Pathogenesis of Staphylococcus aureus Abscesses
2015; Elsevier BV; Volume: 185; Issue: 6 Linguagem: Inglês
10.1016/j.ajpath.2014.11.030
ISSN1525-2191
AutoresScott D. Kobayashi, Natalia Małachowa, Frank R. DeLeo,
Tópico(s)Bacterial biofilms and quorum sensing
ResumoStaphylococcus aureus causes many types of human infections and syndromes—most notably skin and soft tissue infections. Abscesses are a frequent manifestation of S. aureus skin and soft tissue infections and are formed, in part, to contain the nidus of infection. Polymorphonuclear leukocytes (neutrophils) are the primary cellular host defense against S. aureus infections and a major component of S. aureus abscesses. These host cells contain and produce many antimicrobial agents that are effective at killing bacteria, but can also cause non-specific damage to host tissues and contribute to the formation of abscesses. By comparison, S. aureus produces several molecules that also contribute to the formation of abscesses. Such molecules include those that recruit neutrophils, cause host cell lysis, and are involved in the formation of the fibrin capsule surrounding the abscess. Herein, we review our current knowledge of the mechanisms and processes underlying the formation of S. aureus abscesses, including the involvement of polymorphonuclear leukocytes, and provide a brief overview of therapeutic approaches. Staphylococcus aureus causes many types of human infections and syndromes—most notably skin and soft tissue infections. Abscesses are a frequent manifestation of S. aureus skin and soft tissue infections and are formed, in part, to contain the nidus of infection. Polymorphonuclear leukocytes (neutrophils) are the primary cellular host defense against S. aureus infections and a major component of S. aureus abscesses. These host cells contain and produce many antimicrobial agents that are effective at killing bacteria, but can also cause non-specific damage to host tissues and contribute to the formation of abscesses. By comparison, S. aureus produces several molecules that also contribute to the formation of abscesses. Such molecules include those that recruit neutrophils, cause host cell lysis, and are involved in the formation of the fibrin capsule surrounding the abscess. Herein, we review our current knowledge of the mechanisms and processes underlying the formation of S. aureus abscesses, including the involvement of polymorphonuclear leukocytes, and provide a brief overview of therapeutic approaches. Staphylococcus aureus is a widespread commensal bacterium and pathogen. Approximately 50% to 60% of individuals are intermittently or permanently colonized with S. aureus and, thus, there is relatively high potential for infections.1Gorwitz R.J. Kruszon-Moran D. McAllister S.K. McQuillan G. McDougal L.K. Fosheim G.E. Jensen B.J. Killgore G. Tenover F.C. Kuehnert M.J. Changes in the prevalence of nasal colonization with Staphylococcus aureus in the United States, 2001-2004.J Infect Dis. 2008; 197: 1226-1234Crossref PubMed Scopus (633) Google Scholar, 2Wertheim H.F. Melles D.C. Vos M.C. van Leeuwen W. van Belkum A. Verbrugh H.A. Nouwen J.L. The role of nasal carriage in Staphylococcus aureus infections.Lancet Infect Dis. 2005; 5: 751-762Abstract Full Text Full Text PDF PubMed Scopus (1779) Google Scholar Indeed, S. aureus is among the most prominent causes of bacterial infections in the United States and other industrialized countries.3Moran G.J. Krishnadasan A. Gorwitz R.J. Fosheim G.E. McDougal L.K. Carey R.B. Talan D.A. EMERGENcy ID Net Study GroupMethicillin-resistant S. aureus infections among patients in the emergency department.N Engl J Med. 2006; 355: 666-674Crossref PubMed Scopus (1968) Google Scholar, 4de Kraker M.E. Jarlier V. Monen J.C. Heuer O.E. van de Sande N. Grundmann H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System.Clin Microbiol Infect. 2013; 19: 860-868Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar For example, S. aureus was the most frequently recovered bacterium from inpatients among 300 clinical microbiology laboratories in the United States from 1998 to 2005.5Styers D. Sheehan D.J. Hogan P. Sahm D.F. Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States.Ann Clin Microbiol Antimicrob. 2006; 5: 2Crossref PubMed Scopus (313) Google Scholar Staphylococcus aureus ranked second (after Escherichia coli) among bacterial isolates recovered from bacteremias in Europe in 2008, and the prevalence of S. aureus bacteremias increased from 2002 to 2008.4de Kraker M.E. Jarlier V. Monen J.C. Heuer O.E. van de Sande N. Grundmann H. The changing epidemiology of bacteraemias in Europe: trends from the European Antimicrobial Resistance Surveillance System.Clin Microbiol Infect. 2013; 19: 860-868Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar Recently, S. aureus has been reported to be second only to Clostridium difficile as a cause of health care–associated infections in the United States.6Magill S.S. Edwards J.R. Bamberg W. Beldavs Z.G. Dumyati G. Kainer M.A. Lynfield R. Maloney M. McAllister-Hollod L. Nadle J. Ray S.M. Thompson D.L. Wilson L.E. Fridkin S.K. Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey TeamMultistate point-prevalence survey of health care-associated infections.N Engl J Med. 2014; 370: 1198-1208Crossref PubMed Scopus (2457) Google Scholar In addition to its high prevalence, S. aureus is well known for its ability to acquire resistance to antibiotics. Notably, antibiotic resistance in S. aureus has occurred in epidemic waves.7Chambers H.F. DeLeo F.R. Waves of resistance: staphylococcus aureus in the antibiotic era.Nat Rev Microbiol. 2009; 7: 629-641Crossref PubMed Scopus (1718) Google Scholar Penicillin-resistant S. aureus emerged in the late 1940s, and by the mid-1950s, penicillin resistance was so prevalent that the antibiotic was no longer effective for treatment of infections. Methicillin-resistant S. aureus (MRSA) was reported in the early 1960s and then ultimately spread worldwide over the next several decades. MRSA is now endemic in health care facilities in virtually all industrialized countries, although recent data indicate a decrease in the number of invasive MRSA infections in US health care facilities.8Dantes R. Mu Y. Belflower R. Aragon D. Dumyati G. Harrison L.H. Lessa F.C. Lynfield R. Nadle J. Petit S. Ray S.M. Schaffner W. Townes J. Fridkin S. Emerging Infections Program–Active Bacterial Core Surveillance MRSA Surveillance InvestigatorsNational burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011.JAMA Intern Med. 2013; 173: 1970-1978PubMed Google Scholar Community-associated MRSA (CA-MRSA) appeared inexplicably in the 1990s and is currently a major problem in many countries worldwide, including the United States.8Dantes R. Mu Y. Belflower R. Aragon D. Dumyati G. Harrison L.H. Lessa F.C. Lynfield R. Nadle J. Petit S. Ray S.M. Schaffner W. Townes J. Fridkin S. Emerging Infections Program–Active Bacterial Core Surveillance MRSA Surveillance InvestigatorsNational burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011.JAMA Intern Med. 2013; 173: 1970-1978PubMed Google Scholar, 9DeLeo F.R. Otto M. Kreiswirth B.N. Chambers H.F. Community-associated meticillin-resistant Staphylococcus aureus.Lancet. 2010; 375: 1557-1568Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar Unlike health care–associated MRSA infections, which occur in individuals with predisposing risk factors, CA-MRSA typically causes disease in otherwise healthy individuals. Although resistance to β-lactam antibiotics is arguably the greatest problem for treatment of S. aureus infections, the pathogen can develop resistance to multiple antibiotics beyond β-lactams, including vancomycin, an important therapeutic agent for severe MRSA infections.9DeLeo F.R. Otto M. Kreiswirth B.N. Chambers H.F. Community-associated meticillin-resistant Staphylococcus aureus.Lancet. 