The IL-8 Protease SpyCEP/ScpC of Group A Streptococcus Promotes Resistance to Neutrophil Killing
Open accessAbstract
Interleukin-8 (IL-8) promotes neutrophil-mediated host defense through its chemoattractant and immunostimulatory activities. The Group A Streptococcus (GAS) protease SpyCEP (also called ScpC) cleaves IL-8, and SpyCEP expression is strongly upregulated in vivo in the M1T1 GAS strains associated with life-threatening systemic disease including necrotizing fasciitis. Coupling allelic replacement with heterologous gene expression, we show that SpyCEP is necessary and sufficient for IL-8 degradation. SpyCEP decreased IL-8-dependent neutrophil endothelial transmigration and bacterial killing, the latter by reducing neutrophil extracellular trap formation. The knockout mutant lacking SpyCEP was attenuated for virulence in murine infection models, and SpyCEP expression conferred protection to coinfecting bacteria. We also show that the zoonotic pathogen Streptococcus iniae possesses a functional homolog of SpyCEP (CepI) that cleaves IL-8, promotes neutrophil resistance, and contributes to virulence. By inactivating the multifunctional host defense peptide IL-8, the SpyCEP protease impairs neutrophil clearance mechanisms, contributing to the pathogenesis of invasive streptococcal infection.
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SpyCEP cleaves human IL-8/mouse CXCL1 to suppress chemokine-mediated neutrophil recruitment.
“One of the principal mechanisms of GAS-immune escape is the production of surface-associated serine proteases by GAS, such as SpyCEP (also designated ScpC), which cleaves human IL-8/mouse CXCL1 to suppress chemokine-mediated neutrophil recruitment (17), or SpeB, which allows GAS to translocate across the epithelial barrier by degrading several host plasma and matrix proteins (18).”
From Epidermal hepcidin is required for neutrophil response to bacterial infection (2019) · cites this paper as [17]
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Neutrophil Extracellular Traps Kill Bacteria
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., Weinrauch, Y., & Zychlinsky, A. (2004) · Science · doi:10.1126/science.1092385 · Cited by 10,268 · cited 2× · see citing works
“SpyCEP Reduces Neutrophil Production of Extracellular Traps Apart from their phagocytic function, neutrophils can efficiently capture and kill microbes in the extracellular space by extrusion of a matrix of DNA and histones known as neutrophil extracellular traps, or NETs, which ensnare bacteria and subject them to mi…”
BackgroundThe global burden of group A streptococcal diseases
Carapetis, J. R., Steer, A. C., Mulholland, E. K., & Weber, M. (2005) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(05)70267-x · Cited by 3,001 · see citing works
Innate antimicrobial peptide protects the skin from invasive bacterial infection
Nizet, V., Ohtake, T., Lauth, X., Trowbridge, J., Rudisill, J., Dorschner, R. A., Pestonjamasp, V., Piraino, J., Huttner, K., & Gallo, R. L. (2001) · Nature · doi:10.1038/35106587 · Cited by 1,198 · cited 2× · see citing works
“Mouse Infection Models GAS and S.iniae virulence was tested using an established murine model of necrotizing skin infection (Buchanan et al., 2006; Nizet et al., 2001).”
MethodSelf-citationComplete genome sequence of an M1 strain of Streptococcus pyogenes
Ferretti, J. J., McShan, W. M., Ajdić, D., Savić, D. J., Savić, G., Lyon, K., Primeaux, C., Sezate, S. A., Suvorov, A. N., Kenton, S., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.071559398 · Cited by 936 · cited 2× · see citing works
“, 1999), and upstream of genes with high similarity to spy_0421 and metG of M1 GAS (Ferretti et al., 2001).”
BackgroundATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors
Chen, Y., Corriden, R., Inoue, Y., Yip, L., Hashiguchi, N., Zinkernagel, A. S., Nizet, V., Insel, P. A., & JUNGER, W. G. (2006) · Science · doi:10.1126/science.1132559 · Cited by 858 · cited 2× · see citing works
“Endothelial Transcytosis Assay Transmigration of human neutrophils across polar human brain microvascular endothelial cell (hBMEC) monolayers was assessed using an adaptation of a published assay (Chen et al., 2006).”
MethodSelf-citationTranscytosis and Surface Presentation of IL-8 by Venular Endothelial Cells
Middleton, J., Neil, S. J. D., Wintle, J., Clark‐Lewis, I., Moore, H. D., Lam, C., Auer, M., Hub, E., & Rot, A. (1997) · Cell · doi:10.1016/s0092-8674(00)80422-5 · Cited by 729 · cited 2× · see citing works
“Not only does IL-8 act as potent chemoattractant (Kunkel et al., 1991), it also tethers itself to the luminal surface of the microvasculature providing a stop signal to rolling neutrophils (DiVietro et al., 2001; Middleton et al., 1997).”
BackgroundBuchanan, J. T., Simpson, A. J., Aziz, R. K., Liu, G. Y., Kristian, S. A., Kotb, M., Feramisco, J. R., & Nizet, V. (2006) · Current Biology · doi:10.1016/j.cub.2005.12.039 · Cited by 683 · cited 8× · see citing works
“M1T1 GAS express DNases including the phage-encoded Sda1 that contribute to NET degradation and immune evasion (Buchanan et al., 2006; Sumby et al., 2005; Walker et al., 2007).”
BackgroundMethodInfluentialSelf-citationInterleukin-8 (IL-8): The Major Neutrophil Chemotactic Factor in the Lung
Kunkel, S. L., Standiford, T. J., Kasahara, K., & Strieter, R. M. (1991) · Experimental Lung Research · doi:10.3109/01902149109063278 · Cited by 553 · cited 1× · see citing works
“Not only does IL-8 act as potent chemoattractant (Kunkel et al., 1991), it also tethers itself to the luminal surface of the microvasculature providing a stop signal to rolling neutrophils (DiVietro et al., 2001; Middleton et al., 1997).”
BackgroundSumby, P., Whitney, A. R., Graviss, E. A., DeLeo, F. R., & Musser, J. M. (2006) · PLoS Pathogens · doi:10.1371/journal.ppat.0020005 · Cited by 459 · cited 3× · see citing works
“Sumby et al. recently provided a genome-wide analysis using expression microarrays to characterize fundamental differences in the transcriptome of M1T1 GAS isolates isolated from invasive disease cases versus those associated with mucosal site infection (Sumby et al., 2006).”
BackgroundInfluentialBazzoni, F., Cassatella, M. A., Rossi, F., Ceska, M., Dewald, B., & Baggiolini, M. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.3.771 · Cited by 436 · cited 2× · see citing works
“IL-8, formerly known as neutrophil activating peptide-1, is produced in large amounts by neutrophils themselves upon encountering bacteria (Bazzoni et al., 1991; Strieter et al., 1992), and in an autocrine fashion can exert stimulatory effects on oxidative burst function and release of granule…”
BackgroundDNase Sda1 provides selection pressure for a switch to invasive group A streptococcal infection
Walker, M. J., Hollands, A., Sanderson‐Smith, M. L., Cole, J. N., Kirk, J. K., Henningham, A., McArthur, J. D., Dinkla, K., Aziz, R. K., Kansal, R. G., et al. (2007) · Nature Medicine · doi:10.1038/nm1612 · Cited by 427 · cited 1× · see citing works
“M1T1 GAS express DNases including the phage-encoded Sda1 that contribute to NET degradation and immune evasion (Buchanan et al., 2006; Sumby et al., 2005; Walker et al., 2007).”
BackgroundSelf-citationAgnew, W., & Barnes, A. C. (2007) · Veterinary Microbiology · doi:10.1016/j.vetmic.2007.03.002 · Cited by 425 · cited 1× · see citing works
“The Zoonotic Pathogen Streptococcus iniae Possesses a Functional SpyCEP Homolog The b-hemolytic species Streptococcus iniae is an important pathogen in wild and aquacultured fish, where it can produce a fatal meningoencephalitis (Agnew and Barnes, 2007).”
