Editorial For reprint orders, please contact: [email protected]
Group A streptococcus and host metabolism: virulence influences and potential treatments “...these studies emphasize the tight connection that has evolved during evolution between physiology and virulence. Understanding of this connection at the molecular level should pave the way for development of new ways to control severe human infectious diseases.”
Moshe Baruch1, Baruch B Hertzog1, Miriam Ravins1, Catherine Cheng Youting2 & Emanuel Hanski*,1,2 Pathogens must acquire nutrients from the host during the infectious process. Yet, relatively little is understood about the in vivo physiology and metabolism of human pathogens. The importance of this feature to host–pathogen relationships has already been pointed out in the late 1870s by Louis Pasteur who developed a model that described the body as a culture vessel as a means of studying immunity. Interest in the host as a growth environment has resurfaced in recent years, and novel traits were uncovered mostly for intracellular pathogens or pathogens occupying a specific host niche [1] . Much less is known about extracellular pathogens that cause a variety of infections and pass different host niches during their infectious processes. Streptococcus pyogenes (group A streptococcus [GAS]) is an extracellular pathogen that remains an important cause of human morbidity and mortality worldwide. GAS can exist in symbiotic relationships without evoking host immune responses. Yet, upon adherence to epithelial cells of the skin and pharynx, GAS causes a wide array of infections, ranging
from uncomplicated diseases like impetigo and pharyngitis, to severe and potentially life-threatening invasive infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF) [2] . Despite the continuing susceptibility of the bacterium to β-lactam antibiotics, there has been an unexplained resurgence in the prevalence of highly invasive GAS infection over the past 30 years. In 2005, the estimated number of people suffering from serious GAS diseases was approximately 18.1 million, with a further 1.78 million new cases occurring each year, accounting for 517,000 deaths annually [3] . In the absence of an effective GAS vaccine, improved management of GAS infections is urgently needed, particularly for the highly invasive diseases, where prompt antibiotics administration and surgical innervations are often unsuccessful [4] . GAS serotyping is based on the heterogeneity of the nucleotide sequence encoding the N-terminal region of M protein, a key virulence factor of GAS. More than 200 serotypes are known, yet there is no direct correlation between a specific M protein serotype and the capacity of GAS
Keywords
• asparaginase • asparagine • asparagine synthetase • endoplasmic reticulum stress • gene regulation • group A streptococcus • metabolism • virulence
“Despite the continuing susceptibility of the bacterium to β-lactam antibiotics, there has been an unexplained resurgence in the prevalence of highly invasive group A streptococcus infection over the past 30 years.”
1 Dept. of Microbiology & Molecular Genetics, The Institute for Medical Research – Israel–Canada (IMRIC), The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 2 Department of Microbiology National University of Singapore (NUS) & NUS-HUJI, Center for Research Excellence & Technological Enterprise (CREATE), NUS, Singapore *Author for correspondence: [email protected]
10.2217/FMB.14.39 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(6), 713–716
part of
ISSN 1746-0913
713
Editorial Baruch, Hertzog, Ravins, Cheng, Youting & Hanski
“To cause such a vast array of human diseases, group A streptococcus produces a large repertoire of virulence factors that promote: initial adhesion to host cells; colonization; impairment of host defenses; and increased bacterial dissemination.”