2010; 375: 1557-1568Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar Taking these attributes collectively, it is not surprising that there is a high prevalence of S. aureus infections globally or that it remains a leading cause of pathogen-associated morbidity and mortality in the United States.6Magill S.S. Edwards J.R. Bamberg W. Beldavs Z.G. Dumyati G. Kainer M.A. Lynfield R. Maloney M. McAllister-Hollod L. Nadle J. Ray S.M. Thompson D.L. Wilson L.E. Fridkin S.K. Emerging Infections Program Healthcare-Associated Infections and Antimicrobial Use Prevalence Survey TeamMultistate point-prevalence survey of health care-associated infections.N Engl J Med. 2014; 370: 1198-1208Crossref PubMed Scopus (2457) Google Scholar, 8Dantes R. Mu Y. Belflower R. Aragon D. Dumyati G. Harrison L.H. Lessa F.C. Lynfield R. Nadle J. Petit S. Ray S.M. Schaffner W. Townes J. Fridkin S. Emerging Infections Program–Active Bacterial Core Surveillance MRSA Surveillance InvestigatorsNational burden of invasive methicillin-resistant Staphylococcus aureus infections, United States, 2011.JAMA Intern Med. 2013; 173: 1970-1978PubMed Google Scholar, 10Landrum M.L. Neumann C. Cook C. Chukwuma U. Ellis M.W. Hospenthal D.R. Murray C.K. Epidemiology of Staphylococcus aureus blood and skin and soft tissue infections in the US military health system, 2005-2010.JAMA. 2012; 308: 50-59Crossref PubMed Scopus (177) Google Scholar, 11Talan D.A. Krishnadasan A. Gorwitz R.J. Fosheim G.E. Limbago B. Albrecht V. Moran G.J. EMERGENcy ID Net Study GroupComparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.Clin Infect Dis. 2011; 53: 144-149Crossref PubMed Scopus (257) Google Scholar Although S. aureus causes a wide range of diseases and syndromes, including bacteremia, pneumonia, cellulitis, and osteomyelitis, most community-associated infections in the United States are those that affect skin and soft tissues.9DeLeo F.R. Otto M. Kreiswirth B.N. Chambers H.F. Community-associated meticillin-resistant Staphylococcus aureus.Lancet. 2010; 375: 1557-1568Abstract Full Text Full Text PDF PubMed Scopus (994) Google Scholar, 11Talan D.A. Krishnadasan A. Gorwitz R.J. Fosheim G.E. Limbago B. Albrecht V. Moran G.J. EMERGENcy ID Net Study GroupComparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.Clin Infect Dis. 2011; 53: 144-149Crossref PubMed Scopus (257) Google Scholar, 12Fridkin S.K. Hageman J.C. Morrison M. Sanza L.T. Como-Sabetti K. Jernigan J.A. Harriman K. Harrison L.H. Lynfield R. Farley M.M. Active Bacterial Core Surveillance Program of the Emerging Infections Program NetworkMethicillin-resistant Staphylococcus aureus disease in three communities.N Engl J Med. 2005; 352: 1436-1444Crossref PubMed Scopus (1310) Google Scholar Of all military personnel, 4% to 6% ultimately acquire a skin and soft tissue infection (SSTI), and 91% of these infections are caused by S. aureus (70% are MRSA).10Landrum M.L. Neumann C. Cook C. Chukwuma U. Ellis M.W. Hospenthal D.R. Murray C.K. Epidemiology of Staphylococcus aureus blood and skin and soft tissue infections in the US military health system, 2005-2010.JAMA. 2012; 308: 50-59Crossref PubMed Scopus (177) Google Scholar A CA-MRSA strain known as pulsed-field type USA300 (referred to herein as USA300) was the most frequently recovered bacterial isolate from community-associated SSTIs in the early-to-mid 2000s.3Moran G.J. Krishnadasan A. Gorwitz R.J. Fosheim G.E. McDougal L.K. Carey R.B. Talan D.A. EMERGENcy ID Net Study GroupMethicillin-resistant S. aureus infections among patients in the emergency department.N Engl J Med. 2006; 355: 666-674Crossref PubMed Scopus (1968) Google Scholar, 13McDougal L.K. Steward C.D. Killgore G.E. Chaitram J.M. McAllister S.K. Tenover F.C. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database.J Clin Microbiol. 2003; 41: 5113-5120Crossref PubMed Scopus (1210) Google Scholar This particular S. aureus strain gained additional notoriety after it caused skin abscesses in several US professional football players.14Kazakova S.V. Hageman J.C. Matava M. Srinivasan A. Phelan L. Garfinkel B. Boo T. McAllister S. Anderson J. Jensen B. Dodson D. Lonsway D. McDougal L.K. Arduino M. Fraser V.J. Killgore G. Tenover F.C. Cody S. Jernigan D.B. A clone of methicillin-resistant Staphylococcus aureus among professional football players.N Engl J Med. 2005; 352: 468-475Crossref PubMed Scopus (645) Google Scholar USA300 has remained the most frequent organism