BackgroundGupta, A. K., Hasler, P., Holzgreve, W., Gebhardt, G., & Hahn, S. (2005) · Human Immunology · doi:10.1016/j.humimm.2005.11.003 · Cited by 403 · see citing works
Neutrophil Migration Mechanisms, with an Emphasis on the Pulmonary Vasculature
Wagner, J. G., & Roth, R. A. (2000) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01456-x · Cited by 347 · cited 2× · see citing works
“…in association with proliferating bacteria (Dahl et al., 2002), as could be expected since additional microbial components (e.g., fMLP) and host inflammatory response proteins (e.g., C5a, platelet activating factor) possess strong neutrophil chemoattractant properties (Wagner and Roth, 2000).”
BackgroundSumby, P., Barbian, K., Gardner, D. J., Whitney, A. R., Welty, D. M., Long, R. D., Bailey, J. R., Parnell, M. J., Hoe, N. P., Adams, G. G., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406641102 · Cited by 341 · cited 4× · see citing works
“M1T1 GAS express DNases including the phage-encoded Sda1 that contribute to NET degradation and immune evasion (Buchanan et al., 2006; Sumby et al., 2005; Walker et al., 2007).”
BackgroundInfluentialInvasive Infections Due to a Fish Pathogen,Streptococcus iniae
Weinstein, M. R., Litt, M., Kertesz, D. A., Wyper, P. A., Rose, D., Coulter, M., McGeer, A., Facklam, R. R., Ostach, C., Willey, B. M., et al. (1997) · New England Journal of Medicine · doi:10.1056/nejm199708283370902 · Cited by 330 · cited 2× · see citing works
“S. iniae is also recognized as an emerging zoonotic pathogen of humans, producing invasive cellulitis in fish handlers (Weinstein et al., 1997).”
BackgroundMechanism of neutrophil activation by NAF, a novel monocyte‐derived peptide agonist
Thelen, M., Peveri, P., Kernen, P., von Tscharner, V., Walz, A., & Baggiolini, M. (1988) · The FASEB Journal · doi:10.1096/fasebj.2.11.2840318 · Cited by 307 · cited 1× · see citing works
“…by neutrophils themselves upon encountering bacteria (Bazzoni et al., 1991; Strieter et al., 1992), and in an autocrine fashion can exert stimulatory effects on oxidative burst function and release of granule enzymes amplifying bactericidal activity (Simms and D’Amico, 1997; Thelen et al., 1988).”
BackgroundLauth, X., Shike, H., Burns, J. C., Westerman, M. E., Ostland, V. E., Carlberg, J. M., Olst, J. C. V., Nizet, V., Taylor, S. W., Shimizu, C., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109173200 · Cited by 277 · cited 2× · see citing works
“At the end of the assay, wells were treated for 10 min with the fish antimicrobial peptide moronecidin (Lauth et al., 2002) at final concentration 4 mM to kill all extracellular bacteria and Sytox Orange added to final concentration 0.1 mM for staining of dead cells.”
MethodInfluentialSelf-citationChatellier, S., Ihendyane, N., Kansal, R. G., Khambaty, F. M., Basma, H., Norrby‐Teglund, A., Low, D. E., McGeer, A., & Kotb, M. (2000) · Infection and Immunity · doi:10.1128/iai.68.6.3523-3534.2000 · Cited by 270 · cited 5× · see citing works
“M protein dot blot analysis was performed on serial 10-fold dilutions of GAS cells using antibiodies directed at the N-terminal domain of the M1 protein (Chatellier et al., 2000).”
MethodInfluentialDoran, K. S., Liu, G. Y., & Nizet, V. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17335 · Cited by 262 · cited 1× · see citing works
“…will migrate directionally across a human microvascular endothelial cell monolayer, a process we and others have modeled in vitro using a transwell filter insert system (Doran et al., 2003; Edwards st & Microbe 4, 170–178, August 14, 2008 ª2008 Elsevier Inc. 171 et al., 2005; Yao et al., 1996).”
MethodSelf-citationCytokine-induced neutrophil-derived interleukin-8.
Strieter, R. M., Kasahara, K., Allen, R., Standiford, T. J., Rolfe, M. W., Becker, F. S., Chensue, S. W., & Kunkel, S. L. (1992) · PubMed Central · Cited by 253 · see citing works
C5a peptidase alters clearance and trafficking of group A streptococci by infected mice
Ji, Y., McLandsborough, L., Kondagunta, A., & Cleary, P. P. (1996) · Infection and Immunity · doi:10.1128/iai.64.2.503-510.1996 · Cited by 238 · cited 5× · see citing works
“…efficiently degraded the murine CXC chemokines KC and MIP-2 both in vitro and in vivo, impairing mouse neutrophil recruitment to a greater extent than the related GAS protease ScpA, which specifically targets the human complement-derived chemoattractant C5a (Cleary et al., 1992; Ji et al., 1996).”
BackgroundInfluentialEdwards, R. J., Taylor, G. W., Ferguson, M. J., Murray, S., Rendell, N. B., Wrigley, A., Bai, Z., Boyle, J. J., Finney, S. J., Jones, A. G., et al. (2005) · The Journal of Infectious Diseases · doi:10.1086/432485 · Cited by 201 · cited 4× · see citing works
“SpyCEP (also known as ScpC and PrtS) is a predicted 1645 amino acid protein that contains a C-terminal LP(X)TG cell wall anchor, and it was recently identified as a protease capable of degrading and functionally inactivating the major human CXC chemokine interleukin-8 (IL-8) (Edwards et al., 2005; Hidalgo-Grass et al.…”
BackgroundInfluentialSelf-citationCockerill, F. R. (1997) · JAMA · doi:10.1001/jama.1997.03540250046030 · Cited by 200 · cited 1× · see citing works
“…most prevalent sterile site isolates (Chatellier 170 Cell Host & Microbe 4, 170–178, August 14, 2008 ª2008 Elsevie et al., 2000; Cleary et al., 1998; Cockerill et al., 1997; Murono et al., 1999), as corroborated by the nine surveillance centers of the United States Centers for Disease Control…”
BackgroundStreptococcal C5a peptidase is a highly specific endopeptidase
Cleary, P. P., Prahbu, U., Dale, J. B., Wexler, D. E., & Handley, J. (1992) · Infection and Immunity · doi:10.1128/iai.60.12.5219-5223.1992 · Cited by 176 · see citing works
Datta, V., Myskowski, S. M., Kwinn, L. A., Chiem, D. N., Varki, N. M., Kansal, R. G., Kotb, M., & Nizet, V. (2005) · Molecular Microbiology · doi:10.1111/j.1365-2958.2005.04583.x · Cited by 176 · cited 2× · see citing works
“SpyCEP Contributes to GAS Virulence in a Murine Necrotic Skin Infection Models A murine subcutaneous challenge model can be used to examine the contribution of specific bacterial phentoypes to the virulence of M1T1 GAS in vivo (Buchanan et al., 2006; Datta et al., 2005; Sumby et al., 2005).”
BackgroundSelf-citationJeng, A., Sakota, V., Li, Z., Datta, V., Beall, B., & Nizet, V. (2003) · Journal of Bacteriology · doi:10.1128/jb.185.4.1208-1217.2003 · Cited by 164 · cited 3× · see citing works
“…chromosome using primers cepA-upF and cepA-downR, TA cloned into the Gateway-TOPO vector, then subcloned using L-R recombinase into pDestErm, a version of pDCerm (Jeng et al., 2003) engineered to contain L-R recombination sequences in its multiple cloning site, generating expression vector pcepA.”
MethodInfluentialSelf-citationHidalgo‐Grass, C., Mishalian, I., Dan‐Goor, M., Belotserkovsky, I., Eran, Y., Nizet, V., Peled, A., & Hanski, E. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601327 · Cited by 157 · cited 12× · see citing works
“176 Cell Host & Microbe 4, 170–178, August 14, 2008 a2008 Elsevie GAS cepA gene (Hidalgo-Grass et al., 2006).”
