Understanding how leading bacterial pathogens subvert innate immunity to reveal novel therapeutic targets
2007; Elsevier BV; Volume: 120; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2007.06.005
ISSN1097-6825
Autores Tópico(s)Clostridium difficile and Clostridium perfringens research
ResumoStaphylococcus aureus (SA) and group A Streptococcus (GAS) are prominent Gram-positive bacterial pathogens, each associated with a variety of mucosal and invasive human infections. SA and GAS systemic disease reflects diverse abilities of these pathogens to resist clearance by the multifaceted defenses of the human innate immune system. Here we review how SA and GAS avoid the bactericidal activities of cationic antimicrobial peptides, delay phagocyte recruitment, escape neutrophil extracellular traps, inhibit complement and antibody opsonization functions, impair phagocytotic uptake, resist oxidative burst killing, and promote phagocyte lysis or apoptosis. Understanding the molecular basis of SA and GAS innate immune resistance reveals novel therapeutic targets for treatment or prevention of invasive human infections. These future therapies envision alternatives to direct microbial killing, such as blocking disease progression by neutralizing specific virulence factors or boosting key innate immune defenses. Staphylococcus aureus (SA) and group A Streptococcus (GAS) are prominent Gram-positive bacterial pathogens, each associated with a variety of mucosal and invasive human infections. SA and GAS systemic disease reflects diverse abilities of these pathogens to resist clearance by the multifaceted defenses of the human innate immune system. Here we review how SA and GAS avoid the bactericidal activities of cationic antimicrobial peptides, delay phagocyte recruitment, escape neutrophil extracellular traps, inhibit complement and antibody opsonization functions, impair phagocytotic uptake, resist oxidative burst killing, and promote phagocyte lysis or apoptosis. Understanding the molecular basis of SA and GAS innate immune resistance reveals novel therapeutic targets for treatment or prevention of invasive human infections. These future therapies envision alternatives to direct microbial killing, such as blocking disease progression by neutralizing specific virulence factors or boosting key innate immune defenses. Innate immunity in human beings and other higher animals represents an integrated and highly effective system of molecules and cellular systems that defend the host against infection, despite continual encounter with potential pathogens in a complex environment. In addition to the physical barrier function of skin and mucosal epithelium, innate immunity is composed of soluble effectors such as cationic antimicrobial peptides (AMPs) and complement proteins. Sophisticated pattern recognition systems are deployed by the innate immune system to activation and target inflammatory responses. Finally, innate immunity gains a critical contribution from phagocytic cell types such as neutrophils and macrophages capable of directed migration, microbial uptake, and production of a variety of bactericidal compounds. The clinical specialty of infectious diseases largely reflects the spectrum of medical conditions resulting from failures of innate immunity. Often the etiology is intrinsic to the host, including developmental immaturity or senescence of defense functions at extremes of age, genetic or acquired (eg, chemotherapy) immunodeficiencies, loss of barrier integrity (eg, surgical wounds), high-risk exposures and behaviors, or debilitation caused by chronic illness or malnutrition. In other cases, no obvious predisposing host condition can be defined; nevertheless, serious infection develops requiring antibiotic therapy and perhaps surgical drainage and additional supportive measures. On initial presentation, the empiric diagnostic and therapeutic approach to such patients is appropriately focused