recovered from individuals reporting to hospital emergency departments for purulent SSTIs,11Talan D.A. Krishnadasan A. Gorwitz R.J. Fosheim G.E. Limbago B. Albrecht V. Moran G.J. EMERGENcy ID Net Study GroupComparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.Clin Infect Dis. 2011; 53: 144-149Crossref PubMed Scopus (257) Google Scholar with infections classified as abscesses in 85% of these cases.11Talan D.A. Krishnadasan A. Gorwitz R.J. Fosheim G.E. Limbago B. Albrecht V. Moran G.J. EMERGENcy ID Net Study GroupComparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008.Clin Infect Dis. 2011; 53: 144-149Crossref PubMed Scopus (257) Google Scholar Many SSTIs are relatively minor and self-limiting, but complicated SSTIs can be life threatening. There are several defining features or clinical manifestations of complicated S. aureus SSTIs, and these often include formation of large abscesses.15Bae I.G. Tonthat G.T. Stryjewski M.E. Rude T.H. Reilly L.F. Barriere S.L. Genter F.C. Corey G.R. Fowler Jr., V.G. Presence of genes encoding the panton-valentine leukocidin exotoxin is not the primary determinant of outcome in patients with complicated skin and skin structure infections due to methicillin-resistant Staphylococcus aureus: results of a multinational trial.J Clin Microbiol. 2009; 47: 3952-3957Crossref PubMed Scopus (78) Google Scholar Herein, we review our current knowledge of the pathogenesis of S. aureus abscesses, with emphasis on the involvement of polymorphonuclear leukocytes (PMNs; or neutrophils) and selected bacterial molecules. The skin is an essential first line of defense against invading bacterial pathogens, including those present in the external environment and opportunistic skin microbes. At the most basic level, the skin serves as a physical barrier to prevent entry of bacteria into deeper layers of tissue and/or dissemination to internal organ systems. Keratinocytes form this important physical barrier. Traumatic breech of the skin enables entry of pathogenic microorganisms into the underlying tissue and initiates a complex cellular response that includes mobilization of immune cells to the site of infection (Figure 1A). The clinical presentation of bacterial SSTIs can vary from superficial to highly invasive and/or disseminated disease. The importance of S. aureus in SSTIs has long been appreciated since Alexander Ogston first unveiled the role of the pathogen in the etiology of the pyogenic abscess in the late 19th century.16Classics in infectious diseases: "on abscesses": Alexander Ogston (1844-1929).Rev Infect Dis. 1984; 6: 122-128Crossref PubMed Google Scholar Although a diversity of bacteria are currently implicated in SSTIs, S. aureus is overwhelmingly the most prominent cause of infection (eg, a recent study of a large US health care delivery system found approximately 80% of SSTIs to be associated with S. aureus),17Ray G.T. Suaya J.A. Baxter R. Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus.Diagn Microbiol Infect Dis. 2013; 76: 24-30Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar with the most common clinical presentation being abscess and cellulitis (63%). In addition to SSTIs, pyogenic bacterial abscesses can form in deeper tissues, such as underlying muscle, and bacteria can disseminate to form abscesses at distal sites and affect virtually any internal organ system. The overall structure of S. aureus abscesses is consistent regardless of anatomical location, based, at least in part, on lesion histopathology from experimental animal models of infection (eg, rabbit SSTIs18Kobayashi S.D. Malachowa N. Whitney A.R. Braughton K.R. Gardner D.J. Long D. Bubeck Wardenburg J. Schneewind O. Otto M. Deleo F.R. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection.J Infect Dis. 2011; 204: 937-941Crossref PubMed Scopus (199) Google Scholar and murine skin,19Kennedy A.D. Bubeck Wardenburg J. Gardner D.J. Long D. Whitney A.R. Braughton K.R. Schneewind O. DeLeo F.R. Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model.J Infect Dis. 2010; 202: 1050-1058Crossref PubMed Scopus (267) Google Scholar kidney,20Cheng A.G. Kim H.K. Burts M.L. Krausz T. Schneewind O. Missiakas D.M. Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues.FASEB J. 2009; 23: 3393-3404Crossref PubMed Scopus (296) Google Scholar and brain).21Kielian T. Bearden E.D. Baldwin A.C. Esen N. IL-1 and TNF-alpha play a pivotal role in the host immune response in a mouse model of Staphylococcus aureus-induced experimental brain abscess.J Neuropathol Exp Neurol. 2004; 63: 381-396Crossref PubMed Scopus (102) Google Scholar Similarities aside, it is unclear if there are variations in organ-specific immune response and/or bacterial response that may govern the process of abscess formation, depending on anatomical location. Staphylococcus aureus kidney abscesses in mice have features not found in S. aureus skin abscesses in rabbits. For example, Cheng et al20Cheng A.G. Kim H.K. Burts M.L. Krausz T. Schneewind O. Missiakas D.M. Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues.FASEB J. 2009; 23: 3393-3404Crossref PubMed Scopus (296) Google Scholar found a large mass of replicating S. aureus at the center of the kidney abscess that was surrounded by an eosinophilic pseudocapsule—a feature not observed in rabbit skin abscesses.18Kobayashi S.D. Malachowa N. Whitney A.R. Braughton K.R. Gardner D.J. Long D. Bubeck Wardenburg J. Schneewind O. Otto M. Deleo F.R. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection.J Infect Dis. 2011; 204: 937-941Crossref PubMed Scopus (199) Google Scholar Inasmuch as S. aureus can produce molecules that promote abscess formation (see below), it is possible there is species and tissue specificity conferred by these molecules. The pyogenic abscess begins as a localized host acute inflammatory response to bacterial infection. In addition to serving as a physical barrier to protect against microbes, keratinocytes possess pattern recognition receptors that detect invading microbes and, in turn, signal the proinflammatory response.22Krishna S. Miller L.S. Innate and adaptive immune responses against Staphylococcus aureus skin infections.Semin Immunopathol. 2012; 34: 261-280Crossref PubMed Scopus (105) Google Scholar These host cells also produce antimicrobial peptides that have direct activity against S. aureus.23Braff M.H. Zaiou M. Fierer J. Nizet V. Gallo R.L. Keratinocyte production of cathelicidin provides direct activity against bacterial skin pathogens.Infect Immun. 2005; 73: 6771-6781Crossref PubMed Scopus (133) Google Scholar, 24Harder J. Bartels J. Christophers E. Schroder J.M. A peptide antibiotic from human skin.Nature. 1997; 387: 861Crossref PubMed Scopus (1190) Google Scholar As an abscess forms, it acquires several characteristic features. The center of the abscess contains an acute inflammatory exudate composed of many viable and necrotic PMNs, tissue debris, fibrin, and live bacteria (Figure 1).25Kumar V. Abbas A.K. Fausto N. Robbins and Cotran Pathologic Basis of Disease. ed 7.in: Kumar V. Abbas A.K. Fausto N. Elsevier Saunders, Philadelphia2005Google Scholar Maturation of the abscess is accompanied by fibroblastic proliferation and tissue repair at the abscess margin and formation of a fibrous capsule at the periphery (Figure 1). SSTIs that present as bacterial abscesses form in the dermis, epidermis, or subcutaneous tissue and are often accompanied by cellulitis. Abscess formation is a mechanism used by the host to contain and ultimately eliminate the pathogen. Indeed, some SSTIs resolve spontaneously in the absence of treatment. Notably, PMNs play a prominent role in the formation and resolution of abscesses. Circulating PMNs are elicited from the vasculature to the infection site in response to tissue damage,26Kolaczkowska E. Kubes P. Neutrophil recruitment and function in health and inflammation.Nat Rev Immunol. 2013; 13: 159-175Crossref PubMed Scopus (3111) Google Scholar host proinflammatory molecules, and signals imparted directly by bacteria.27Miller L.S. Cho J.S. Immunity against Staphylococcus aureus cutaneous infections.Nat Rev Immunol. 