BackgroundMethodResultInfluentialSelf-citationHidalgo‐Grass, C., Dan‐Goor, M., Maly, A., Eran, Y., Kwinn, L. A., Nizet, V., Ravins, M., Jaffe, J., PEYSER, A. B., Moses, A. E., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15643-2 · Cited by 144 · cited 2× · see citing works
“These results find clinical correlation in the striking paucity of neutrophils at the site of infection that was observed in a subset of human cases of GAS NF consistent with a primary deficit in chemoattractant function (Cockerill et al., 1998; Hidalgo-Grass et al., 2004).”
Self-citationStreptococcus iniae Phosphoglucomutase Is a Virulence Factor and a Target for Vaccine Development
Buchanan, J. T., Stannard, J. A., Lauth, X., Ostland, V. E., Powell, H. C., Westerman, M. E., & Nizet, V. (2005) · Infection and Immunity · doi:10.1128/iai.73.10.6935-6944.2005 · Cited by 124 · cited 2× · see citing works
“iniae strain K288 was isolated from the brain of a moribund hybrid striped bass at the Kent SeaTech aquaculture facility (Buchanan et al., 2005).”
BackgroundSelf-citationDiVietro, J. A., Smith, M. J., Smith, B. R. E., Petruzzelli, L., Larson, R. A., & Lawrence, M. B. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.7.4017 · Cited by 113 · cited 1× · see citing works
“Not only does IL-8 act as potent chemoattractant (Kunkel et al., 1991), it also tethers itself to the luminal surface of the microvasculature providing a stop signal to rolling neutrophils (DiVietro et al., 2001; Middleton et al., 1997).”
BackgroundSumby, P., Zhang, S., Whitney, A. R., Falugi, F., Grandi, G., Graviss, E. A., DeLeo, F. R., & Musser, J. M. (2008) · Infection and Immunity · doi:10.1128/iai.01354-07 · Cited by 91 · cited 5× · see citing works
“The specificity of our assays was aided by the achievement of single gene replacement of cepA (independent of scpA) and single gene complementation that were technically unsuccessful, respectively, in other recent informative studies of the GAS IL-8 protease activity (HidalgoGrass et al., 2006; Sumby et al., 2008).”
BackgroundMethodInfluentialVoyich, J. M., Braughton, K. R., Sturdevant, D. E., Vuong, C., Kobayashi, S. D., Porcella, S. F., Otto, M. J., Musser, J. M., & DeLeo, F. R. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.2.1194 · Cited by 82 · cited 1× · see citing works
“The prominence of GAS among bacteria able to cause serious systemic infections even in previously healthy humans reflects the diverse capacities of this pathogen to avoid eradication by phagocyte defenses of the innate immune system (Kwinn and Nizet, 2007; Voyich et al., 2004).”
BackgroundStreptococcus iniaeVirulence Is Associated with a Distinct Genetic Profile
Fuller, J. D., Bast, D. J., Nizet, V., Low, D. E., & de Azavedo, J. C. S. (2001) · Infection and Immunity · doi:10.1128/iai.69.4.1994-2000.2001 · Cited by 77 · cited 2× · see citing works
“Like GAS, S. iniae is virulent in the murine subcutaneous infection model (Fuller et al., 2001).”
BackgroundSelf-citationDahl, P. R., Perniciaro, C., Holmkvist, K. A., O’Connor, M. I., & Gibson, L. E. (2002) · Journal of the American Academy of Dermatology · doi:10.1067/mjd.2002.120536 · Cited by 71 · cited 2× · see citing works
“However, in advanced human necrotic disease, prominent neutrophil infiltrates ultimately accumulate in association with proliferating bacteria (Dahl et al., 2002), as could be expected since additional microbial components (e.g., fMLP) and host inflammatory response proteins (e.g., C5a, platelet…”
BackgroundFournier's gangrene: ten-year experience in a medical center in northern Taiwan.
Kuo, C.-F., Wang, W., Lee, C.-M., Liu, C.-P., & Tseng, H.-K. (2007) · PubMed · Cited by 71 · see citing works
How Group A Streptococcus Circumvents Host Phagocyte Defenses
Kwinn, L. A., & Nizet, V. (2007) · Future Microbiology · doi:10.2217/17460913.2.1.75 · Cited by 66 · cited 1× · see citing works
“The prominence of GAS among bacteria able to cause serious systemic infections even in previously healthy humans reflects the diverse capacities of this pathogen to avoid eradication by phagocyte defenses of the innate immune system (Kwinn and Nizet, 2007; Voyich et al., 2004).”
BackgroundSelf-citationSerum opacity factor promotes group A streptococcal epithelial cell invasion and virulence
Timmer, A. M., Kristian, S. A., Datta, V., Jeng, A., Gillen, C. M., Walker, M. J., Beall, B., & Nizet, V. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05337.x · Cited by 64 · cited 1× · see citing works
“Using MOI = 5 bacteria/cell, cellular adherence and antibiotic protection (invasion) assays were performed as described (Timmer et al., 2006).”
MethodSelf-citationStreptococcus iniae β-hemolysin streptolysin S is a virulence factor in fish infection
Locke, J. B., Colvin, K. M., Varki, N. M., Vicknair, M. R., Nizet, V., & Jt, B. (2007) · Diseases of Aquatic Organisms · doi:10.3354/dao076017 · Cited by 60 · see citing works
Self-citationCockerill, F. R., Thompson, R. L., Musser, J. M., Schlievert, P. M., Talbot, J., Holley, K. E., Harmsen, W. S., Ilstrup, D. M., Kohner, P. C., Kim, M. H., et al. (1998) · Clinical Infectious Diseases · doi:10.1086/516376 · Cited by 56 · see citing works
Nobbs, A. H., Shearer, B., Drobni, M., Jepson, M. A., & Jenkinson, H. F. (2006) · Cellular Microbiology · doi:10.1111/j.1462-5822.2006.00768.x · Cited by 54 · cited 1× · see citing works
“An underlying mechanism may be found in the recent observation that GAS is capable of triggering IL-8 release from Hep-2 cells, and that the cytokine can promote GAS entry into cells (Nobbs et al., 2007); SpyCEP degradation of IL-8 would interfere with this pathway.”
BackgroundTaylor, F. B., Bryant, A. E., Blick, K. E., Hack, E., Jansen, P. M., Kosanke, S. D., & Stevens, D. L. (1999) · Clinical Infectious Diseases · doi:10.1086/520147 · Cited by 54 · cited 1× · see citing works
“Likewise, in a baboon model of GAS soft-tissue infection, the risk of septicemia and mortality was inversely correlated to the magnitude of neutrophil influx at the site of infection (Taylor et al., 1999).”
BackgroundInterleukin-8 gene expression in Staphylococcus aureus-infected endothelial cells
Yao, L., Lowy, F. D., & Berman, J. W. (1996) · Infection and Immunity · doi:10.1128/iai.64.8.3407-3409.1996 · Cited by 53 · cited 2× · see citing works
“…will migrate directionally across a human microvascular endothelial cell monolayer, a process we and others have modeled in vitro using a transwell filter insert system (Doran et al., 2003; Edwards st & Microbe 4, 170–178, August 14, 2008 ª2008 Elsevier Inc. 171 et al., 2005; Yao et al., 1996).”
BackgroundMethodCleary, P. P., LaPenta, D., Vessela, R., Lam, H., & Cue, D. R. (1998) · Infection and Immunity · doi:10.1128/iai.66.11.5592-5597.1998 · Cited by 53 · cited 1× · see citing works
“…over 20 years as the most prevalent sterile site isolates (Chatellier 170 Cell Host & Microbe 4, 170–178, August 14, 2008 ª2008 Elsevie et al., 2000; Cleary et al., 1998; Cockerill et al., 1997; Murono et al., 1999), as corroborated by the nine surveillance centers of the United States Centers…”
BackgroundDalton, T. L., Hobb, R. I., & Scott, J. R. (2006) · Microbial Pathogenesis · doi:10.1016/j.micpath.2006.01.005 · Cited by 50 · cited 2× · see citing works
“This comprehensive analysis showed that a frameshift mutation in the gene covS, encoding the sensor kinase component of an important GAS global transcriptional regulator (Dalton et al., 2006; Mitrophanov et al., 2006), resulted in striking effects on GAS gene expression including the upregulation of several proven or…”
BackgroundCloning and Analysis of the l -Lactate Utilization Genes from Streptococcus iniae
Gibello, A., Collins, M. D., Domı́nguez, L., Fernández‐Garayzábal, J. F., & Richardson, P. T. (1999) · Applied and Environmental Microbiology · doi:10.1128/aem.65.10.4346-4350.1999 · Cited by 38 · cited 2× · see citing works
“iniae) (Gibello et al., 1999), and upstream of genes with high similarity to spy_0421 and metG of M1 GAS (Ferretti et al.”