714
to cause invasive diseases [5] . Nonetheless, GAS M1T1 clone, first detected in the mid-1980s in the USA, has since disseminated worldwide and remains a major cause of severe invasive human infections [6] . To cause such a vast array of human diseases, GAS produces a large repertoire of virulence factors that promote: initial adhesion to host cells; colonization; impairment of host defenses; and increased bacterial dissemination [7] . Factors promoting GAS spreading contain multiple lytic enzymes and toxins, including the poreforming toxins streptolysin O (SLO) and streptolysin S (SLS) [7] . These toxins contributed to the early stages of soft-tissue GAS infections and their activities may be interconnected [8] . In addition, it was reported that SLO dysregulates intracellular calcium in human keratinocytes, causing endoplasmic reticulum (ER) stress [9] . This subsequently leads to mitochondrial depolarization and apoptosis that is followed by cell desquamation and loss of epithelial integrity [9] . The ER is a central organelle for protein biosynthesis, folding and traffic. When the load of proteins exceeds the ER processing capacity, an imbalance is created within the ER and is referred to as ER stress. To alleviate the ER stress and return to proteostasis, a complex signaling cascade, termed the unfolded protein response (UPR), is triggered. At early stages of ER stress, UPR initiates a new gene-expression program aimed to increase the ER capacity of protein folding and to attenuate general protein translation. If however the stress remains unmitigated, UPR will consequently initiate programmed cell death [10] . It is important to indicate here that one of the transcription factors that is involved in the reprograming of gene expression during UPR and starvation stresses is ATF4 [11] . One of the genes whose transcription is stimulated by ATF4 is asparagine synthetase (ASNS), which catalyzes the conversion of aspartate to asparagine (ASN) [11] . While searching for the conditions under which the GAS quorum-sensing locus sil is self-activated, we discovered that the bacterium induces UPR in host cells through which it gains ASN. ASN is subsequently utilized by GAS for enhancing its proliferation rate and altering its gene-expression profile [12] . sil is situated on an mobile genetic element that may have been acquired before GAS speciation and remained present in approximately 20% of GAS clinical isolates [13] . In the GAS M14
Future Microbiol. (2014) 9(6)
serotype, sil controls virulence as was shown using different animal models of human NF [14–16] . Hitherto, we were able to activate sil by providing the bacterium with a minute quantity of synthetic autoinducer peptide SilCR [13] , but we could not find the conditions under which sil is naturally self-activated. Just recently, we discovered that sil is temporarily self-activated in vivo, during the initial stages of soft-tissue infection. Furthermore, we discovered that sil is also activated ex vivo upon adherence to various types of eukaryotic cells [12] . This ex vivo activation is apparent only at low multiplicity of infection (MOI) and cell intactness is crucial, as higher MOI or disruption of eukaryotic cells before GAS infection is detrimental to the activation [12] . sil activation required formation of physical contact between the bacterium and host cells during which delivery of SLO and SLS from the bacterium to host cells occurred [12] . We wished to delineate the cellular process that is triggered by the toxins in host cells and examined the involvement of autophagy, apoptosis and necrosis. These processes are affected by the hemolysin toxins and were shown to be linked to GAS pathogenesis. Using mutated mouse embryonic fibroblast cells (MEFs) in combination with various pharmacological agents, we ruled out the involvement of the indicated cellular processes in sil activation. The fact that host cell intactness was essential to observe sil activation and hemolysins were involved, together with the report that SLO triggers ER stress [9] , hinted at the involvement of the latter. Indeed, induction of UPR using the ER stressors thapsigargin (TG) and dithiothreitol produced conditioned media capable of activating sil. Furthermore, addition of TG to MEFs infected by GAS accelerated sil activation [12] . During testing of different eukaryotic cells for the ability to activate sil, we discovered that ASN, which is present in the rich cell medium F12 but absent in DMEM medium, per se is responsible for sil activation [12] . This finding, taken together with the fact that ASNS transcription of host cells is strongly upregulated during UPR by ATF4 [11] , led us to examine ASNS transcription during MEFs infection by GAS. As predicted, we found that that there is a significant increase in ASNS transcription in GAS-infected MEFs that is dependent on SLO and SLS [12] . Taken together, these results supported the model in which delivery of SLO and SLS toxins from
future science group
Group A streptococcus & host metabolism: virulence influences & potential treatments GAS to eukaryotic cells during GAS adherence generates ER stress. This in turn leads to UPR, production of ATF4, activation of ASNS and release of ASN to the medium. ASN is sensed by GAS to activate sil. To corroborate this model we used asparaginase (ASNase), which is a widely used chemotherapeutic agent [17] . As expected, ASNase obliterated sil activation in vivo and ex vivo, but most fascinatingly also arrested GAS growth [12] . We found that ASNase arrests the growth of GAS irrespective of its serotype or presence/absence of sil. Therefore, we profiled RNA expression of GAS serotype M1T1 after addition of ASNase using RNA sequencing (RNA-seq). We found that 16.7% of GAS genes had a significantly altered expression in the absence versus the presence of ASN. Among others, the transcription of genes involved in GAS replication such as polA and lig was downregulated in ASN absence, while the transcription of genes encoding SLO and SLS was upregulated [12] . Finally, we tested the ability of ASNase to prevent GAS bacteremia and found that ASNase prevented GAS proliferation in whole human blood and in a murine model of human GAS bacteremia [12] . The strategy of GAS to gain ASN from the host may be a central feature of its pathogenesis. It could help GAS to assess its population size that is in close contact with the host cells. It also may reveal to the pathogen the status of its host, whether or not it can sustain more stress to release even more nutrients without progressing
Brown SA, Palmer KL, Whiteley M. Revisiting the host as a growth medium. Nat. Rev. Microbiol. 6(9), 657–666 (2008).
