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A Host Proteome Atlas of Streptococcus pyogenes Infection
Cell Systems
Preview A Host Proteome Atlas of Streptococcus pyogenes Infection Amelia T. Soderholm1 and Mark J. Walker1,2,* 1School
of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia Infectious Diseases Research Centre, University of Queensland, St. Lucia, QLD 4072, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.cels.2018.05.003 2Australian
Multiplex quantitative proteomics analysis of mice infected with Group A Streptococcus reveals organ-specific biomarkers of infection. Group A Streptococcus (GAS) causes common superficial infections such as pharyngitis and impetigo. However, much less common invasive infections in humans are responsible for significant morbidity and mortality globally each year (Walker et al., 2014). As the host signaling pathways and components engaged during GAS infection are not well characterized, in this issue of Cell Systems, Lapek et al. (2018) investigated the host response by identifying organspecific changes in protein levels during GAS systemic murine infection. Organspecific infection markers revealed that a robust response to infection was initiated across all organs examined. Several organ-specific markers could be detected in GAS-infected human patient blood samples, indicating the potential clinical relevance of these findings. This study provides a significant advance in our understanding of the dynamic host proteome during GAS infection, and the quantitative proteomics methodology employed can be readily adapted to investigate host proteomic responses to numerous other pathogens. To define organ-specific host responses to infection, Lapek et al. (2018) infected mice with GAS or a mock treatment and then performed quantitative proteomic analysis of organs from these mice, including brain, heart, lungs, kidney, spleen, liver, and blood. In total, 11,394 proteins were detected across all organs and treatments, and the protein abundances detected enabled samples to be grouped according to organ type and treatment (GAS or mock-infected), with the exception of the brain. This was likely due to the inability of GAS to cross the blood-brain barrier, as infection with the blood-brain permeable
Group B Streptococcus enabled clustering of brain proteome data according to treatment condition. Organ-specific markers of infection were identified by an organ-by-organ binary approach, with proteins deemed organ-specific markers of infection if they were at least 2-fold higher or lower in response to infection within that organ only, at Benjamini-Hochberg false discovery rate of <0.01. To identify the most robust organ-specific markers, the authors performed an outlier analysis in parallel, and proteins detected by both approaches were termed markers of systemic infection (MSI). To visualize the dynamic changes in host protein levels during GAS infection, Lapek et al. used organ-specific infection markers identified by either statistical method to construct an atlas of proteinprotein interaction networks. Regardless of organ, most markers were found to be highly connected in both upregulated and downregulated protein sets, suggesting that proteins are functionally regulated at the complex or pathway level. Upregulated pathways included the complement and coagulation cascades, which are known to play important roles during GAS infection. For example, GAS escapes being sequestered by the coagulation pathway through the expression of streptokinase (Cook et al., 2012, McArthur et al., 2008). The mTOR pathway, which is inhibited by inflammatory cytokines, was found to be downregulated, while the proteasome, which is involved in the activation of inflammatory proteins, was upregulated. These findings provide further evidence to indicate that a robust pro-inflammatory response against GAS is being mounted during infection.
536 Cell Systems 6, May 23, 2018 ª 2018 Elsevier Inc.
Given that GAS infection is associated with numerous sequelae and complications that afflict different organs, a key aim of this study was to gain insight into the disease processes that occur in each organ during GAS infection (Figure 1). Rheumatic heart disease is a common immune sequela associated with repeated GAS infection, and while this disease does not occur in mouse models, heart-specific markers identified in this study warrant further consideration. Lapek et al. (2018) discovered that heartspecific MSI that are associated with cardiac injury are upregulated in response to systemic GAS infection. These include myosin light chain 3 (Myl3), fatty acid binding protein 3 (Fabp3) and myoglobin (Mb). Cross-reactivity between human cardiac myosin and streptococcal antigens has previously been reported (Khavandi et al., 2008), indicating Myl3 may possibly hold biological relevance to the autoimmune processes that drive the development of rheumatic heart disease in humans. Post-streptococcal glomerulonephritis is a kidney inflammatory disease associated with GAS infections, and kidneyspecific markers identified in this study may potentially be associated with this disease. Upregulated kidney-specific MSI include cytochrome p450 4A10 (Cyp4a10), cytochrome P450 4A14 (Cyp4a14), and solute carrier family 22 member 5 (Slc22a5), which are produced in response to peroxisome proliferatoractivated receptor signaling (PPARs) and may be the result of cytokine storms that occur during systemic GAS infection. These MSI, in addition to E3 ubiquitinprotein ligase Msl2 and V-type proton ATPase subunit G3 (Atp6v1g3), are also implicated in the phagocytic response.
