized host acute 319
258 these cases.11 Many SSTIs are relatively minor and self- inflammatory response to bacterial infection. In addition to 320
259 limiting, but complicated SSTIs can be life threatening. serving as a physical barrier to protect against microbes, 321
260 There are several defining features or clinical manifestations keratinocytes possess pattern recognition receptors that 322
261 of complicated S. aureus SSTIs, and these often include detect invading microbes and, in turn, signal the proin- 323
262 formation of large abscesses.15 flammatory response.22 These host cells also produce 324
263 Herein, we review our current knowledge of the patho- antimicrobial peptides that have direct activity against S. 325
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genesis of S. aureus abscesses, with emphasis on the aureus.23,24 As an abscess forms, it acquires several char-
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involvement of polymorphonuclear leukocytes (PMNs; or acteristic features. The center of the abscess contains an 328
267 neutrophils) and selected bacterial molecules. acute inflammatory exudate composed of many viable and 329
268 necrotic PMNs, tissue debris, fibrin, and live bacteria 330
269 (Figure 1).25 Maturation of the abscess is accompanied by 331
270 S. aureus SSTIs fibroblastic proliferation and tissue repair at the abscess 332
271 margin and formation of a fibrous capsule at the periphery 333
272 The skin is an essential first line of defense against invading (Figure 1). SSTIs that present as bacterial abscesses form in 334
273 bacterial pathogens, including those present in the external the dermis, epidermis, or subcutaneous tissue and are often 335
274 environment and opportunistic skin microbes. At the most accompanied by cellulitis. Abscess formation is a mecha- 336
275 basic level, the skin serves as a physical barrier to prevent entry nism used by the host to contain and ultimately eliminate 337
276 338
of bacteria into deeper layers of tissue and/or dissemination to the pathogen. Indeed, some SSTIs resolve spontaneously in
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internal organ systems. Keratinocytes form this important the absence of treatment. Notably, PMNs play a prominent 340
279 physical barrier. Traumatic breech of the skin enables entry of role in the formation and resolution of abscesses. 341
280 pathogenic microorganisms into the underlying tissue and Circulating PMNs are elicited from the vasculature to the Q3 342
281 initiates a complex cellular response that includes mobilization infection site in response to tissue damage,26 host proin- 343
282 ½F1 of immune cells to the site of infection (Figure 1A). The flammatory molecules, and signals imparted directly by bac- 344
283 clinical presentation of bacterial SSTIs can vary from super- teria.27 For example, S. aureus induces expression of many 345
284 ficial to highly invasive and/or disseminated disease. The host proinflammatory factors in vitro or during experimental 346
285 importance of S. aureus in SSTIs has long been appreciated infection in mice, including IL-1a,28 IL-1b,29 IL-6,30 IL-8,31 347
286 since Alexander Ogston first unveiled the role of the pathogen IL-17,32 leukotriene B4,31 tumor necrosis factor-a,33 348
287 in the etiology of the pyogenic abscess in the late 19th cen- CXCL1,34 and CXCL2.34 These factors are known to pro- 349
288 350
tury.16 Although a diversity of bacteria are currently impli- mote PMN extravasation and recruitment to infected tissues.