BackgroundControl of Streptococcus pyogenes virulence: Modeling of the CovR/S signal transduction system
Mitrophanov, A. Y., Churchward, G. G., & Borodovsky, M. Y. (2006) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2006.11.009 · Cited by 25 · cited 2× · see citing works
“This comprehensive analysis showed that a frameshift mutation in the gene covS, encoding the sensor kinase component of an important GAS global transcriptional regulator (Dalton et al., 2006; Mitrophanov et al., 2006), resulted in striking effects on GAS gene expression including the upregulation of several proven or…”
BackgroundPurushothaman, S. S., Park, H., & Cleary, P. P. (2004) · PubMed · Cited by 24 · see citing works
Murono, K., Fujita, K., Saijo, M., Hirano, Y., Zhang, J., & MURAI, T. (1999) · The Pediatric Infectious Disease Journal · doi:10.1097/00006454-199903000-00009 · Cited by 16 · cited 1× · see citing works
“…site isolates (Chatellier 170 Cell Host & Microbe 4, 170–178, August 14, 2008 ª2008 Elsevie et al., 2000; Cleary et al., 1998; Cockerill et al., 1997; Murono et al., 1999), as corroborated by the nine surveillance centers of the United States Centers for Disease Control Emerging Infections Program…”
BackgroundSTUDIES ON POLYMORPHONUCLEAR LEUKOCYTE BACTERICIDAL FUNCTION
Simms, H. H., & D'Amico, R. D. (1997) · Shock · doi:10.1097/00024382-199702000-00002 · Cited by 14 · cited 2× · see citing works
“, 1992), and in an autocrine fashion can exert stimulatory effects on oxidative burst function and release of granule enzymes amplifying bactericidal activity (Simms and D’Amico, 1997; Thelen et al., 1988).”
BackgroundBacteriology of necrotizing fasciitis: a review of 58 cases.
Ou, L. F., Yeh, F.-C., Fang, R. H., & Yu, K. W. (1993) · PubMed · Cited by 14 · see citing works
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Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus
Walker, M. J., Barnett, T. C., McArthur, J. D., Cole, J. N., Gillen, C. M., Henningham, A., Sriprakash, K. S., Sanderson-Smith, M. L., & Nizet, V. (2014) · Clinical Microbiology Reviews · doi:10.1128/cmr.00101-13 · Cited by 908 · see citing works
“killing (267) and enhances virulence a murine model of systemic”
BackgroundSelf-citationNuclease Expression by Staphylococcus aureus Facilitates Escape from Neutrophil Extracellular Traps
Berends, E. T. M., Horswill, A. R., Haste, N. M., Monestier, M., Nizet, V., & von Köckritz‐Blickwede, M. (2010) · Journal of Innate Immunity · doi:10.1159/000319909 · Cited by 491 · see citing works
Self-citationMolecular insight into invasive group A streptococcal disease
Cole, J. N., Barnett, T. C., Nizet, V., & Walker, M. J. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2648 · Cited by 375 · see citing works
Self-citationCorruption of Innate Immunity by Bacterial Proteases
Potempa, J., & Pike, R. N. (2008) · Journal of Innate Immunity · doi:10.1159/000181144 · Cited by 277 · see citing works
“Follow-up studies have identified the gene encoding Sly CEP and found that the protease shares an extensive homology to the well-known C5a peptidase (ScpA). In addition, it was shown that IL-8 Sly CEP cleaves the C-terminal domain of the murine CXC chemokines, KC and MIP-2, and is an essential factor for S. pyogenes p…”
BackgroundInnate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps
von Köckritz‐Blickwede, M., & Nizet, V. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0481-0 · Cited by 269 · see citing works
“Streptococcus pyogenes Reduction of NET production by IL-8 protease SpyCEP [ 51 ]”
BackgroundMethodSelf-citationUlfig, A., & Leichert, L. I. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03591-y · Cited by 239 · see citing works
von Schillde, M., Hörmannsperger, G., Weiher, M., Alpert, C.-A., Hahne, H., Bäuerl, C., Huynegem, K. V., Steidler, L., Hrnčíř, T., Pérez‐Martínez, G., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.02.006 · Cited by 234 · see citing works
Lauth, X., von Köckritz‐Blickwede, M., McNamara, C. W., Myskowski, S. M., Zinkernagel, A. S., Beall, B., Ghosh, P., Gallo, R. L., & Nizet, V. (2009) · Journal of Innate Immunity · doi:10.1159/000203645 · Cited by 182 · see citing works
“M1 protein also interferes with antibacterial peptides derived from human s-2 glycoprotein I, a heparin-binding plasma protein [ , ,”
BackgroundSelf-citationStaphylococcus aureus Manipulates Innate Immunity through Own and Host-Expressed Proteases
Pietrocola, G., Nobile, G., Rindi, S., & Speziale, P. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00166 · Cited by 178 · see citing works
“As consequence, SpyCEP impairs the recruitment of neutrophils at the site of infection and bacterial clearance (Zinkernagel et al., 2008).”
BackgroundBacterial Proteases and Virulence
Frees, D., Brøndsted, L., & Ingmer, H. (2013) · Subcellular Biochemistry · doi:10.1007/978-94-007-5940-4_7 · Cited by 159 · see citing works
Streptolysin S-like virulence factors: the continuing sagA
Molloy, E. M., Cotter, P. D., Hill, C., Mitchell, D. A., & Ross, R. P. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2624 · Cited by 152 · see citing works
“GAS is known to produce virulence factors that diminish the host's immune response to infectio”
IL-1β is an innate immune sensor of microbial proteolysis
LaRock, C. N., Todd, J., LaRock, D. L., Olson, J., O’Donoghue, A. J., Robertson, A. A. B., Cooper, M. A., Hoffman, H. M., & Nizet, V. (2016) · Science Immunology · doi:10.1126/sciimmunol.aah3539 · Cited by 150 · see citing works
Self-citationGetting under the Skin: The Immunopathogenesis of Streptococcus pyogenes Deep Tissue Infections
Johansson, L., Thulin, P., Low, D. E., & Norrby‐Teglund, A. (2010) · Clinical Infectious Diseases · doi:10.1086/653116 · Cited by 145 · see citing works
Bensi, G., Mora, M., Tuscano, G., Biagini, M., Chiarot, E., Bombaci, M., Capo, S., Falugi, F., Manetti, A. G. O., Donato, P., et al. (2012) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m111.015693 · Cited by 140 · see citing works
“5C), indicating that antibodies against this protein prevent the inhibition of neutrophil recruitment in vivo, thus favoring bacterial phagocytosis and killing (24, 25).”
BackgroundRocha, J. D. B., Nascimento, M. T. C., Decote-Ricardo, D., Côrte-Real, S., Morrot, A., Heise, N., Nunes, M. P., Previato, J. O., Mendonça-Previato, L., DosReis, G. A., et al. (2015) · Scientific Reports · doi:10.1038/srep08008 · Cited by 136 · see citing works
Cole, J. N., Pence, M. A., von Köckritz‐Blickwede, M., Hollands, A., Gallo, R. L., Walker, M. J., & Nizet, V. (2010) · mBio · doi:10.1128/mbio.00191-10 · Cited by 134 · see citing works
“The isogenic in-frame allelic exchange knockout mutants 5448 cepA (16), 5448 dltA (17), 5448 nga (13), 5448 emm1 (12), 5448 slo (13), 5448 lsa (18), 5448 speB (10), 5448 sagA (14), and 5448 pili (15) have been described previously.”