Cell Systems
Preview The spleen, which plays an alpha-1-acid glycoprotein 2, important role in systemic implasma protease C1 inhibitor, mune regulation, upregulated and complement component MSI including Type IV (T4) C8 alpha chain. and Type VI (T6) collagens. To determine whether the Collagens are extracellular MSI identified in this study matrix proteins that bind to are relevant to human infecGAS during infection, and tion, Lapek et al. (2018) increased levels of T4 have analyzed their presence in previously been linked to blood from GAS-infected paGAS-associated rheumatic tients. While the human and diseases (Dinkla et al., 2003). mouse response to infection The brain and lung were were found to be significantly found to have the fewest ordifferent, three MSI were gan-specific markers of the highly expressed in human organs analyzed, indicating patient blood: liver biothese organs may not particimarkers Icam1 and proteinpate in the robust immune rez-dependent protease inhibisponses elicited during systor (Serpina10) and heart temic infection. In the brain, biomarker alpha-1-acid cytochrome p450 Cyp2 and glycoprotein 2 (Orm2). Icam1 Cyp3 protein families related is a general marker for sepsis to the metabolism of arachiand has previously been donic acid were upregulated. shown to enhance GAS adheArachidonic acid is metabosion to human monocytes lized into pro- and anti-in(Oda et al., 2017), while Serflammatory products and pin10 may increase immune may play a protective funccell penetration into the liver tion in the brain against host during sepsis. Less is known immune responses during of Orm2; however, its homoinfection. Within the liver, cylog Orm1 is degraded by the tochrome p450s, which are GAS endoglycosidase Enknown to be dampened by doS2 (Sjo¨gren et al., 2013) pathogens and inflammatory and can be used to predict pathways, were found to be patient outcome in sepsis. downregulated. Proteins in The three MSI identified in glutathione metabolism were both mouse and human blood upregulated, with glutathione samples in this study may be Figure 1. Organ-Specific Protein Markers and Pathways Identified being an antioxidant imporuseful diagnostic markers for during Systemic GAS Murine Infection tant in protecting the host GAS infection in humans, Heart-specific biomarkers include cardiac-injury-associated myosin light chain from reactive oxygen species and future studies into the 3 (Myl3), fatty acid-binding protein (Fabp3), and myoglobin (Mb). Kidney-spegenerated by immune cells to function and specificity of cific biomarkers include PPAR-induced cytochrome p450 4A10 (Cyp4a10), cytochrome P450 4A14 (Cyp414), and solute carrier family 22 member 5 destroy GAS during infection. these MSI during GAS infec(Slc22a5), as well as phagocytic response-associated proteins E3 ubiquitinHowever, as GAS possesses tion are necessary. protein ligase Msl2 and V-type proton ATPase subunit G3 Atp6v1g3. Spleena glutathione peroxidase alFinally, Lapek et al. (2018) specific biomarkers include T4 and T6 collagen subunits, which may be involved in autoantigenic processing. In the brain, cytochrome p450 families (Cyp2 and lowing it to tolerate high condetermined whether the MSI Cyp3) associated with arachidonic acid metabolism were upregulated, while in centrations of hydrogen identified here are pathogen the liver, cytochrome p450 and glutathione metabolism pathways were also peroxide (Brenot et al., specific or general markers detected to be upregulated. Murine biomarkers with homologs also detected in 2004), this suggests that the of infection. This was the blood from GAS-infected human patients were Icam1, protein z-dependent protease inhibitor (Serpin10), and heart biomarker alpha-1-acid glycoprotein upregulation of glutathioneachieved by comparing the 2 (Orm2). related proteins is perhaps in proteomic responses of response to the high-ROS spleens from mice systemienvironment that GAS promotes for its gans, as well as a correlation in protein cally infected with Salmonella enterica seown survival (Gibson et al., 2000). abundances between the datasets, was rovar Typhimurium (STM) to spleens from Next, Lapek et al. (2018) investigated observed. A total of 19 organ-specific GAS-infected mice. No splenic MSI were the ability of organ-specific markers to proteins were detected in the blood. upregulated during STM infection, and a be traced in the whole blood of infected Three organ-specific proteins containing poor correlation between splenic remice. A high degree of overlap between signal peptides were secreted by the liver sponses to GAS and STM was observed, the proteins quantified from blood and or- and involved in the acute phase response: suggesting that both pathogens induce Cell Systems 6, May 23, 2018 537
Cell Systems
Preview unique host proteome responses. A future challenge will be to compare the observations from this study to other Gram-positive bacterial pathogens to determine whether these host responses identified are specific to GAS or to Gram-positive bacteria in general. The organ proteome atlas constructed by Lapek et al. (2018) is an unbiased, host-centric, systems-level approach to studying host-pathogen interactions. By utilizing quantitative proteomics, the authors were able to define complex and intricate host responses to infection. Future proteomic studies and transcriptomic and metabolic analyses will provide even greater power in identifying pathways for targeted investigation. The quantitative proteomics strategy outlined by Lapek et al. (2018) shows potential to map infection responses in mice to specific organs and to statistically prioritize protein biomarkers. The clinical relevance of this work was demonstrated by tracking organ-derived proteins in mouse blood samples, a subset of which were detectable in the blood of GAS-infected patients. This study represents a signifi-
538 Cell Systems 6, May 23, 2018
cant milestone in elucidating the complex host responses elicited during GAS infection and showcases a method that can be easily adapted to study the host proteome in response to other pathogens.