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cated in SSTIs, S. aureus is overwhelmingly the most Keratinocytes,35 T cells,34 PMNs,32 and macrophages36 pro- 352
291 prominent cause of infection (eg, a recent study of a large US duce chemotactic factors that contribute to the large influx of 353
292 health care delivery system found approximately 80% of neutrophils that occurs in response to S. aureus SSTIs. In 354
293 SSTIs to be associated with S. aureus),17 with the most com- addition, experimental animal models provide evidence that 355
294 mon clinical presentation being abscess and cellulitis (63%). S. aureus SSTIs result in increased numbers of PMNs in cir- 356
295 In addition to SSTIs, pyogenic bacterial abscesses can culation,37 and myeloid progenitor cells are recruited to infec- 357
296 form in deeper tissues, such as underlying muscle, and tion sites where they undergo granulopoiesis.37,38 The 358
297 bacteria can disseminate to form abscesses at distal sites and accumulation and persistence of PMNs, followed by necrotic 359
298 affect virtually any internal organ system. The overall cell lysis, contribute to the overall pathology of S. aureus SSTIs. 360
299 structure of S. aureus abscesses is consistent regardless of 361
300 362
anatomical location, based, at least in part, on lesion histo-
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pathology from experimental animal models of infection Innate Host Defense against S. aureus 363
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303 (eg, rabbit SSTIs18 and murine skin,19 kidney,20 and Infectionsdthe Role of PMNs 365
304 brain).21 Similarities aside, it is unclear if there are varia- 366
305 tions in organ-specific immune response and/or bacterial PMNs are arguably the most important cellular defense 367
306 response that may govern the process of abscess formation, against invading bacteria, such as S. aureus. Indeed, ge- 368
307 depending on anatomical location. Staphylococcus aureus netic disorders that negatively affect PMN function typi- 369
308 kidney abscesses in mice have features not found in cally predispose individuals to severe (and frequent) 370
309 S. aureus skin abscesses in rabbits. For example, Cheng bacterial and fungal infections. For example, individuals 371
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373 CD16 (FcgRIIIb, low-affinity IgG receptor), CD89 (FcaR, 435

374 IgA receptor), and CD23 (FcεRI, IgE receptor). Bacteria 436
375 opsonized with complement are recognized by PMN sur- 437
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face receptors, including ClqR, CD35, CD11b/CD18
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(CR3), and CD11c/CD18 (CR4). Ingested bacteria are 440
379 sequestered within membrane-bound vacuoles called 441
380 phagosomes (Figure 2). 442
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382 Killing of Bacteria 444
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384 PMN phagocytosis is followed by the execution of bacte- 446
385 ricidal mechanisms, including the production of superoxide 447
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radicals and other reactive oxygen species (ROS), and

387 enrichment of antimicrobial peptides, proteins, and degra- 449
388 450
dative enzymes in the phagosome (Figure 2). ROS are
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generated by a multicomponent membrane-bound complex 452
391 known as the NADPH-dependent oxidase,39 which is 453
392 defective in individuals with chronic granulomatous dis- 454
393 Figure 2 Polymorphonuclear leukocyte phagocytosis and microbicidal ease. In resting neutrophils, components of the NADPH 455
processes. Surface receptors for host opsonins, such as complement and anti-
394 oxidase are either cytosolic (p40phox, p47phox, p67phox, 456
body, promote ingestion of S. aureus, which, in turn, activates the microbicidal
395 processes that operate in a bacteria-containing phagosome (the cytoplasmic and the GTPase Rac2) or located in membranes (flavo- 457
396 vacuole containing bacteria). The enzyme complex responsible for generation cytochrome b558). NADPH oxidase assembly involves 458
397 of superoxidedNADPH oxidasedis depicted by the blue cluster of shapes on translocation of the cytosolic protein components to the 459
398 the phagosome membrane. CR, complement receptor; HOCl, hypochlorous acid; plasma or phagosome membrane and their subsequent as- 460
399 Q9 MPO, myeloperoxidase; ROS, reactive oxygen species. sociation with flavocytochrome b558, a transmembrane 461
400 462
heterodimer that serves as the nidus of the assembling
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402 with chronic granulomatous disease, a genetic disorder enzyme complex. After activation of the NADPH oxidase, 464
403 characterized by the inability of PMNs and other phago- electrons are transported from cytosolic NADPH to molec- 465
404 cytes to produce superoxide, often acquire severe and ular oxygen, thereby generating superoxide anion.39 Multiple 466
405 recurrent S. aureus infections. These infections often oxygen metabolites, including hydrogen peroxide, superox- 467
406 manifest as abscesses that can ultimately transform into ide anion, and hypochlorous acid, contribute to neutrophil 468
407 granulomas, which obstruct organ function and must be bactericidal activity.40 469
408 surgically removed. Inasmuch as PMNs play a central role In addition to activation of PMN oxygen-dependent 470
409 in S. aureus abscess formation and the resolution of bactericidal mechanisms, phagocytosis triggers degranula- 471
410 infection, it is important to understand basic functions of tion, which involves fusion of cytoplasmic granules with the 472
411 phagosome membrane (Figure 2).41,42 Peroxidase-negative 473
these prominent host cells.