BackgroundSelf-citationWoytschak, J., Keller, N., Krieg, C., Impellizzieri, D., Thompson, R. W., Wynn, T. A., Zinkernagel, A. S., & Boyman, O. (2016) · Immunity · doi:10.1016/j.immuni.2016.06.025 · Cited by 121 · see citing works
“As previously published, subcutaneous inoculation of GAS led to a large skin lesionwithin 48 hr, with further progression after 72 hr (Figure 1A).”
MethodInfluentialSelf-citationEvasion of Neutrophil Extracellular Traps by Respiratory Pathogens
Storisteanu, D. M. L., Pocock, J., Cowburn, A. S., Juss, J. K., Nadesalingam, A., Nizet, V., & Chilvers, E. R. (2017) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2016-0193ps · Cited by 112 · see citing works
Self-citationTowards Control ofStreptococcus iniae
Baiano, J. C. F., & Barnes, A. C. (2009) · Emerging infectious diseases · doi:10.3201/eid1512.090232 · Cited by 108 · see citing works
“It is encoded by the cepI gene, resulting in a 1,631-aa protein with a C-terminal LPXTG gram-positive anchor motif and is homologous to the cepA gene in GAS (20).”
BackgroundRamírez-Larrota, J. S., & Eckhard, U. (2022) · Biomolecules · doi:10.3390/biom12020306 · Cited by 108 · see citing works
Streptococcal toxins: role in pathogenesis and disease
Barnett, T. C., Cole, J. N., Rivera-Hernández, T., Henningham, A., Paton, J. C., Nizet, V., & Walker, M. J. (2015) · Cellular Microbiology · doi:10.1111/cmi.12531 · Cited by 102 · see citing works
“SpyCEP also promotes resistance to neutrophil killing by reducing 2015 John Wiley & Sons Ltd, Cellular Microbiology, 17, 1721–1741 the production of neutrophil extracellular traps (Zinkernagel et al., 2008).”
BackgroundInfluentialSelf-citationHollands, A., Pence, M. A., Timmer, A. M., Osvath, S. R., Turnbull, L., Whitchurch, C. B., Walker, M. J., & Nizet, V. (2010) · The Journal of Infectious Diseases · doi:10.1086/653124 · Cited by 101 · see citing works
“Specific point mutations in covR/S and truncation mutations in covS result in considerable down-regulation of SpeB expression but concurrent up-regulation of many virulence factor genes, including those encoding Sda1, interleukin 8 protease SpyCEP, streptolysin O, streptococcal inhibitor of complement, and the hyaluro…”
BackgroundSelf-citationda Silva, F. P., & Nizet, V. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0320-3 · Cited by 99 · see citing works
“The presence and kinetics of free circulating neutrophilderived DNA/NETs appear to serve as a useful marker of sepsis disease severity and multiple organ failure in patients following multiple traumas [84].”
BackgroundInfluentialSelf-citationZnO and TiO2 nanoparticles as novel antimicrobial agents for oral hygiene: a review
Khan, S. T., Al-Khedhairy, A. A., & Musarrat, J. (2015) · Journal of Nanoparticle Research · doi:10.1007/s11051-015-3074-6 · Cited by 100 · see citing works
“…(Höglund et al. 2014), proteases like immunoglobulin A1 protease, IL-8 protease (Cole et al. 1994; Frandsen et al. 1986; Kolenbrander et al. 2002; Zinkernagel et al. 2008), and glycosidases (Bradshaw et al. 1994) in addition to the substances required for their binding on oral surfaces such as…”
BackgroundClindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome
Andreoni, F., Zürcher, C., Tarnutzer, A., Schilcher, K., Neff, A., Keller, N., Maggio, E. M., Poyart, C., Schuepbach, R. A., & Zinkernagel, A. S. (2016) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiw229 · Cited by 96 · see citing works
“present in the skin lesions were enumerated [19].”
BackgroundMethodSelf-citationEffect of posttranslational processing on the in vitro and in vivo activity of chemokines
Mortier, A., Gouwy, M., Damme, J. V., & Proost, P. (2010) · Experimental Cell Research · doi:10.1016/j.yexcr.2010.11.016 · Cited by 94 · see citing works
“[70] A.”
BackgroundA decade of molecular pathogenomic analysis of group A Streptococcus
Musser, J. M., & Shelburne, S. A. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38095 · Cited by 86 · see citing works
Kurupati, P., Turner, C. E., Tziona, I., Lawrenson, R. A., Alam, F. M., Nohadani, M., Stamp, G., Zinkernagel, A. S., Nizet, V., Edwards, R. J., et al. (2010) · Molecular Microbiology · doi:10.1111/j.1365-2958.2010.07065.x · Cited by 85 · see citing works
“…peptidases (scpA and B), which do not cleave chemokines (Hill et al., 1988; Cleary et al., 1992), and a separate family of CXC chemokine-cleaving cell envelope proteinases (CEPs), which do not cleave C5a (Harris et al., 2003; Zinkernagel et al., 2008; Bryan and Shelver, 2009; Turner et al., 2009b).”
InfluentialSelf-citationEmerging Role of the Interleukin‐8 Cleaving Enzyme SpyCEP in ClinicalStreptococcus pyogenesInfection
Turner, C. E., Kurupati, P., Jones, M. D., Edwards, R. J., & Sriskandan, S. (2009) · The Journal of Infectious Diseases · doi:10.1086/603541 · Cited by 85 · see citing works
“This finding is consistent with the findings of Zinkernagal et al [6] and Hidalgo-Grass et al [22], who demonstrated that mutagenesis of cepA (or scpC) led to attenuation of infection severity in mouse models.”
Self-citationA brief review on Group A Streptococcus pathogenesis and vaccine development
Castro, S. A., & Dorfmueller, H. C. (2021) · Royal Society Open Science · doi:10.1098/rsos.201991 · Cited by 79 · see citing works
Enteric bacterial proteases in inflammatory bowel disease- pathophysiology and clinical implications
Carroll, I. M. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i43.7531 · Cited by 82 · see citing works
Turner, C. E., Kurupati, P., Wiles, S., Edwards, R. J., & Sriskandan, S. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.06.042 · Cited by 79 · see citing works
Self-citationOkumura, C. Y. M., & Nizet, V. (2014) · Annual Review of Microbiology · doi:10.1146/annurev-micro-092412-155711 · Cited by 76 · see citing works
“NETs: neutrophil extracellular traps, an antimicrobial decondensed chromatin structure released from neutrophils containing histones, AMPs, and granule proteases (137), whereas GBS produces a similar serine protease (CspA), which cleaves the related CXC chemokines Gro-α, Gro-β, and Gro-γ (15).”
Self-citationFritzer, A., Senn, B. M., Minh, D. B., Hanner, M., Gelbmann, D., Noiges, B., Henics, T., Schulze, K., Guzmán, C. A., GOODACRE, J. A., et al. (2010) · Infection and Immunity · doi:10.1128/iai.00295-10 · Cited by 72 · see citing works
Neutrophil extracellular traps in bacterial infections and evasion strategies
Baz, A. A., Hao, H., Lan, S., Li, Z., Liu, S., Chen, S., & Chu, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1357967 · Cited by 76 · see citing works
Yung, S. C., & Murphy, P. M. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00276 · Cited by 69 · see citing works
Kansal, R. G., Datta, V., Aziz, R. K., Abdeltawab, N. F., Rowe, S., & Kotb, M. (2010) · The Journal of Infectious Diseases · doi:10.1086/651019 · Cited by 67 · see citing works
Mattioda, V., Benedetti, V., Tessarolo, C., Oberto, F., Favole, A., Gallo, M., Martelli, W., Crescio, M. I., Berio, E., Masoero, L., et al. (2023) · Biomolecules · doi:10.3390/biom13010140 · Cited by 70 · see citing works
“IL-8 is an important chemokine involved in neutrophil recruitment during the acute inflammatory response, which plays similar roles in humans and mice; in particular, IL-8 (also called CXCL-8) has important functions as a chemotactic factor by attracting neutrophils, basophils and T-cells to clear pathogens and protec…”
BackgroundAlexander, L. E. C., Maisey, H. C., Timmer, A. M., Rooijakkers, S. H. M., Gallo, R. L., von Köckritz‐Blickwede, M., & Nizet, V. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0566-9 · Cited by 66 · see citing works
“Upon in vivo selection, two of the most strongly upregulated GAS M1T1 genes, the IL-8 peptidase SpyCEP and the phage-encoded DNAse Sda1, promote resistance to NET-mediated killing, by blocking IL-8 stimulation of NET production and by degrading the DNA backbone of NETs, respectively [23, 35, 45].”