Lapek, J.D., Jr., Mills, R.H., Wozniak, J.M., Campeau, A., Fang, R.H., Wei, X., van de Groep, K., Perez-Lopez, A., van Sorge, N.M., Raffatellu, M., et al. (2018). Defining host responses during systemic bacterial infection through construction of a murine organ proteome atlas. Cell Syst. 6, this issue, 579–592.
REFERENCES
McArthur, J.D., McKay, F.C., Ramachandran, V., Shyam, P., Cork, A.J., Sanderson-Smith, M.L., Cole, J.N., Ringdahl, U., Sjo¨bring, U., Ranson, M., and Walker, M.J. (2008). Allelic variants of streptokinase from Streptococcus pyogenes display functional differences in plasminogen activation. FASEB J. 22, 3146–3153.
Brenot, A., King, K.Y., Janowiak, B., Griffith, O., and Caparon, M.G. (2004). Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes. Infect. Immun. 72, 408–413. Cook, S.M., Skora, A., Gillen, C.M., Walker, M.J., and McArthur, J.D. (2012). Streptokinase variants from Streptococcus pyogenes isolates display altered plasminogen activation characteristics implications for pathogenesis. Mol. Microbiol. 86, 1052–1062. Dinkla, K., Rohde, M., Jansen, W.T., Carapetis, J.R., Chhatwal, G.S., and Talay, S.R. (2003). Streptococcus pyogenes recruits collagen via surfacebound fibronectin: a novel colonization and immune evasion mechanism. Mol. Microbiol. 47, 861–869. Gibson, C.M., Mallett, T.C., Claiborne, A., and Caparon, M.G. (2000). Contribution of NADH oxidase to aerobic metabolism of Streptococcus pyogenes. J. Bacteriol. 182, 448–455. Khavandi, A., Whitaker, J., Elkington, A., Probert, J., and Walker, P.R. (2008). Acute streptococcal myopericarditis mimicking myocardial infarction. Am. J. Emerg. Med. 26, 638.
Oda, M., Domon, H., Kurosawa, M., Isono, T., Maekawa, T., Yamaguchi, M., Kawabata, S., and Terao, Y. (2017). Streptococcus pyogenes phospholipase A2 induces the expression of adhesion molecules on human umbilical vein endothelial cells and aorta of mice. Front. Cell. Infect. Microbiol. 7, 300. Sjo¨gren, J., Struwe, W.B., Cosgrave, E.F., Rudd, P.M., Stervander, M., Allhorn, M., Hollands, A., Nizet, V., and Collin, M. (2013). EndoS2 is a unique and conserved enzyme of serotype M49 group A Streptococcus that hydrolyses N-linked glycans on IgG and a1-acid glycoprotein. Biochem. J. 455, 107–118. Walker, M.J., Barnett, T.C., McArthur, J.D., Cole, J.N., Gillen, C.M., Henningham, A., Sriprakash, K.S., Sanderson-Smith, M.L., and Nizet, V. (2014). Disease manifestations and pathogenic mechanisms of Group A Streptococcus. Clin. Microbiol. Rev. 27, 264–301.