412 474
granules, including secretory vesicles, gelatinase granules,
413 475
Q4 Phagocytosis of Bacteria and specific granules, are a reservoir of functionally
414 476
415 important membrane proteins, such as CR3, formyl peptide 477
416 Neutrophils are recruited rapidly to the site of infection and receptor, flavocytochrome b558, and b2-integrins.40,43 478
417 remove invading microorganisms through a process known Peroxidase-positive granules (primary/azurophilic gran- 479
418 ½F2 as phagocytosis (Figure 2). Bacteria express a litany of ules) contain the bulk of oxygen-independent antimicrobial 480
419 molecules on their surface, such as lipopolysaccharide, agents of neutrophils, including a-defensins, cathepsins, 481
420 lipoprotein, and lipoteichoic acid, and these pathogen- proteinase-3, elastase, azurocidin, lysozyme, and bacteri- 482
421 associated molecular patterns interact with receptors on cidal permeabilityeincreasing protein.43 Thus, fusion of 483
422 the surface of neutrophils. In general, ligation of the azurophilic granules with phagosomes enriches these 484
423 neutrophil pattern recognition receptors (eg, Toll-like re- microbe-containing vacuoles with a relatively large 485
424 486
ceptors and CD14) activates signal transduction pathways repertoire of antimicrobial agents. PMN antimicrobial ac-
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426
that ultimately contribute to bactericidal activity. PMN tivity, composed of ROS and a broad range of antimicro- 488
427 phagocytosis is most efficiently promoted by opsonization bial peptides and enzymes, is sufficient to kill most 489
428 of bacteria with antibody and complement. Specific anti- invading bacteria. Notwithstanding, bacterial pathogens, 490
429 body binds to epitopes on the surface of bacteria and enables such as S. aureus, have the ability to evade the host innate 491
430 the deposition of complement. Antibodies bound to the immune response to promote disease. Indeed, there are 492
431 bacterial surface are recognized by neutrophil receptors numerous S. aureus molecules that can contribute to 493
432 specific for the Fc region, including CD64 (FcgRI, IgG destruction of PMNs, and these molecules are discussed 494
433 receptor), CD32 (FcgRIIa, low-affinity IgG receptor), below in more detail. 495
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517 Figure 3 Staphylococcus aureus virulence molecules. Staphylococcus aureus can produce multiple types of molecules that contribute to virulence and 579
518 pathogenesis. Many of these molecules have been linked to the pathogenesis of abscesses (red text). AhpCF, alkyl hydroperoxide reductase subunits C and F; Q10 580
519 Aur, aureolysin; BsaA, glutathione peroxidase; CHIPS, chemotaxis inhibitory protein of staphylococcus; Clf, clumping factor; Cna, collagen adhesin; Coa, 581
520 coagulase; CPS, capsule; Eap, extracellular adherence protein; Efb, extracellular fibrinogen binding protein; FLIPr, formyl peptide receptor-like 1 inhibitory 582
521 protein; fMLP, N-formyl-methionyl-leucyl-phenylalanine; FnBPAB, fibronectin binding protein A and B; Hla, a-hemolysin; HlgABC, gamma-hemolysin subunits 583
A, B, and C; IcaADBCR, intercellular adhesin subunits A, D, B, C, and R; Isd, iron-regulated surface determinant; KatA, catalase; LTA, lipoteichoic acid; Luk,
522 584
leukocidin; MprF, multiple peptide resistance factor; OatA, O-acetyltransferase A; PSM, phenol-soluble modulin; PVL, Panton-Valentine leukocidin; ROS,
523 reactive oxygen species; Sak, staphylokinase; Sbi, staphylococcal IgG-binding protein; SCIN, staphylococcal complement inhibitor; SdrCDE, Ser-Asp rich
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524 fibrinogen/bone sialoprotein-binding protein subunits C, D, and E; SE, Staphylococcal enterotoxin; SOD, superoxide dismutase; Spa, Staphylococcal protein A; 586
525 SSL, staphylococcal superantigen-like protein; SXN, staphyloxanthin; TrxAB, thioredoxin (TrxA) and thioredoxin reductase (TrxB); vWbp, von Willebrand factor 587
526 binding protein; WTA, wall techoic acid. 588
527 589
528 590
529 Molecules Produced by S. aureus that of PSGL-1 on the PMN surface and P-selectin on the endo- 591