2
Cunningham MW. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13(3), 470–511 (2000).
3
4
5
Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5(11), 685–694 (2005). Johansson L, Thulin P, Low DE, NorrbyTeglund A. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin. Infect. Dis. 51(1), 58–65 (2010). McMillan DJ, Dreze PA, Vu T et al. Updated model of group A Streptococcus M proteins based on a comprehensive
future science group
6
7
“The strategy of group A streptococcus to gain asparagine from the host may be a central feature of its pathogenesis. It could help group A streptococcus to assess its population size that is in close contact with the host cells.”
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. worldwide study. Clin. Microbiol. Infect. 19(5), E222–E229 (2013).
References 1
into irreversible cell death. Consequently, these assessments may be used by GAS to regulate the level of virulence factors expression, avoiding destruction of the host before reaching a critical mass, which is necessary to ensure successful deep-tissue invasion. Indeed we found that the expression of SLO and SLS is inversely dependent on ASN level [12] . Interestingly, very recently it was reported that Mycobacterium tuberculosis, which induces ER stress in granulomas during infection in humans [18] , exploits host ASN to assimilate nitrogen and resist acid stress during infection [19] . We propose that M. tuberculosis employs a similar strategy as GAS to gain ASN from the host. In summary, these studies emphasize the tight connection that has evolved during evolution between physiology and virulence. Understanding of this connection at the molecular level should pave the way for development of new ways to control severe human infectious diseases.
Editorial
Maamary PG, Ben Zakour NL, Cole JN et al. Tracing the evolutionary history of the pandemic group A streptococcal M1T1 clone. FASEB J. 26(11), 4675–4684 (2012). Sitkiewicz I, Hryniewicz W. Pyogenic streptococci – danger of re-emerging pathogens. Pol. J. Microbiol. 59(4), 219–226 (2010).
8
Fontaine MC, Lee JJ, Kehoe MA. Combined contributions of streptolysin O and streptolysin S to virulence of serotype M5 Streptococcus pyogenes strain Manfredo. Infect. Immun. 71(7), 3857–3865 (2003).
9
Cywes Bentley C, Hakansson A, Christianson J, Wessels MR. Extracellular group A Streptococcus induces keratinocyte apoptosis by dysregulating calcium signalling. Cell. Microbiol. 7(7), 945–955 (2005).
10 Walter P, Ron D. The unfolded protein
response: from stress pathway to homeostatic regulation. Science 334(6059), 1081–1086 (2011). 11 Balasubramanian MN, Butterworth EA,
Kilberg MS. Asparagine synthetase: regulation by cell stress and involvement in tumor biology. Am. J. Physiol. Endocrinol. Metab. 304(8), e789–e799 (2013). 12 Baruch M, Belotserkovsky I, Hertzog BB
et al. An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell 156(1–2), 97–108 (2014). 13 Belotserkovsky I, Baruch M, Peer A et al.
Functional analysis of the quorum-sensing streptococcal invasion locus (sil). PLoS Pathog. 5(11), e1000651 (2009). 14 Hidalgo-Grass C, Dan-Goor M, Maly A et al.
Effect of a bacterial pheromone peptide on host chemokine degradation in group A
www.futuremedicine.com
715
Editorial Baruch, Hertzog, Ravins, Cheng, Youting & Hanski streptococcal necrotising soft-tissue infections. Lancet 363(9410), 696–703 (2004). 15 Hidalgo-Grass C, Ravins M, Dan-Goor M,
Jaffe J, Moses AE, Hanski E. A locus of group A Streptococcus involved in invasive disease and DNA transfer. Mol. Microbiol. 46(1), 87–99 (2002).