Preview A Host Proteome Atlas of Streptococcus pyogenes Infection Amelia T. Soderholm1 and Mark J. Walker1,2,* 1School
of Chemistry and Molecular Biosciences, University of Queensland, St. Lucia, QLD 4072, Australia Infectious Diseases Research Centre, University of Queensland, St. Lucia, QLD 4072, Australia *Correspondence: [email protected] https://doi.org/10.1016/j.cels.2018.05.003 2Australian
Multiplex quantitative proteomics analysis of mice infected with Group A Streptococcus reveals organ-specific biomarkers of infection. Group A Streptococcus (GAS) causes common superficial infections such as pharyngitis and impetigo. However, much less common invasive infections in humans are responsible for significant morbidity and mortality globally each year (Walker et al., 2014). As the host signaling pathways and components engaged during GAS infection are not well characterized, in this issue of Cell Systems, Lapek et al. (2018) investigated the host response by identifying organspecific changes in protein levels during GAS systemic murine infection. Organspecific infection markers revealed that a robust response to infection was initiated across all organs examined. Several organ-specific markers could be detected in GAS-infected human patient blood samples, indicating the potential clinical relevance of these findings. This study provides a significant advance in our understanding of the dynamic host proteome during GAS infection, and the quantitative proteomics methodology employed can be readily adapted to investigate host proteomic responses to numerous other pathogens. To define organ-specific host responses to infection, Lapek et al. (2018) infected mice with GAS or a mock treatment and then performed quantitative proteomic analysis of organs from these mice, including brain, heart, lungs, kidney, spleen, liver, and blood. In total, 11,394 proteins were detected across all organs and treatments, and the protein abundances detected enabled samples to be grouped according to organ type and treatment (GAS or mock-infected), with the exception of the brain. This was likely due to the inability of GAS to cross the blood-brain barrier, as infection with the blood-brain permeable
Group B Streptococcus enabled clustering of brain proteome data according to treatment condition. Organ-specific markers of infection were identified by an organ-by-organ binary approach, with proteins deemed organ-specific markers of infection if they were at least 2-fold higher or lower in response to infection within that organ only, at Benjamini-Hochberg false discovery rate of <0.01. To identify the most robust organ-specific markers, the authors performed an outlier analysis in parallel, and proteins detected by both approaches were termed markers of systemic infection (MSI). To visualize the dynamic changes in host protein levels during GAS infection, Lapek et al. used organ-specific infection markers identified by either statistical method to construct an atlas of proteinprotein interaction networks. Regardless of organ, most markers were found to be highly connected in both upregulated and downregulated protein sets, suggesting that proteins are functionally regulated at the complex or pathway level. Upregulated pathways included the complement and coagulation cascades, which are known to play important roles during GAS infection. For example, GAS escapes being sequestered by the coagulation pathway through the expression of streptokinase (Cook et al., 2012, McArthur et al., 2008). The mTOR pathway, which is inhibited by inflammatory cytokines, was found to be downregulated, while the proteasome, which is involved in the activation of inflammatory proteins, was upregulated. These findings provide further evidence to indicate that a robust pro-inflammatory response against GAS is being mounted during infection.
536 Cell Systems 6, May 23, 2018 ª 2018 Elsevier Inc.
Given that GAS infection is associated with numerous sequelae and complications that afflict different organs, a key aim of this study was to gain insight into the disease processes that occur in each organ during GAS infection (Figure 1). Rheumatic heart disease is a common immune sequela associated with repeated GAS infection, and while this disease does not occur in mouse models, heart-specific markers identified in this study warrant further consideration. Lapek et al. (2018) discovered that heartspecific MSI that are associated with cardiac injury are upregulated in response to systemic GAS infection. These include myosin light chain 3 (Myl3), fatty acid binding protein 3 (Fabp3) and myoglobin (Mb). Cross-reactivity between human cardiac myosin and streptococcal antigens has previously been reported (Khavandi et al., 2008), indicating Myl3 may possibly hold biological relevance to the autoimmune processes that drive the development of rheumatic heart disease in humans. Post-streptococcal glomerulonephritis is a kidney inflammatory disease associated with GAS infections, and kidneyspecific markers identified in this study may potentially be associated with this disease. Upregulated kidney-specific MSI include cytochrome p450 4A10 (Cyp4a10), cytochrome P450 4A14 (Cyp4a14), and solute carrier family 22 member 5 (Slc22a5), which are produced in response to peroxisome proliferatoractivated receptor signaling (PPARs) and may be the result of cytokine storms that occur during systemic GAS infection. These MSI, in addition to E3 ubiquitinprotein ligase Msl2 and V-type proton ATPase subunit G3 (Atp6v1g3), are also implicated in the phagocytic response.