Self-citationAzuar, A., Jin, W., Mukaida, S., Hussein, W. M., Tóth, I., & Skwarczyński, M. (2019) · Vaccines · doi:10.3390/vaccines7030058 · Cited by 65 · see citing works
“SpyCEP purified from an M81 GAS strain cleaved the C-terminus of IL-8 at residues Glu59 and Arg60 and inactivated its chemotactic properties [114].”
BackgroundAmelung, S., Nerlich, A. G., Rohde, M., Spellerberg, B., Cole, J. N., Nizet, V., Chhatwal, G. S., & Talay, S. R. (2011) · Cellular Microbiology · doi:10.1111/j.1462-5822.2011.01610.x · Cited by 63 · see citing works
“An in-frame allelic exchange of fbaB with chloramphenicol acetyltransferase (cat) was obtained in S. pyogenes A60 by using the method previously described (Zinkernagel et al., 2008).”
Self-citationLynskey, N. N., Goulding, D., Gierula, M., Turner, C. E., Dougan, G., Edwards, R. J., & Sriskandan, S. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003842 · Cited by 62 · see citing works
“Results were validated by western blot for a selection of differentially expressed proteins using rabbit anti-sera raised against SpyCEP [48], NADP-G3PD, HSP70 and fructose bis-phosphate aldolase [47] (Figure S2).”
MethodInfluentialSelf-citationEgesten, A., Olin, A. I., Linge, H. M., Yadav, M. C., Mörgelin, M., Karlsson, A., & Collin, M. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004769 · Cited by 62 · see citing works
“pyogenes has recently been shown to produce another interesting protease, the cell wall-anchored serine protease, SpyCEP, that degrades the CXC chemokine, IL-8/CXCL8, and thus promotes resistance against of neutrophil killing [38,39,40,41].”
Pandey, M., Langshaw, E. L., Hartas, J., Lam, A. K.-Y., Batzloff, M. R., & Good, M. F. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500157 · Cited by 60 · see citing works
“This strain has upregulated SpyCEP, which degrades CXC chemokines (14, 27, 38, 39), resulting in reduced CXC-induced neutrophil transmigration and, thus, conferring resistance to GAS killing by isolated neutrophils (38).”
BackgroundSchilcher, K., Andreoni, F., Uchiyama, S., Ogawa, T., Schuepbach, R. A., & Zinkernagel, A. S. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu091 · Cited by 58 · see citing works
Self-citationThe contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis
Reglinski, M., & Sriskandan, S. (2013) · Virulence · doi:10.4161/viru.26400 · Cited by 59 · see citing works
Self-citationExtracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection
Siggins, M. K., Lynskey, N. N., Lamb, L., Johnson, L. A., Huse, K. K., Pearson, M., Banerji, S., Turner, C. E., Woollard, K. J., Jackson, D. G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18454-0 · Cited by 59 · see citing works
Self-citationStreptococcus iniae SF1: Complete Genome Sequence, Proteomic Profile, and Immunoprotective Antigens
Zhang, B., Zhang, J., & Sun, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091324 · Cited by 57 · see citing works
“iniae have been reported to contribute to pathogenicity by breaking down host immunoproteins [93].”
BackgroundZingaretti, C., Falugi, F., Nardi‐Dei, V., Pietrocola, G., Mariani, M., Liberatori, S., Tontini, M., Tani, C., Speziale, P., Grandi, G., et al. (2010) · The FASEB Journal · doi:10.1096/fj.09-145631 · Cited by 56 · see citing works
Responses of innate immune cells to group A Streptococcus.
Fieber, C., & Kovarik, P. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00140 · Cited by 56 · see citing works
Epidermal hepcidin is required for neutrophil response to bacterial infection
Malerba, M., Louis, S., Cuvellier, S., Shambat, S. M., Hua, C., Gomart, C., Fouet, A., Ortonne, N., Decousser, J.-W., Zinkernagel, A. S., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci126645 · Cited by 55 · see citing works
“One of the principal mechanisms of GAS-immune escape is the production of 6 surface-associated serine proteases by GAS, such as SpyCEP (also designated ScpC), that 7 cleaves human IL-8/mouse CXCL1 to suppress chemokine-mediated neutrophil recruitment 8 (17) or SpeB, which allows GAS to translocate across the epithelia…”
BackgroundSelf-citationStreptococcus agalactiae CspA Is a Serine Protease That Inactivates Chemokines
Bryan, J. D., & Shelver, D. W. (2008) · Journal of Bacteriology · doi:10.1128/jb.01124-08 · Cited by 55 · see citing works
“In relation to noninvasive isolates, invasive GAS isolates produce high levels of SpyCEP/ ScpC, and this protease has been implicated in necrotizing fasciitis (8).”
BackgroundInfluentialDöhrmann, S., Cole, J. N., & Nizet, V. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005682 · Cited by 52 · see citing works
“SpyCEP enhances GAS resistance to neutrophil killing and is required for full virulence in a mouse model of systemic GAS infection [8,9].”
BackgroundSelf-citationSoderholm, A. T., Barnett, T. C., Sweet, M. J., & Walker, M. J. (2018) · Journal of Leukocyte Biology · doi:10.1189/jlb.4mr0617-227rr · Cited by 51 · see citing works
Recruited Macrophages Control Dissemination of Group A Streptococcus from Infected Soft Tissues
Mishalian, I., Ordan, M., Peled, A., Maly, A., Eichenbaum, M. B., Ravins, M., Aychek, T., Jung, S., & Hanski, E. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1101385 · Cited by 52 · see citing works
Self-citationShumba, P., Shambat, S. M., & Siemens, N. (2019) · Toxins · doi:10.3390/toxins11060332 · Cited by 55 · see citing works
“Moreover, SpyCEP promotes resistance to phagocytic clearance of bacteria by reducing formation of NETs [189].”
BackgroundInfluentialMeyers, S., Crescente, M., Verhamme, P. B., & Martinod, K. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.316930 · Cited by 51 · see citing works
Staphylococcus aureus versus neutrophil: Scrutiny of ancient combat
Nasser, A., Moradi, M., Jazireian, P., Safari, H., Sani, M. A., Pourmand, M. R., & Azimi, T. (2019) · Microbial Pathogenesis · doi:10.1016/j.micpath.2019.04.026 · Cited by 49 · see citing works
How microorganisms avoid phagocyte attraction
Bestebroer, J., de Haas, C. J. C., & van Strijp, J. A. G. (2009) · FEMS Microbiology Reviews · doi:10.1111/j.1574-6976.2009.00202.x · Cited by 48 · see citing works
“These data were very recently confirmed by Zinkernagel et al. (2008), who demonstrated that the knockout mutant lacking SpyCEP was attenuated for virulence in murine infection models.”
ResultPandey, M., Mortensen, R. J., Calcutt, A., Powell, J. L., Batzloff, M. R., Dietrich, J., & Good, M. F. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501994 · Cited by 48 · see citing works
“pyogenes cell envelope proteinase (SpyCEP) (8, 9).”