530 Affect/Alter PMN Function and Viability thelial lining, thereby blocking PMN rolling in the vessel.46,47 592
531 Extracellular adherence protein hinders association of Mac-1 593
532 S. aureus Immune Evasion Molecules and intercellular adhesion molecule-1 or binding of lympho- 594
533 cyte function-associated antigen-1 to intercellular adhesion Q5 595
534 Staphylococcus aureus produces an array of potential molecule-1, which negatively affects PMN adhesion and 596
535 virulence factors that play an important role on every level diapedesis through the endothelium of the blood vessel.48 597
536 of host-pathogen interactions, including immune evasion 598
After extravasation, PMNs migrate toward infection sites on
537 molecules that allow bacteria to circumvent host innate and 599
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the basis of an increasing gradient of chemoattractants, which 600
adaptive immunity. A multitude of these virulence factors involve, in part, the formyl peptide receptor, C5a receptor, and
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protects S. aureus from bactericidal activity of PMNs or formyl peptide receptor like-1. To counter this process, the
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541 directly alters neutrophil function.44 These molecules can chemotaxis inhibitory protein of staphylococcus and staphy- 603
542 be categorized according to their functions, and include lococcal complement inhibitor are directed to inhibit chemo- 604
543 those that do the following: i) affect PMN recruitment, ii) taxis dependent on C5a and formyl peptide receptor, and 605
544 moderate the effects of phagocyte microbicides, iii) alter formyl peptide receptor-like 1 inhibitory protein impedes Q6 606
545 phagocytosis, and iv) cause host cell lysis (cytolytic formyl peptide receptor like-1edependent migration of 607
546 ½F3 toxins) (Figure 3). PMNs.49e52 At the site of S. aureus infection, PMNs 608
547 As an example, S. aureus secretes short N-formylated encounter secreted cytolytic toxins that can permeabilize host 609
548 peptides, which are produced during protein biosynthesis or 610
cell plasma membranes and/or cause rapid cytolysis and must
549 released during bacterial cytolysis. These peptides generate a 611
550
overcome the effects of molecules that potentially inhibit 612
chemotactic gradient for PMNs.45 N-formylated peptides, bacterial uptake. Among these antiphagocytic molecules are
551 613
along with other bacteria-derived molecules, also signal resi- protein A, which binds the Fc region of IgG (thereby blocking
552 614
553 dent host cells to produce proinflammatory molecules (che- opsonization with specific antibody), clumping factor A, and 615
554 moattractants) that signal PMN recruitment. The battle extracellular fibrinogen binding protein, which blocks 616
555 between S. aureus and PMNs begins early during infection, phagocytosis by depositing fibrinogen on the bacterial 617
556 during which time, for example, secreted staphylococcal surface.53e55 Despite these obstacles, S. aureus is readily 618
557 superantigen-like protein-5 and protein-11 obstruct interaction engulfed by PMNsdespecially by those that are adherent. 619
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621 Bacterial pathogens have also evolved mechanisms to and a-type phenol-soluble modulins, g-hemolysin, and d- 683
622 protect against oxygen-dependent and oxygen-independent toxin.62e72 Permeabilization of the cell membrane by Panton- 684
623 killing by human PMNs (Figure 3). For example, S. aureus Valentine leukocidin or leukocidin GH can cause neutrophil 685
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uses alkyl hydroperoxide reductase, catalase, and superoxide lysis that results in the formation of structures called neutro-
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dismutase to protect against ROS.56 Moreover, staphylococcal phil extracellular traps, which are web-like structures of nu- 688
627 golden pigment or staphyloxanthin functions as an antioxidant clear DNA to which histones and other cationic molecules are 689
628 and is additional protection against ROS.57 Staphylococcus bound non-specifically.73e75 Whether these structures play a 690