2011; 11: 505-518Crossref PubMed Scopus (282) Google Scholar For example, S. aureus induces expression of many host proinflammatory factors in vitro or during experimental infection in mice, including IL-1α,28Olaru F. Jensen L.E. Staphylococcus aureus stimulates neutrophil targeting chemokine expression in keratinocytes through an autocrine IL-1alpha signaling loop.J Invest Dermatol. 2010; 130: 1866-1876Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar IL-1β,29Cho J.S. Guo Y. Ramos R.I. Hebroni F. Plaisier S.B. Xuan C. Granick J.L. Matsushima H. Takashima A. Iwakura Y. Cheung A.L. Cheng G. Lee D.J. Simon S.I. Miller L.S. Neutrophil-derived IL-1beta is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.PLoS Pathog. 2012; 8: e1003047Crossref PubMed Scopus (165) Google Scholar IL-6,30Puel A. Picard C. Lorrot M. Pons C. Chrabieh M. Lorenzo L. Mamani-Matsuda M. Jouanguy E. Gendrel D. Casanova J.L. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6.J Immunol. 2008; 180: 647-654Crossref PubMed Scopus (125) Google Scholar IL-8,31Konig B. Prevost G. Piemont Y. Konig W. Effects of Staphylococcus aureus leukocidins on inflammatory mediator release from human granulocytes.J Infect Dis. 1995; 171: 607-613Crossref PubMed Scopus (142) Google Scholar IL-17,32Cho J.S. Pietras E.M. Garcia N.C. Ramos R.I. Farzam D.M. Monroe H.R. Magorien J.E. Blauvelt A. Kolls J.K. Cheung A.L. Cheng G. Modlin R.L. Miller L.S. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice.J Clin Invest. 2010; 120: 1762-1773Crossref PubMed Scopus (478) Google Scholar leukotriene B4,31Konig B. Prevost G. Piemont Y. Konig W. Effects of Staphylococcus aureus leukocidins on inflammatory mediator release from human granulocytes.J Infect Dis. 1995; 171: 607-613Crossref PubMed Scopus (142) Google Scholar tumor necrosis factor-α,33Prabhakara R. Foreman O. De Pascalis R. Lee G.M. Plaut R.D. Kim S.Y. Stibitz S. Elkins K.L. Merkel T.J. Epicutaneous model of community-acquired Staphylococcus aureus skin infections.Infect Immun. 2013; 81: 1306-1315Crossref PubMed Scopus (35) Google Scholar CXCL1,34McLoughlin R.M. Solinga R.M. Rich J. Zaleski K.J. Cocchiaro J.L. Risley A. Tzianabos A.O. Lee J.C. CD4+ T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections.Proc Natl Acad Sci U S A. 2006; 103: 10408-10413Crossref PubMed Scopus (89) Google Scholar and CXCL2.34McLoughlin R.M. Solinga R.M. Rich J. Zaleski K.J. Cocchiaro J.L. Risley A. Tzianabos A.O. Lee J.C. CD4+ T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections.Proc Natl Acad Sci U S A. 2006; 103: 10408-10413Crossref PubMed Scopus (89) Google Scholar These factors are known to promote PMN extravasation and recruitment to infected tissues. Keratinocytes,35Minegishi Y. Saito M. Nagasawa M. Takada H. Hara T. Tsuchiya S. Agematsu K. Yamada M. Kawamura N. Ariga T. Tsuge I. Karasuyama H. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.J Exp Med. 2009; 206: 1291-1301Crossref PubMed Scopus (197) Google Scholar T cells,34McLoughlin R.M. Solinga R.M. Rich J. Zaleski K.J. Cocchiaro J.L. Risley A. Tzianabos A.O. Lee J.C. CD4+ T cells and CXC chemokines modulate the pathogenesis of Staphylococcus aureus wound infections.Proc Natl Acad Sci U S A. 2006; 103: 10408-10413Crossref PubMed Scopus (89) Google Scholar PMNs,32Cho J.S. Pietras E.M. Garcia N.C. Ramos R.I. Farzam D.M. Monroe H.R. Magorien J.E. Blauvelt A. Kolls J.K. Cheung A.L. Cheng G. Modlin R.L. Miller L.S. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice.J Clin Invest. 2010; 120: 1762-1773Crossref PubMed Scopus (478) Google Scholar and macrophages36Abtin A. Jain R. Mitchell A.J. Roediger B. Brzoska A.J. Tikoo S. Cheng Q. Ng L.G. Cavanagh L.L. von Andrian U.H. Hickey M.J. Firth N. Weninger W. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection.Nat Immunol. 2014; 15: 45-53Crossref PubMed Scopus (202) Google Scholar produce chemotactic factors that contribute to the large influx of neutrophils that occurs in response to S. aureus SSTIs. In addition, experimental animal models provide evidence that S. aureus SSTIs result in increased numbers of PMNs in circulation,37Kim M.H. Granick J.L. Kwok C. Walker N.J. Borjesson D.L. Curry F.R. Miller L.S. Simon S.I. Neutrophil survival and c-kit(+)-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution.Blood. 