BackgroundEislmayr, K., Bestehorn, A., Morelli, L., Borroni, M., Walle, L. V., Lamkanfi, M., & Kovarik, P. (2022) · Science Advances · doi:10.1126/sciadv.abj7293 · Cited by 47 · see citing works
Miller, E. W., Danger, J. L., Ramalinga, A., Horstmann, N., Shelburne, S. A., & Sumby, P. (2015) · Molecular Microbiology · doi:10.1111/mmi.13136 · Cited by 44 · see citing works
“, 1996), the chemokine protease (SpyCEP/ScpC) (Zinkernagel et al., 2008), Mac (Mac/ IdeS) (Lei et al.”
BackgroundBonifait, L., Vaillancourt, K., Gottschalk, M. G., Frenette, M., & Grenier, D. (2010) · Veterinary Microbiology · doi:10.1016/j.vetmic.2010.09.024 · Cited by 44 · see citing works
“Many reports have been published showing that subtilisin-like proteases produced by pathogenic streptococci are able to degrade natural proteins (Edwards et al., 2005; Harris et al., 2003; Hidalgo-Grass et al., 2006; Karlsson et al., 2007; Zinkernagel et al., 2008).”
BackgroundLiu, M., Zhu, H. F., Li, J., Garcia, C. C., Feng, W., Kirpotina, L. N., Hilmer, J. K., Tavares, L. P., Layton, A. W., Quinn, M. T., et al. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002624 · Cited by 44 · see citing works
“neutrophil recruitment by degrading the chemotactic C5a peptide and IL-8/CXC chemokines, respectively [2,3,4,5].”
BackgroundLandoni, V. I., Chiarella, P., Martire‐Greco, D., Schierloh, P., van Rooijen, N., Rearte, B., Palermo, M. S., Isturiz, M. A., & Fernández, G. C. (2012) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2012.04560.x · Cited by 46 · see citing works
Li, J., Liu, G., Feng, W., Zhou, Y., Liu, M., Wiley, J. A., & Lei, B. (2014) · Infection and Immunity · doi:10.1128/iai.01458-13 · Cited by 42 · see citing works
Hurst, J. R., Shannon, B. A., Craig, H. C., Rishi, A., Tuffs, S. W., & McCormick, J. K. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1011013 · Cited by 43 · see citing works
“pyogenes [63], we show that depleting neutrophils 378 or macrophages did not affect wildtype S.”
BackgroundGood, M. F., Pandey, M., Batzloff, M. R., & Tyrrell, G. J. (2015) · Expert Review of Vaccines · doi:10.1586/14760584.2015.1081817 · Cited by 39 · see citing works
“SpyCEP has also been explored as a GAS vaccine candidate [69,93].”
BackgroundDöhrmann, S., Anik, S., Olson, J., Anderson, E. L., Etesami, N. S., No, H., Snipper, J., Nizet, V., & Okumura, C. Y. M. (2014) · Infection and Immunity · doi:10.1128/iai.01921-14 · Cited by 36 · see citing works
“A significant portion of the global burden of invasive GAS disease is attributable to the prevalent M1T1 clone (4, 5), which encodes multiple immune evasion genes, including factors that impede neutrophil recruitment, limit phagocytosis (6, 7), resist antimicrobial peptides (8, 9), and degrade NETs (10, 11).”
BackgroundSelf-citationInteraction of Bacterial Exotoxins with Neutrophil Extracellular Traps: Impact for the Infected Host
von Köckritz‐Blickwede, M., Blodkamp, S., & Nizet, V. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00402 · Cited by 34 · see citing works
“out by released factors including proteases (Zinkernagel et al., 2008).”
Self-citationLaRock, D. L., Russell, R., Johnson, A. F., Wilde, S., & LaRock, C. N. (2020) · Infection and Immunity · doi:10.1128/iai.00356-20 · Cited by 34 · see citing works
“Many virulence factors important at other body sites are also essential at this site, including capsule (18), superantigens (14), SpyCEP (19), ScpA (15), and the regulator CovRS (13).”
BackgroundGenetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse
Krishnan, K. C., Mukundan, S., Alagarsamy, J., Hur, J., Nookala, S., Siemens, N., Svensson, M., Hyldegaard, O., Norrby‐Teglund, A., & Kotb, M. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005732 · Cited by 33 · see citing works
“Although GAS causes NSTIs in humans, successful animal models have been developed through the use of conventional inbred and outbred mouse strains; however, mice are generally more resistant to GAS NSTIs than humans and thus require higher initial GAS inoculum than humans to develop NSTIs [16 – 23].”
Streptococcus iniae in aquaculture: a review of pathogenesis, virulence, and antibiotic resistance
Juárez-Cortés, M. Z., Vázquez, L. E. C., Martínez‐Díaz, S. F., & Cardona-Félix, C. S. (2024) · International Journal of Veterinary Science and Medicine · doi:10.1080/23144599.2024.2348408 · Cited by 34 · see citing works
“Another virulence factor on the cell surface is the polysaccharide deacetylase encoded by the Pdi gene, this polysaccharide gives the bacterium resistance to lysozyme destruction and provides it with the ability to adhere to and invade epithelial cells [76].”
Biswas, D., Ambalavanan, P., Ravins, M., Anand, A., Sharma, A., Lim, K. X. Z., Tan, R. Y. M., Lim, H. Y., Sol, A., Bachrach, G., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108766 · Cited by 33 · see citing works
Self-citationPlaying With Fire: Proinflammatory Virulence Mechanisms of Group A Streptococcus
Wilde, S., Johnson, A. F., & LaRock, C. N. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.704099 · Cited by 33 · see citing works
Li, J., Zhu, H. F., Feng, W., Liu, M., Song, Y., Zhang, X., Zhou, Y., Bei, W., & Lei, B. (2013) · Infection and Immunity · doi:10.1128/iai.01218-12 · Cited by 32 · see citing works
“The competitive growth result of the spyCEP mutant confirms the previous results (10, 37).”
BackgroundResultInfluentialImportance of Toll-Like Receptor 9 in Host Defense against M1T1 Group A Streptococcus Infections
Zinkernagel, A. S., Hruz, P. L., Uchiyama, S., von Köckritz‐Blickwede, M., Schuepbach, R. A., Hayashi, T., Carson, D. A., & Nizet, V. (2011) · Journal of Innate Immunity · doi:10.1159/000329550 · Cited by 32 · see citing works
Self-citationOkumura, C. Y. M., Anderson, E. L., Döhrmann, S., Tran, D. N., Olson, J., von Pawel‐Rammingen, U., & Nizet, V. (2013) · mBio · doi:10.1128/mbio.00499-13 · Cited by 31 · see citing works
“These factors include the surface hyaluronic acid capsule, the pore-forming hemolysin streptolysin O, DNase Sda1, the streptococcal inhibitor of complement (SIC), and the interleukin-8 (IL-8) peptidase SpyCEP.”
BackgroundSelf-citationSarkar, P., & Sumby, P. (2016) · Molecular Microbiology · doi:10.1111/mmi.13584 · Cited by 30 · see citing works
“For example, the capsule has antiphagocytic properties (Wessels and Bronze, 1994) while SpyCEP reduces neutrophil migration and activation by degrading chemokine gradients (Zinkernagel et al., 2008).”
Li, M.-F., Zhang, B., Li, J., & Sun, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096222 · Cited by 30 · see citing works
The intricate pathogenicity of Group A Streptococcus : A comprehensive update
Bergsten, H., & Nizet, V. (2024) · Virulence · doi:10.1080/21505594.2024.2412745 · Cited by 30 · see citing works
“This activity significantly hinders the recruitment of neutrophils to infection sites (Figure 2), thereby facilitating the persistence and spread of GAS [128,129].”
BackgroundSelf-citationThacharodi, A., Hassan, S., Vithlani, A., Ahmed, T., Kavish, S., Blacknell, N.-M. G., Alqahtani, A., & Pugazhendhi, A. (2024) · iScience · doi:10.1016/j.isci.2024.111677 · Cited by 29 · see citing works
Chiappini, N., Seubert, A., Telford, J. L., Grandi, G., Serruto, D., Margarit, I., & Janulczyk, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040411 · Cited by 29 · see citing works
“Previous work has suggested that mutants lacking spyCEP are less virulent in animal models, although there are conflicting results [4,7–11].”