629 aureus has multiple, redundant molecules/systems that pro- direct role in the formation of abscesses is not clear, although 691
630 mote resistance to antimicrobial peptides, and such resistance there is no question that abscesses contain a bolus of lysed 692
631 typically involves modification of the cell wall.44 PMNs and PMN debris, which includes extracellular DNA. 693
632 Thus, given the prominent role played by PMNs in host 694
633 defense against S. aureus infections, and considering the 695
634 pathogen has many molecules that can potentially contribute Hla and Dermonecrosis 696
635 to evasion of neutrophil function, it is not surprising that 697
636 698
PMNs play a major role in the formation of abscesses. a-Hemolysin (Hla; a-toxin) is one of the earliest studied
637 699
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staphylococcal virulence factors.76,77 This pore-forming 700
639 Lysis of PMNs and the Role of S. aureus Secreted Toxins cytotoxin is freely secreted by S. aureus as a water- 701
640 soluble monomer, and then binds the surface of target 702
641 To maintain proper homeostasis, the host immune system is cells, forming a heptameric transmembrane pore.78 Forma- 703
642 subject to constant turnover of cells, including neutrophils. tion of functional pores generates ion imbalance, including 704
643 Typically, aging PMNs undergo apoptosis and are removed efflux of potassium cations and ATP or influx of calcium 705
644 by macrophages in a process known as efferocytosis.58 ions, and ultimately leads to cell death. Hla targets many 706
645 However, bacteria such as S. aureus have the ability to alter different cell types, including epithelial and endothelial 707
646 and/or circumvent this process and cause PMN lysis.59 cells, blood cells, and platelets.79 708
647 Because PMNs contain numerous cytotoxic and proin- Hla plays a crucial role in the pathogenesis of S. aureus 709
648 710
flammatory molecules, uncontrolled lysis can have pivotal SSTIs and, in particular, promotes dermonecrosis in animal
649 711
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consequences to host health and additionally can promote infection models. Functional inactivation of the gene encod- 712
651 dissemination of bacteria previously contained within phag- ing Hla by mutagenesis or deletion, or passive or active 713
652 osomes. Recent studies revealed that after PMN engulfment, immunization against this toxin, significantly reduces size of 714
653 S. aureus is able to divert PMNs from conventional apoptotic abscesses and virtually eliminates dermonecrosis in animal 715
654 pathways and cause subsequent lysis of these host cells by infection models.18,19,80e82 The relatively recent discovery of 716
655 means of a process termed programmed necrosis.60 In vitro an Hla receptorda disintegrin and metalloprotease 10dwas 717
656 studies have shown that within 3 to 4 hours after phagocytosis a major advance for our understanding of the role played by 718
657 of S. aureus, neutrophils initiate morphological changes, such Hla during SSTIs.83 By activating a disintegrin and metal- 719
658 as blebbing, increase exposure of phosphatidylserine on the loprotease 10, Hla contributes to proteolysis of E-cadherin, 720
659 surface of the cell, and nuclear condensation, which are which leads to the disruption of the adherens junction in the 721
660 722
hallmarks of PMN apoptosis. Although the initial steps of epithelial layer, thereby prompting potential remodeling of
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programmed necrosis are similar to apoptosis, S. aureusein- the epithelial layer and consequently pathogen dissemina- 724
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Q7 duced programmed necrosis is a receptor-interacting protein tion.83,84 In a similar manner, Hla contributes to the breach of 725
664 1edependent process that does not result in activation of blood vessel endothelium integrity by causing proteolysis of 726
665 caspases 2, 3, 8, and 9.60 Moreover, PMN phagocytosis of S. the extracellular domain of vascular endothelial cadherin.85 Q8 727
666 aureus is accompanied by increased expression of CD47 (a The toxin also promotes a vigorous host inflammatory 728