2011; 117: 3343-3352Crossref PubMed Scopus (82) Google Scholar and myeloid progenitor cells are recruited to infection sites where they undergo granulopoiesis.37Kim M.H. Granick J.L. Kwok C. Walker N.J. Borjesson D.L. Curry F.R. Miller L.S. Simon S.I. Neutrophil survival and c-kit(+)-progenitor proliferation in Staphylococcus aureus-infected skin wounds promote resolution.Blood. 2011; 117: 3343-3352Crossref PubMed Scopus (82) Google Scholar, 38Granick J.L. Falahee P.C. Dahmubed D. Borjesson D.L. Miller L.S. Simon S.I. Staphylococcus aureus recognition by hematopoietic stem and progenitor cells via TLR2/MyD88/PGE2 stimulates granulopoiesis in wounds.Blood. 2013; 122: 1770-1778Crossref PubMed Scopus (42) Google Scholar The accumulation and persistence of PMNs, followed by necrotic cell lysis, contribute to the overall pathology of S. aureus SSTIs. PMNs are arguably the most important cellular defense against invading bacteria, such as S. aureus. Indeed, genetic disorders that negatively affect PMN function typically predispose individuals to severe (and frequent) bacterial and fungal infections. For example, individuals with chronic granulomatous disease, a genetic disorder characterized by the inability of PMNs and other phagocytes to produce superoxide, often acquire severe and recurrent S. aureus infections. These infections often manifest as abscesses that can ultimately transform into granulomas, which obstruct organ function and must be surgically removed. Inasmuch as PMNs play a central role in S. aureus abscess formation and the resolution of infection, it is important to understand basic functions of these prominent host cells. Neutrophils are recruited rapidly to the site of infection and remove invading microorganisms through a process known as phagocytosis (Figure 2). Bacteria express a litany of molecules on their surface, such as lipopolysaccharide, lipoprotein, and lipoteichoic acid, and these pathogen-associated molecular patterns interact with receptors on the surface of neutrophils. In general, ligation of the neutrophil pattern recognition receptors (eg, Toll-like receptors and CD14) activates signal transduction pathways that ultimately contribute to bactericidal activity. PMN phagocytosis is most efficiently promoted by opsonization of bacteria with antibody and complement. Specific antibody binds to epitopes on the surface of bacteria and enables the deposition of complement. Antibodies bound to the bacterial surface are recognized by neutrophil receptors specific for the Fc region, including CD64 (FcγRI, IgG receptor), CD32 (FcγRIIa, low-affinity IgG receptor), CD16 (FcγRIIIb, low-affinity IgG receptor), CD89 (FcαR, IgA receptor), and CD23 (FcεRI, IgE receptor). Bacteria opsonized with complement are recognized by PMN surface receptors, including ClqR, CD35, CD11b/CD18 (CR3), and CD11c/CD18 (CR4). Ingested bacteria are sequestered within membrane-bound vacuoles called phagosomes (Figure 2). PMN phagocytosis is followed by the execution of bactericidal mechanisms, including the production of superoxide radicals and other reactive oxygen species (ROS), and enrichment of antimicrobial peptides, proteins, and degradative enzymes in the phagosome (Figure 2). ROS are generated by a multicomponent membrane-bound complex known as the NADPH-dependent oxidase,39Quinn M.T. Gauss K.A. Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases.J Leukoc Biol. 2004; 76: 760-781Crossref PubMed Scopus (389) Google Scholar which is defective in individuals with chronic granulomatous disease. In resting neutrophils, components of the NADPH oxidase are either cytosolic (p40phox, p47phox, p67phox, and the GTPase Rac2) or located in membranes (flavocytochrome b558). NADPH oxidase assembly involves translocation of the cytosolic protein components to the plasma or phagosome membrane and their subsequent association with flavocytochrome b558, a transmembrane heterodimer that serves as the nidus of the assembling enzyme complex.
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