toward a relatively short list of likely etiologic agents. The Gram-positive bacteria Staphylococcus aureus (SA) and group A Streptococcus (GAS) are preeminent human pathogens responsible for a wide spectrum of superficial and invasive disease conditions. SA accounts for >10 million skin and soft tissue infections annually in the United States alone1McCaig L.F. McDonald L.C. Mandal S. Jernigan D.B. Staphylococcus aureus-associated skin and soft tissue infections in ambulatory care.Emerg Infect Dis. 2006; 12: 1715-1723Crossref PubMed Scopus (240) Google Scholar and is the single leading cause of hospital acquired infections.2Jones RN. Global epidemiology of antimicrobial resistance among community-acquired and nosocomial pathogens: a five-year summary from the SENTRY Antimicrobial Surveillance Program (1997-2001).Semin Respir Crit Care Med. 2003; 24: 121-134Crossref PubMed Scopus (149) Google Scholar Each year worldwide, GAS is responsible for more than 700 million cases of pharyngitis or skin infection and more than 650,000 invasive infections.3Carapetis J.R. Steer A.C. Mulholland E.K. Weber M. The global burden of group A streptococcal diseases.Lancet Infect Dis. 2005; 5: 685-694Abstract Full Text Full Text PDF PubMed Scopus (1882) Google Scholar Both pathogens can produce infections in essentially every human organ or tissue, including severe life-threatening conditions such as necrotizing fasciitis, endocarditis, sepsis, and toxic shock syndrome. The propensity of SA and GAS to produce systemic infections, often in otherwise healthy children and adults, defines a capacity of each pathogen to resist host innate immune clearance mechanisms that normally function to prevent microbial dissemination beyond epithelial surfaces. This review focuses on the multiple virulence factors of SA and GAS capable of interfering with the host innate immune defenses, placing a particular emphasis on recent discoveries established through molecular analysis of the pathogens. The multifaceted basis of SA and GAS resistance to cationic antimicrobial peptides (AMPs), complement, and host phagocytic cell function is outlined. Our enhanced understanding of the mechanisms of SA and GAS pathogenicity and the subtle limitations of innate immunity they exploit reveal novel avenues for infectious disease therapy. Recent discoveries using knockout mice have confirmed that cationic AMPs such as cathelicidins and β-defensins play a crucial role in restricting microbial proliferation to skin and mucosal surfaces and in preventing spread to the deep tissues, where serious infection may develop. For example, cathelicidin-deficient mice are more susceptible to necrotizing GAS skin infection,4Nizet V. Ohtake T. Lauth X. Trowbridge J. Rudisill J. Dorschner R.A. et al.Innate antimicrobial peptide protects the skin from invasive bacterial infection.Nature. 2001; 414: 454-457Crossref PubMed Scopus (1006) Google Scholar and β-defensin knockout mice exhibit reduced clearance of SA from the urinary tract.5Morrison G. Kilanowski F. Davidson D. Dorin J. Characterization of the mouse beta defensin 1, Defb1, mutant mouse model.Infect Immun. 2002; 70: 3053-3060Crossref PubMed Scopus (179) Google Scholar Skin keratinocytes and mucosal epithelial cells produce very low levels of AMPs under baseline conditions, but their expression of AMPs can be induced dramatically in response to injury or infectious stimuli. These epithelial barrier functions are further supplemented by AMPs produced by leukocytes (eg, neutrophils) recruited during an inflammatory response. Defects in local AMP production are noted in atopic dermatitis and may help explain the clinical predisposition for bacterial superinfection in individuals with this condition.6Ong P.Y. Ohtake T. Brandt C. Strickland I. Boguniewicz M. Ganz T. et al.Endogenous antimicrobial peptides and skin infections in atopic dermatitis.N Engl J Med. 2002; 347: 1151-1160Crossref PubMed Scopus (1611) Google