667 don’t eat me signal), a molecule that has been shown to prevent response, and this response has been linked to increased 729
668 efferocytosis of apoptotic PMNs by macrophages.60 Notably, morbidity and mortality in animal infection models (eg, in S. 730
669 bacterial burden plays an essential role in directing PMNs aureus pneumonia).86 Hla also acts directly or indirectly with 731
670 toward programmed necrosis. Inasmuch as a relatively high intracellular host sensor molecules, notably, members of the 732
671 bacteria/PMN ratio (10:1) is sufficient to induce the process, a nucleotide-binding domain leucine-rich repeat containing 733
672 734
low bacterial burden (1:1) requires additional caspase inhibi- (NLR) family, such as NLRC2 and NLRP3.87e89 Activation
673 735
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tion. Furthermore, engulfment of S. aureus by PMNs alters of the NLRP3 inflammasome by Hla and costimulation of 736
675 macrophage production of cytokines, such as IL-6, IL-8, or NLRC2 by Hla and muramyl dipeptide trigger downstream 737
676 tumor necrosis factor-a, and lowers secretion of IL-1b, which activation of caspase 1, which subsequently leads to activa- 738
677 is an essential cytokine in subcutaneous infections.29,60,61 tion of the potent proinflammatory cytokine IL-1b that 739
678 In addition to triggering programmed necrosis, S. aureus largely contributes to PMN influx to the site of infection.87,88 740
679 secretes virulence factors that promote direct lysis of neutro- The ability of Hla to cause host cell cytolysis (and thus 741
680 phils (Figure 3). Among them are leukotoxins, such as Pan- destabilize the dermis) and elicit neutrophil recruitment 742
681 ton-Valentine leukocidin, leukocidin GH, or leukocidin DE, likely plays a central role in the pathogenesis of SSTIs. More 743
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745 notably, Hla can promote dermonecrosis in animal skin Treatment and Future Perspective 807
746 infection models, a more severe manifestation of SSTIs. 808
747 Whether this virulence attribute of Hla is recapitulated in Staphylococcus aureus is a human commensal microbe and 809
748 810
human SSTIs remains unknown, but the toxin is potentially a has been a cause of infections throughout recorded history.
749 811
750
target for therapeutics designed to moderate the severity of There is no question that it will continue to be a significant 812
751 disease. Key features of mature abscesses in experimental cause of human infections. Many of the infections caused by 813
752 animal models and those of humans have many similar at- S. aureus are nonsevere SSTIs that are self-limiting or 814
753 tributes, and thus the experimental abscesses in animals seem resolve without therapeutic intervention. However, severe or 815
754 to be a reasonable approximation of S. aureus skin abscesses complicated SSTIs require some type of therapy or treat- 816
755 in humans. However, there are clear differences between ment. Indeed, skin infections often led to invasive disease or 817
756 experimental S. aureus abscesses in animals and human S. death before the antibiotic era.65 818
757 aureus abscesses. These differences include those in the The Infectious Diseases Society of America has set forth 819
758 innate immune systems of experimental animals and humans; specific guidelines for treatment of S. aureus SSTIs.99 820
759 for example, there are known differences in the ability of Incision and drainage alone is the recommended treat- 821
760 822
leukocidins, such as Panton-Valentine leukocidin, to cause ment for cutaneous abscesses, whereas antibiotics are
761 823
762
cytolysis of rodent and human PMNs.90 recommended only for abscesses associated with severe 824
763 and/or disseminated disease or those that fail to respond to 825
764 Coagulases incision and drainage.100 That said, outpatients with minor 826
765 abscesses can be treated with empirical antibiotic therapy 827
766 Although the contribution of Hla to S. aureus SSTIs is clear that is effective against CA-MRSA.100 Such antibiotics 828
767 in animal infection models, there is little known about the include trimethoprim-sulfamethoxazole, clindamycin, and 829