Cell Systems
Preview The spleen, which plays an alpha-1-acid glycoprotein 2, important role in systemic implasma protease C1 inhibitor, mune regulation, upregulated and complement component MSI including Type IV (T4) C8 alpha chain. and Type VI (T6) collagens. To determine whether the Collagens are extracellular MSI identified in this study matrix proteins that bind to are relevant to human infecGAS during infection, and tion, Lapek et al. (2018) increased levels of T4 have analyzed their presence in previously been linked to blood from GAS-infected paGAS-associated rheumatic tients. While the human and diseases (Dinkla et al., 2003). mouse response to infection The brain and lung were were found to be significantly found to have the fewest ordifferent, three MSI were gan-specific markers of the highly expressed in human organs analyzed, indicating patient blood: liver biothese organs may not particimarkers Icam1 and proteinpate in the robust immune rez-dependent protease inhibisponses elicited during systor (Serpina10) and heart temic infection. In the brain, biomarker alpha-1-acid cytochrome p450 Cyp2 and glycoprotein 2 (Orm2). Icam1 Cyp3 protein families related is a general marker for sepsis to the metabolism of arachiand has previously been donic acid were upregulated. shown to enhance GAS adheArachidonic acid is metabosion to human monocytes lized into pro- and anti-in(Oda et al., 2017), while Serflammatory products and pin10 may increase immune may play a protective funccell penetration into the liver tion in the brain against host during sepsis. Less is known immune responses during of Orm2; however, its homoinfection. Within the liver, cylog Orm1 is degraded by the tochrome p450s, which are GAS endoglycosidase Enknown to be dampened by doS2 (Sjo¨gren et al., 2013) pathogens and inflammatory and can be used to predict pathways, were found to be patient outcome in sepsis. downregulated. Proteins in The three MSI identified in glutathione metabolism were both mouse and human blood upregulated, with glutathione samples in this study may be Figure 1. Organ-Specific Protein Markers and Pathways Identified being an antioxidant imporuseful diagnostic markers for during Systemic GAS Murine Infection tant in protecting the host GAS infection in humans, Heart-specific biomarkers include cardiac-injury-associated myosin light chain from reactive oxygen species and future studies into the 3 (Myl3), fatty acid-binding protein (Fabp3), and myoglobin (Mb). Kidney-spegenerated by immune cells to function and specificity of cific biomarkers include PPAR-induced cytochrome p450 4A10 (Cyp4a10), cytochrome P450 4A14 (Cyp414), and solute carrier family 22 member 5 destroy GAS during infection. these MSI during GAS infec(Slc22a5), as well as phagocytic response-associated proteins E3 ubiquitinHowever, as GAS possesses tion are necessary. protein ligase Msl2 and V-type proton ATPase subunit G3 Atp6v1g3. Spleena glutathione peroxidase alFinally, Lapek et al. (2018) specific biomarkers include T4 and T6 collagen subunits, which may be involved in autoantigenic processing. In the brain, cytochrome p450 families (Cyp2 and lowing it to tolerate high condetermined whether the MSI Cyp3) associated with arachidonic acid metabolism were upregulated, while in centrations of hydrogen identified here are pathogen the liver, cytochrome p450 and glutathione metabolism pathways were also peroxide (Brenot et al., specific or general markers detected to be upregulated. Murine biomarkers with homologs also detected in 2004), this suggests that the of infection. This was the blood from GAS-infected human patients were Icam1, protein z-dependent protease inhibitor (Serpin10), and heart biomarker alpha-1-acid glycoprotein upregulation of glutathioneachieved by comparing the 2 (Orm2). related proteins is perhaps in proteomic responses of response to the high-ROS spleens from mice systemienvironment that GAS promotes for its gans, as well as a correlation in protein cally infected with Salmonella enterica seown survival (Gibson et al., 2000). abundances between the datasets, was rovar Typhimurium (STM) to spleens from Next, Lapek et al. (2018) investigated observed. A total of 19 organ-specific GAS-infected mice. No splenic MSI were the ability of organ-specific markers to proteins were detected in the blood. upregulated during STM infection, and a be traced in the whole blood of infected Three organ-specific proteins containing poor correlation between splenic remice. A high degree of overlap between signal peptides were secreted by the liver sponses to GAS and STM was observed, the proteins quantified from blood and or- and involved in the acute phase response: suggesting that both pathogens induce Cell Systems 6, May 23, 2018 537