Scholar Relative resistance to efficient AMP killing is increasingly recognized as a discriminating feature of important human pathogens, including SA and GAS. The AMP avoidance mechanisms deployed by these 2 pathogens are diverse and include charge modifications of the cell membrane, proteolytic degradation, and the AMP binding and inactivation activities of specific bacterial surface or secreted proteins. By incorporating positively charged residues into their cell wall lipoteichoic and teichoic acid, SA and GAS increase electrostatic repulsion of the defense peptides. For example, D-alanylation of teichoic acids mediated by the dlt operon is present in both pathogens, promoting resistance to AMP and neutrophil killing.7Peschel A. Otto M. Jack R.W. Kalbacher H. Jung G. Gotz F. Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides.J Biol Chem. 1999; 274: 8405-8410Crossref Scopus (783) Google Scholar, 8Kristian S.A. Datta V. Weidenmaier C. Kansal R. Fedtke I. Peschel A. et al.D-alanylation of teichoic acids promotes group A Streptococcus antimicrobial peptide resistance, neutrophil survival, and epithelial cell invasion.J Bacteriol. 2005; 187: 6719-6725Crossref Scopus (180) Google Scholar In addition, positively charged lysyl-phosphatidylglycerol modifications of teichoic acids are encoded in the functions of the SA mprF or lysC genes and contribute to human AMP resistance.9Staubitz P. Neumann H. Schneider T. Wiedemann I. Peschel A. MprF-mediated biosynthesis of lysylphosphatidylglycerol, an important determinant in staphylococcal defensin resistance.FEMS Microbiol Lett. 2004; 231: 67-71Crossref PubMed Scopus (135) Google Scholar, 10Nishi H. Komatsuzawa H. Fujiwara T. McCallum N. Sugai M. Reduced content of lysyl-phosphatidylglycerol in the cytoplasmic membrane affects susceptibility to moenomycin, as well as vancomycin, gentamicin, and antimicrobial peptides, in Staphylococcus aureus.Antimicrob Agents Chemother. 2004; 48: 4800-4807Crossref Scopus (111) Google Scholar SA mutants defective in Dlt and MprF show reduced virulence in small animal infection models.11Collins L.V. Kristian S.A. Weidenmaier C. Faigle M. Van Kessel K.P. Van Strijp J.A. et al.Staphylococcus aureus strains lacking D-alanine modifications of teichoic acids are highly susceptible to human neutrophil killing and are virulence attenuated in mice.J Infect Dis. 2002; 186: 214-219Crossref Scopus (188) Google Scholar, 12Weidenmaier C. Peschel A. Kempf V.A. Lucindo N. Yeaman M.R. Bayer A.S. DltABCD- and MprF-mediated cell envelope modifications of Staphylococcus aureus confer resistance to platelet microbicidal proteins and contribute to virulence in a rabbit endocarditis model.Infect Immun. 2005; 73: 8033-8038Crossref Scopus (120) Google Scholar The SA metalloprotease aureolysin can cleave and inactivate human cathelicidin LL-37, thereby contributing to the bacterium's resistance to innate immune clearance.13Sieprawska-Lupa M. Mydel P. Krawczyk K. Wojcik K. Puklo M. Lupa B. et al.Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases.Antimicrob Agents Chemother. 2004; 48: 4673-4679Crossref Scopus (384) Google Scholar Similarly, the secreted cysteine protease SpeB of GAS can be retained on the bacterial surface, where it proves capable of degrading LL-37 and protecting the bacteria against its antimicrobial action.14Nyberg P. Rasmussen M. Bjorck L. α2-Macroglobulin-proteinase complexes protect Streptococcus pyogenes from killing by the antimicrobial peptide LL-37.J Biol Chem. 2004; 279: 52820-52823Crossref Scopus (69) Google Scholar Complex binding of human neutrophil α-defensins by staphylokinase neutralizes their bactericidal effect against SA,15Jin T. Bokarewa M. Foster T. Mitchell J. Higgins J. Tarkowski A. Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism.J Immunol. 