768 contribution of additional staphylococcal factors to abscess doxycycline or minocycline.99,100 By comparison, vanco- 830
769 formation and development. Notwithstanding, several recent mycin, linezolid, daptomycin, televancin, and clindamycin 831
770 studies provide evidence that S. aureus coagulase (Coa) and are among the antibiotics recommended for hospitalized 832
771 von Willebrand factor binding protein (vWbp) facilitate patients with complicated SSTIs, which include major 833
772 834
abscess formation in a mouse model of disseminated abscesses.99
773 835
774
infection.91e93 Coa and vWbp are perhaps best known for Given the ability of S. aureus to develop resistance to 836
775 their ability to alter host defense by promoting coagulation antibiotics rapidly, it is worthwhile to consider alternative 837
776 and altering normal hemostasis, and thus contribute to S. therapies fordor prophylactic measures to preventdsevere 838
777 aureus pathogenesis.91,94 Both Coa and vWbp activate S. aureus disease. A potential therapeutic and/or prophy- 839
778 prothrombin in a non-proteolytic manner, which diverts lactic approach is the use of active or passive vaccination 840
779 prothrombin activation away from host regulation.95,96 against S. aureus molecules known to promote severe 841
780 Furthermore, the C-terminal domain of Coa binds fibrin- SSTIs. There has been significant effort put forth in recent 842
781 ogen and subsequently enables proteolytic conversion of years to develop a vaccine designed to protect against S. 843
782 fibrinogen to fibrin, and the deposition of fibrin. Coagulase aureus infection, but these vaccines have failed in human 844
783 and high levels of vWbp accumulate at the abscess pe- clinical trials.101 One confounding issue is our lack of 845
784 846
ripheries, and these molecules likely contribute to abscess knowledge about the factors (both host and microbe) that
785 847
786
development via formation of a pseudocapsule (also called contribute to protective immunity against S. aureus in- 848
787 fibrous capsule) and microcolony-associated meshwork.97 fections. Recently, Fritz et al102 reported that anti-Hla 849
788 These structures generate a mechanical barrier that hinders antibody titers correlate with protection against subsequent 850
789 the recognition and phagocytosis of bacteria by host neu- S. aureus infection, albeit SSTIs elicit a limited protective 851
790 trophils and other immune cells.98 Single Coa or vWbp immune response. Consistent with those findings, work in 852
791 deletion mutants alter bacterial survival and/or decrease mouse infection models has demonstrated that antibodies 853
792 abscess formation, but the greatest decrease in abscess for- directed against Hla, Coa, and vWbp protect against severe 854
793 mation occurs with coa/vwbp double deletion mutant strains S. aureus skin disease.19,93 Sampedro et al103 took these 855
794 in animal infection models. This phenomenon is likely models one step further by testing the ability of anti-Hla 856
795 correlated with functional redundancy of Coa and vWbp approaches, which include direct toxin neutralization or 857
796 858
during prothrombin activation and fibrin deposition.93,97 receptor blocking, to moderate or prevent recurrent S.
797 859
798
The importance of Coa and vWbp in the formation of aureus SSTIs in a mouse model. 860
799 S. aureus abscesses is best illustrated by recent vaccine Collectively, these studies suggest that it should be 861
800 studies, in which active and passive immunization with possible to use a vaccine or similar (eg, receptor blocking) 862
801 antibodies against Coa and vWbp significantly reduced approach for treatment, moderation, or prevention of severe 863
802 number of lesions in a murine kidney abscess model.93,97 SSTIs. Although significant progress has been made (eg, use 864
803 Whether such an approach would be successful in treat- of incision and drainage as a treatment approach), more 865
804 ment or prevention of severe/complicated SSTIs remains work is needed in this general area to develop therapies that 866
805 unclear. are not dependent on antibiotics. 867
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