ResultDipotassium Glycyrrhizininate Improves Skin Wound Healing by Modulating Inflammatory Process
Leite, C. D. S., Bonafé, G. A., Pires, O. C., dos Santos, T. W., Pereira, G. P., Pereira, J. A., Rocha, T., Martinez, C. A. R., Ortega, M. M., & Ribeiro, M. L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043839 · Cited by 30 · see citing works
“IL-8 is expressed by leukocytes, monocytes, and macrophages, and to a lesser extent by fibroblasts, endothelial cells, and keratinocytes [87].”
BackgroundStreptococcus pyogenes Hijacks Host Glutathione for Growth and Innate Immune Evasion
Brouwer, S., Jespersen, M. G., Ong, C. Y., Oliveira, D. M. P. D., Keller, B., Cork, A. J., Djoko, K. Y., Davies, M. R., & Walker, M. J. (2022) · mBio · doi:10.1128/mbio.00676-22 · Cited by 28 · see citing works
“Other downregulated virulence genes included sdaB , encoding streptodornase B SdaB/MF-1 (39), and scpC , encoding the interleukin 8 (IL-8) protease SpyCEP/ScpC (40).”
BackgroundFiebig, A., Loof, T. G., Babbar, A., Itzek, A., Koehorst, J. J., Schaap, P. J., & Nitsche-Schmitz, D. P. (2015) · International Journal of Medical Microbiology · doi:10.1016/j.ijmm.2015.06.002 · Cited by 28 · see citing works
Two-photon microscopy of host-pathogen interactions: acquiring a dynamic picture of infectionin vivo
Konjufca, V. H., & Miller, M. J. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01289.x · Cited by 26 · see citing works
“…inhibition of complement (Lambris et al., 2008), downregulation of major histocompatibility complexes (Antoniou and Powis, 2008), suppressing chemokine signalling by secretion of decoy receptors (Alexander-Brett and Fremont, 2007) and proteases (Zinkernagel et al., 2008), as well as many others.”
BackgroundMechanisms and immune crosstalk of neutrophil extracellular traps in response to infection
Liu, Q., Chen, R., Zhang, Z., Sha, Z., & Wu, H. (2025) · mBio · doi:10.1128/mbio.00189-25 · Cited by 27 · see citing works
“For instance, the cysteine protease SpyCEP from group A Streptococcus (GAS) can cleave IL-8, while its functional homolog, CepI, found in the zoonotic pathogen Streptococcus suis , also targets IL-8, enhancing bacterial virulence (44).”
Degradation of interleukin 8 by the serine protease MucD of Pseudomonas aeruginosa
Okuda, J., Hayashi, N., Minagawa, S., Gotoh, N., & Tanabe, S. (2011) · Journal of Infection and Chemotherapy · doi:10.1007/s10156-011-0257-7 · Cited by 27 · see citing works
“Group A Streptococcus (GAS) is known to secrete an IL-8-degrading protease [24–26].”
BackgroundNozawa, T., Iibushi, J., Toh, H., Minowa‐Nozawa, A., Murase, K., Aikawa, C., & Nakagawa, I. (2021) · mBio · doi:10.1128/mbio.01974-20 · Cited by 28 · see citing works
Evolutionary inactivation of a sialidase in group B Streptococcus
Yamaguchi, M., Hirose, Y., Nakata, M., Uchiyama, S., Yamaguchi, Y., Goto, K., Sumitomo, T., Lewis, A. L., Kawabata, S., & Nizet, V. (2016) · Scientific Reports · doi:10.1038/srep28852 · Cited by 26 · see citing works
Self-citationMcKenna, S., Malito, E., Rouse, S. L., Abate, F., Bensi, G., Chiarot, E., Micoli, F., Mancini, F., Moriel, D. G., Grandi, G., et al. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.03.004 · Cited by 26 · see citing works
“However, SpyCEP can be released from the bacterial surface as a soluble enzyme and it is likely that flexibility in the C-terminal linker plays a role in facilitating this event [6,8].”
BackgroundSelf-citationSoderholm, A. T., Barnett, T. C., Korn, O., Rivera-Hernández, T., Seymour, L. M., Schulz, B. L., Nizet, V., Wells, C. A., Sweet, M. J., & Walker, M. J. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00160 · Cited by 25 · see citing works
“…by previous studies as a serine protease that cleaves the human chemokines CXCL1, CXCL2, CXCL6, and CXCL8/IL-8, abrogating their biological activity, and enabling resistance of GAS to phagocytic clearance (Edwards et al., 2005; Sumby et al., 2008; Zinkernagel et al., 2008; Turner et al., 2009).”
BackgroundMethodInfluentialSelf-citationGoldblatt, J., Lawrenson, R. A., Muir, L., Dattani, S., Hoffland, A., Tsuchiya, T., Kanegasaki, S., Sriskandan, S., & Pease, J. E. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801688 · Cited by 25 · see citing works
“The prominence of SpyCEP among GAS virulence factors has been ably demonstrated by loss-of-function and gainof-function analyses (15, 16).”
BackgroundSelf-citationMoustafa, E. M., Farrag, F. A., Dawood, M. A. O., Shahin, K., Hamza, A., Decamp, O., Mohamed, R. A., Elsabagh, M., Eltholth, M. M., & Omar, A. A. E.-D. (2020) · Aquaculture Research · doi:10.1111/are.15073 · Cited by 24 · see citing works
Richter, J., Monteleone, M. M., Cork, A. J., Barnett, T. C., Nizet, V., Brouwer, S., Schroder, K., & Walker, M. J. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12499 · Cited by 23 · see citing works
Self-citationSemen microbiota and cytokines of healthy and infertile men
Ov, B., Nb, P., Ivanova, E. V., Chaynikova, I. N., Bekpergenova, A. V., Bondarenko, T. A., & Kuzmin, M. D. (2021) · Asian Journal of Andrology · doi:10.4103/aja202169 · Cited by 24 · see citing works
Xing, X., Bi, S., Fan, X., Jin, M., Liu, W., & Wang, B. (2019) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiz352 · Cited by 23 · see citing works
Movert, E., Wu, Y., Lambeau, G. J., Touqui, L., & Areschoug, T. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100499 · Cited by 21 · see citing works
Kaur, S. J., Nerlich, A. G., Bergmann, S., Rohde, M., Fulde, M., Zähner, D., Hanski, E., Zinkernagel, A. S., Nizet, V., Chhatwal, G. S., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.098053 · Cited by 22 · see citing works
Self-citation
- Authors
- Zinkernagel, A. S., Timmer, A. M., Pence, M. A., Locke, J. B., Buchanan, J. T., Turner, C. E., Mishalian, I., Sriskandan, S., Hanski, E., & Nizet, V.
- Affiliations
- Imperial College London (GB)
- Hebrew University of Jerusalem (IL)
- University of California San Diego (US)
- Corresponding author
- Hanski, Emanuel
- Nizet, Victor
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 4
- Issue
- 2
- Pages
- 170-178
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC2631432
- OpenAlex
- W2078710694
- Cited by
- 184
- References
- 55
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 19 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 11 · 2014: 13 · 2013: 10 · 2012: 8
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1811 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, San Diego
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (AI077780, R01AI077780)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052728)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Streptococcal Infections and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Neonatal and Maternal Infections
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- SCPC, Streptococcus pyogenes, interleukin-8, neutrophil killing, neutrophil extracellular traps, neutrophil transmigration, bacterial virulence, Streptococcus iniae, CEPI, necrotizing fasciitis, invasive streptococcal infection, co-infection
- MeSH terms
- Animals, Cells, Cultured, Humans, Mice, Inbred C57BL, Neutrophils, Peptide Hydrolases, Skin, Streptococcal Infections, Streptococcus, Streptococcus pyogenes, Virulence, Interleukin-8, Endothelial Cells, Mice, Host-Pathogen Interactions
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