2004; 172: 1169-1176Google Scholar and the streptococcal inhibitor of complement protein binds and inactivates both α-defensins and cathelicidin LL-37.16Fernie-King B.A. Seilly D.J. Lachmann P.J. The interaction of streptococcal inhibitor of complement (SIC) and its proteolytic fragments with the human beta defensins.Immunology. 2004; 111: 444-452Crossref PubMed Scopus (58) Google Scholar Circulating leukocytes respond to chemotactic signals to leave the vasculature and migrate to the site of infection. Although chemoattractants include products from the bacteria cell wall (eg, N-formyl peptides), the strongest and most specific stimuli are host-derived, including the CXC chemokine IL-8 and the complement-derived anaphylotoxin C5a. By pathogen interference with host chemokine functions, the kinetics of the innate immune response are delayed favoring bacterial survival. Interestingly, GAS appears to target the chemotactic peptides directly, whereas SA blocks essential host receptor functions. IL-8 acts as a potent chemoattractant17Kunkel S.L. Standiford T. Kasahara K. Strieter R.M. Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung.Exp Lung Res. 1991; 17: 17-23Crossref PubMed Scopus (480) Google Scholar and can be found tethered to the luminal surface of the microvasculature, where it provides a stop signal to rolling neutrophils.18Middleton J. Neil S. Wintle J. Clark-Lewis I. Moore H. Lam C. et al.Transcytosis and surface presentation of IL-8 by venular endothelial cells.Cell. 1997; 91: 385-395Abstract Full Text Full Text PDF PubMed Scopus (608) Google Scholar, 19DiVietro J.A. Smith M.J. Smith B.R. Petruzzelli L. Larson R.S. Lawrence M.B. Immobilized IL-8 triggers progressive activation of neutrophils rolling in vitro on P-selectin and intercellular adhesion molecule-1.J Immunol. 2001; 167: 4017-4025Google Scholar GAS produce a protease (SpyCEP, also known as ScpC) that specifically cleaves the C-terminus of IL-8, leading to functional inactivation of the chemokine.20Edwards R.J. Taylor G.W. Ferguson M. Murray S. Rendell N. Wrigley A. et al.Specific C-terminal cleavage and inactivation of interleukin-8 by invasive disease isolates of Streptococcus pyogenes.J Infect Dis. 2005; 192: 783-790Crossref Scopus (137) Google Scholar Mutation of SpyCEP dramatically reduces GAS virulence in the mouse necrotizing fasciitis model and is correlated with increased neutrophil influx to the site of infection.21Hidalgo-Grass C. Mishalian I. Dan-Goor M. Belotserkovsky I. Eran Y. Nizet V. et al.A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues.EMBO J. 2006; 25: 4628-4637Crossref Scopus (109) Google Scholar C5a is an 11-kd fragment of the complement cascade with multiple inflammatory properties including the recruitment of neutrophils and stimulation of their bactericidal capacity.22DeMaster E. Schnitzler N. Cheng Q. Cleary P. M(+) group a streptococci are phagocytized and killed in whole blood by C5a-activated polymorphonuclear leukocytes.Infect Immun. 2002; 70: 350-359Crossref PubMed Scopus (15) Google Scholar GAS sheds surface dehydrogenase, which binds and inactivates human C5a23Terao Y. Yamaguchi M. Hamada S. Kawabata S. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils.J Biol Chem. 2006; 281: 14215-14223Crossref Scopus (122) Google Scholar and expresses an endopeptidase, ScpA, which cleaves this chemoattractant within the critical domain for leukocyte receptor recognition.24Cleary P.P. Prahbu U. Dale J.B. Wexler D.E. Handley J. Streptococcal C5a peptidase is a highly specific endopeptidase.Infect Immun. 1992; 60: 5219-5223Crossref PubMed Google Scholar Many SA strains produce the chemotaxis inhibitory protein of staphylococci (CHIPS), which binds with high avidity to the leukocyte receptors for C5a and N-formyl peptides, thereby blocking functional engagement of the respective chemoattractants.25Postma B. Poppelier M.J. van Galen J.C. Prossnitz E.R. van Strijp J.A. de Haas C.J. et al.Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor.J Immunol. 