Cell Systems
Preview unique host proteome responses. A future challenge will be to compare the observations from this study to other Gram-positive bacterial pathogens to determine whether these host responses identified are specific to GAS or to Gram-positive bacteria in general. The organ proteome atlas constructed by Lapek et al. (2018) is an unbiased, host-centric, systems-level approach to studying host-pathogen interactions. By utilizing quantitative proteomics, the authors were able to define complex and intricate host responses to infection. Future proteomic studies and transcriptomic and metabolic analyses will provide even greater power in identifying pathways for targeted investigation. The quantitative proteomics strategy outlined by Lapek et al. (2018) shows potential to map infection responses in mice to specific organs and to statistically prioritize protein biomarkers. The clinical relevance of this work was demonstrated by tracking organ-derived proteins in mouse blood samples, a subset of which were detectable in the blood of GAS-infected patients. This study represents a signifi-
538 Cell Systems 6, May 23, 2018
cant milestone in elucidating the complex host responses elicited during GAS infection and showcases a method that can be easily adapted to study the host proteome in response to other pathogens.
Lapek, J.D., Jr., Mills, R.H., Wozniak, J.M., Campeau, A., Fang, R.H., Wei, X., van de Groep, K., Perez-Lopez, A., van Sorge, N.M., Raffatellu, M., et al. (2018). Defining host responses during systemic bacterial infection through construction of a murine organ proteome atlas. Cell Syst. 6, this issue, 579–592.
REFERENCES
McArthur, J.D., McKay, F.C., Ramachandran, V., Shyam, P., Cork, A.J., Sanderson-Smith, M.L., Cole, J.N., Ringdahl, U., Sjo¨bring, U., Ranson, M., and Walker, M.J. (2008). Allelic variants of streptokinase from Streptococcus pyogenes display functional differences in plasminogen activation. FASEB J. 22, 3146–3153.
Brenot, A., King, K.Y., Janowiak, B., Griffith, O., and Caparon, M.G. (2004). Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes. Infect. Immun. 72, 408–413. Cook, S.M., Skora, A., Gillen, C.M., Walker, M.J., and McArthur, J.D. (2012). Streptokinase variants from Streptococcus pyogenes isolates display altered plasminogen activation characteristics implications for pathogenesis. Mol. Microbiol. 86, 1052–1062. Dinkla, K., Rohde, M., Jansen, W.T., Carapetis, J.R., Chhatwal, G.S., and Talay, S.R. (2003). Streptococcus pyogenes recruits collagen via surfacebound fibronectin: a novel colonization and immune evasion mechanism. Mol. Microbiol. 47, 861–869. Gibson, C.M., Mallett, T.C., Claiborne, A., and Caparon, M.G. (2000). Contribution of NADH oxidase to aerobic metabolism of Streptococcus pyogenes. J. Bacteriol. 182, 448–455. Khavandi, A., Whitaker, J., Elkington, A., Probert, J., and Walker, P.R. (2008). Acute streptococcal myopericarditis mimicking myocardial infarction. Am. J. Emerg. Med. 26, 638.
Oda, M., Domon, H., Kurosawa, M., Isono, T., Maekawa, T., Yamaguchi, M., Kawabata, S., and Terao, Y. (2017). Streptococcus pyogenes phospholipase A2 induces the expression of adhesion molecules on human umbilical vein endothelial cells and aorta of mice. Front. Cell. Infect. Microbiol. 7, 300. Sjo¨gren, J., Struwe, W.B., Cosgrave, E.F., Rudd, P.M., Stervander, M., Allhorn, M., Hollands, A., Nizet, V., and Collin, M. (2013). EndoS2 is a unique and conserved enzyme of serotype M49 group A Streptococcus that hydrolyses N-linked glycans on IgG and a1-acid glycoprotein. Biochem. J. 455, 107–118. Walker, M.J., Barnett, T.C., McArthur, J.D., Cole, J.N., Gillen, C.M., Henningham, A., Sriprakash, K.S., Sanderson-Smith, M.L., and Nizet, V. (2014). Disease manifestations and pathogenic mechanisms of Group A Streptococcus. Clin. Microbiol. Rev. 27, 264–301.