2004; 172: 6994-7001Google Scholar SAs also express the extracellular adherence protein that binds and inhibits intercellular adhesion molecule-1 (ICAM-1), the endothelial receptor required to initiate leukocyte adhesion and diapadesis.26Haggar A. Ehrnfelt C. Holgersson J. Flock J.I. The extracellular adherence protein from Staphylococcus aureus inhibits neutrophil binding to endothelial cells.Infect Immun. 2004; 72: 6164-6167Crossref Scopus (40) Google Scholar It has recently been appreciated that, apart from their phagocytic function, neutrophils can efficiently capture and kill microbes in the extracellular space. This process involves neutrophil extrusion of a matrix of DNA and histones known as neutrophil extracellular traps (NETs) that ensnare bacteria, even in septic blood.27Brinkmann V. Reichard U. Goosmann C. Fauler B. Uhlemann Y. Weiss D.S. et al.Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535Crossref PubMed Scopus (5700) Google Scholar, 28Clark S.R. Ma A.C. Tavener S.A. McDonald B. Goodarzi Z. Kelly M.M. et al.Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.Nat Med. 2007; 13: 463-469Crossref PubMed Scopus (1503) Google Scholar The trapped bacteria are then subjected to microbicidal effectors including peptidoglycan recognition protein S and the granule proteases elastase and myeloperoxidase.27Brinkmann V. Reichard U. Goosmann C. Fauler B. Uhlemann Y. Weiss D.S. et al.Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535Crossref PubMed Scopus (5700) Google Scholar, 29Cho J.H. Fraser I.P. Fukase K. Kusumoto S. Fujimoto Y. Stahl G.L. et al.Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity.Blood. 2005; 106: 2551-2558Crossref Scopus (103) Google Scholar With chromatin representing the principal scaffold of NETs, bacterial degradation of DNA represents a potential mechanism for pathogens to escape this aspect of innate immunity. A GAS strain with mutations in 3 encoded deoxyribonucleases (DNases) is significantly more susceptible to neutrophil killing and attenuated in murine skin and systemic infection models as well as pharyngeal infection of cynomolgus macaques.30Sumby P. Barbian K.D. Gardner D.J. Whitney A.R. Welty D.M. Long R.D. et al.Extracellular deoxyribonuclease made by group A Streptococcus assists pathogenesis by enhancing evasion of the innate immune response.Proc Natl Acad Sci U S A. 2005; 102: 1679-1684Crossref Scopus (252) Google Scholar The most prominent of these DNases was the highly active bacteriophage-encoded Sda1, present in the secreted proteome of the virulent M1T1 GAS clone associated with severe, invasive infections.31Aziz R.K. Ismail S.A. Park H.W. Kotb M. Post-proteomic identification of a novel phage-encoded streptodornase, Sda1, in invasive M1T1 Streptococcus pyogenes.Mol Microbiol. 2004; 54: 184-197Crossref Scopus (63) Google Scholar Targeted mutagenesis and heterologous expression of DNase Sda1 reveal that the enzyme is necessary and sufficient for promoting GAS NET degradation and resistance to neutrophil killing in vitro and in vivo.32Buchanan J.T. Simpson A.J. Aziz R.K. Liu G.Y. Kristian S.A. Kotb M. et al.DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps.Curr Biol. 2006; 16: 396-400Abstract Full Text Full Text PDF PubMed Scopus (510) Google Scholar After activation of the classic, lectin, or alternative complement pathways, opsonization of foreign microbes occurs through deposition of C3b and its cleavage fragment iC3b on their surface. Complement receptors (CRs) on neutrophils and macrophages engage the bound C3b (CR1) or iC3b (CR3 and CR4) to facilitate phagocytosis. Because the complement system is capable of efficient self-amplification, potential host cell damage is mitigated by the counterregulatory proteins such as C4b-binding protein (C4BP), factor H (FH), and factor I (FI) that dampen the activity level of complement. SA and GAS exhibit the capacity to manipulate key host complement regulatory pathways selectively to thwart efficient opsonophagocytosis. Cleavage of C3 to opsonically active C3b is accomplished after assembly of C3 convertase complexes C4bC2a (classic/lectin pathways) or C3bBb (alternative pathway) on the bacterial surface. The secreted ∼10-kd SA protein known as staphylococcal complement inhibitor (SCIN) binds and stabilizes both convertases on the bacterial surface, preventing generation of additional convertases, impairing their enzymatic activities, and effectively inhibiting all 3 complement pathways.33Rooijakkers S.H. Ruyken M. Roos A. Daha M.R. Presanis J.S. Sim R.B. et al.Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases.Nat Immunol. 2005; 6: 920-927Crossref Scopus (313) Google Scholar Host regulatory protein C4BP interferes with the assembly of the C4bC2a C3 convertase of the classic/lectin pathway. GAS is able to acquire C4BP selectively from human serum through the action of the hypervariable regions of several M-protein family members, thereby inhibiting classical pathway activation34Thern A. Stenberg L. Dahlback B. Lindahl G. Ig-binding surface proteins of Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a regulatory component of the complement system.J Immunol. 1995; 154: 375-386Google Scholar, 35Morfeldt E. Berggard K. Persson J. Drakenberg T. Johnsson E. Lindahl E. et al.Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein: implications for antigenic variation.J Immunol. 2001; 167: 3870-3877Crossref Scopus (56) Google Scholar; a strong correlation can be established between C4BP acquisition on the GAS surface and evasion of phagocytosis.36Berggard K. Johnsson E. Morfeldt E. Persson J. Stalhammar-Carlemalm M. Lindahl G. Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes.Mol Microbiol. 2001; 42: 539-551Crossref Scopus (69) Google Scholar Factor H and its splice variant FH-like protein 1 (FHL-1) are central fluid-phase regulators of the alternative complement pathway, functioning to accelerate the decay of the C3bBb C3 convertase and acting as cofactors for FI-mediated degradation of C3b.37Zipfel P.F. Hellwage J. Friese M.A. Hegasy G. Jokiranta S.T. Meri S. Factor H and disease: a complement regulator affects vital body functions.Mol Immunol. 1999; 36: 241-248Crossref PubMed Scopus (85) Google Scholar The cell wall anchored M protein has long been known to restrict deposition of C3b on the GAS surface, a function that can be correlated to resistance to phagocytosis.38Jacks-Weis J. Kim Y. Cleary P.P. Restricted deposition of C3 on M+ group A streptococci: correlation with resistance to phagocytosis.J Immunol. 1982; 128: 1897-1902PubMed Google Scholar Many GAS M proteins were found capable of binding FH and FHL-1 through their conserved C-repeat region and/or hypervariable N-terminal regions,39Johnsson E. Berggard K. Kotarsky H. Hellwage J. Zipfel P.F. Sjobring U. et al.Role of the hypervariable region in streptococcal M proteins: binding of a human complement inhibitor.J Immunol. 1998; 161: 4894-4901Google Scholar but the overall significance of M protein binding to FH and FHL-1 to complement resistance remains controversial. In GAS strains of the M1 serotype, the M protein is dispensable for FH and FHL-1 binding; instead, the surface-anchored protein Fba mediates interactions with these complement regulatory factors. Fba promotes M1 GAS survival in human whole blood and prevents deposition of C3b on the bacterial cell surface.40Pandiripally V. Gregory E. Cue D. Acquisition of regulators of complement activation by Streptococcus pyogenes serotype M1.Infect Immun. 2002; 70: 6206-6214Crossref PubMed Scopus (81) Google Scholar SA is also capable of manipulating host FI function, thereby shedding opsonically active C3b from the bacterial surface and impeding phagocytosis.41Cunnion K.M. Buescher E.S. Hair P.S. Serum complement factor I decreases Staphylococcus aureus phagocytosis.J Lab Clin Med. 2005; 146: 279-286Abstract Full Text Full Text PDF Scopus (18) Google Scholar Deposition of complement on the SA or GAS surface can also occur via the classic pathway under nonimmune conditions, but can be blocked by the ability of each pathogen to bind fibrinogen, which reduces accumulation of the C4bC2a C3 convertase. Binding of fibrinogen to the B and C repeats of GAS M protein plays an important role in restricting the number of epitopes that can serve as targets for opsonization.42Sandin C. Carlsson F. Lindahl G. Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes.Mol Microbiol. 2006; 59: 20-30Crossref PubMed Scopus (55) Google Scholar The M-related protein Mrp, expressed by more than half of GAS strains, also recruits fibrinogen to the bacterial surface in a fashion that impairs complement deposition.43Courtney H.S. Hasty D.L. Dale J.B. Anti-phagocytic mechanisms of Streptococcus pyogenes: binding of fibrinogen to M-related protein.Mol Microbiol. 2006; 59: 936-947Crossref PubMed Scopus (70) Google Scholar The surface-anchored SA fibrinogen-binding protein known as clumping factor acts in a similar fashion, effectively reducing opsonophagocytosis by macrophages and neutrophils.44Palmqvist N. Patti J.M. Tarkowski A. Josefsson E. Expression of staphylococcal clumping factor A impedes macrophage phagocytosis.Microbes Infect. 2004; 6: 188-195Crossref Scopus (49) Google Scholar, 45Higgins J. 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Surface-bound plasmin can then cleave human C3b and C3bi from the bacterial cell wall and impair neutrophil phagocytosis.47Rooijakkers S.H. van Wamel W.J. Ruyken M. van Kessel K.P. van Strijp J.A. Anti-opsonic properties of staphylokinase.Microbes Infect. 2005; 7: 476-484Crossref PubMed Scopus (162) Google Scholar GAS expresses streptokinase, a protein with similar plasminogen-binding and zymogen activator capacities. The interaction of streptokinase with complement factors has not been studied in detail, but its role in plasmin accumulation on the bacterial surface is critical to development of GAS invasive infection.48Sun H. Ringdahl U. Homeister J.W. Fay W.P. Engleberg N.C. Yang A.Y. et al.Plasminogen is a critical host pathogenicity factor for group A streptococcal infection.Science. 2004; 305: 1283-1286Crossref Scopus (313) Google Scholar, 49Cole J.N. McArthur J.D. McKay F.C. Sanderson-Smith M.L. Cork A.J. 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Effect of SpeB and EndoS from Streptococcus pyogenes on human immunoglobulins.Infect Immun. 2001; 69: 7187-7189Crossref Scopus (150) Google Scholar Mac-1, a second GAS cysteine protease, cleaves IgG in vitro and in vivo, targeting the lower Fc region,52Akesson P. Moritz L. Truedsson M. Christensson B. von Pawel-Rammingen U. IdeS, a highly specific immunoglobulin G (IgG)-cleaving enzyme from Streptococcus pyogenes, is inhibited by specific IgG antibodies generated during infection.Infect Immun. 2006; 74: 497-503Crossref PubMed Scopus (41) Google Scholar and also binds FcγRIIIB (CD16) on the surface of neutrophils inhibiting phagocytosis and activation of the oxidative burst.53Lei B. DeLeo F.R. Hoe N.P. Graham M.R. Mackie S.M. Cole R.L. et al.Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis.Nat Med. 2001; 7: 1298-1305Crossref PubMed Scopus (138) Google Scholar The closely related IgG endopeptidase Mac-2 likewise binds Fcγ receptors and competitively inhibits host phagocyte recognition of IgG on the bacterial surface.54Agniswamy J. Lei B. Musser J.M. Sun P.D. Insight of host immune evasion mediated by two variants of group a Streptococcus Mac protein.J Biol Chem. 2004; 279: 52789-52796Crossref PubMed Scopus (52) Google Scholar The secreted GAS protein EndoS hydrolyzes the chitobiose core of the asparagine-linked glycan on IgG, preventing recognition of IgG by phagocyte Fc receptors, blocking complement activation through the classic pathway, and impairing opsonophagocytosis.55Collin M. Svensson M.D. Sjoholm A.G. Jensenius J.C. Sjobring U. Olsen A. EndoS and SpeB from Strept
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