716
16 Kizy AE, Neely MN. First Streptococcus
pyogenes signature-tagged mutagenesis screen identifies novel virulence determinants. Infect. Immun. 77(5), 1854–1865 (2009). 17 Pui CH, Robison LL, Look AT. Acute
lymphoblastic leukaemia. Lancet 371(9617), 1030–1043 (2008).
Future Microbiol. (2014) 9(6)
18 Seimon TA, Kim MJ, Blumenthal A et al.
Induction of ER stress in macrophages of tuberculosis granulomas. PLoS ONE 5(9), e12772 (2010). 19 Gouzy A, Larrouy-Maumus G, Bottai D et al.
Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress during infection. PLoS Pathog. 10(2), e1003928 (2014).
future science group
Group A streptococcus and host metabolism: virulence influences and potential treatments “...these studies emphasize the tight connection that has evolved during evolution between physiology and virulence. Understanding of this connection at the molecular level should pave the way for development of new ways to control severe human infectious diseases.”
Moshe Baruch1, Baruch B Hertzog1, Miriam Ravins1, Catherine Cheng Youting2 & Emanuel Hanski*,1,2 Pathogens must acquire nutrients from the host during the infectious process. Yet, relatively little is understood about the in vivo physiology and metabolism of human pathogens. The importance of this feature to host–pathogen relationships has already been pointed out in the late 1870s by Louis Pasteur who developed a model that described the body as a culture vessel as a means of studying immunity. Interest in the host as a growth environment has resurfaced in recent years, and novel traits were uncovered mostly for intracellular pathogens or pathogens occupying a specific host niche [1] . Much less is known about extracellular pathogens that cause a variety of infections and pass different host niches during their infectious processes. Streptococcus pyogenes (group A streptococcus [GAS]) is an extracellular pathogen that remains an important cause of human morbidity and mortality worldwide. GAS can exist in symbiotic relationships without evoking host immune responses. Yet, upon adherence to epithelial cells of the skin and pharynx, GAS causes a wide array of infections, ranging
from uncomplicated diseases like impetigo and pharyngitis, to severe and potentially life-threatening invasive infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF) [2] . Despite the continuing susceptibility of the bacterium to β-lactam antibiotics, there has been an unexplained resurgence in the prevalence of highly invasive GAS infection over the past 30 years. In 2005, the estimated number of people suffering from serious GAS diseases was approximately 18.1 million, with a further 1.78 million new cases occurring each year, accounting for 517,000 deaths annually [3] . In the absence of an effective GAS vaccine, improved management of GAS infections is urgently needed, particularly for the highly invasive diseases, where prompt antibiotics administration and surgical innervations are often unsuccessful [4] . GAS serotyping is based on the heterogeneity of the nucleotide sequence encoding the N-terminal region of M protein, a key virulence factor of GAS. More than 200 serotypes are known, yet there is no direct correlation between a specific M protein serotype and the capacity of GAS
Keywords
• asparaginase • asparagine • asparagine synthetase • endoplasmic reticulum stress • gene regulation • group A streptococcus • metabolism • virulence
“Despite the continuing susceptibility of the bacterium to β-lactam antibiotics, there has been an unexplained resurgence in the prevalence of highly invasive group A streptococcus infection over the past 30 years.”
1 Dept. of Microbiology & Molecular Genetics, The Institute for Medical Research – Israel–Canada (IMRIC), The Hebrew University of Jerusalem, Faculty of Medicine, Jerusalem, Israel 2 Department of Microbiology National University of Singapore (NUS) & NUS-HUJI, Center for Research Excellence & Technological Enterprise (CREATE), NUS, Singapore *Author for correspondence: [email protected]
10.2217/FMB.14.39 © 2014 Future Medicine Ltd
Future Microbiol. (2014) 9(6), 713–716
part of
ISSN 1746-0913
713
Editorial Baruch, Hertzog, Ravins, Cheng, Youting & Hanski
“To cause such a vast array of human diseases, group A streptococcus produces a large repertoire of virulence factors that promote: initial adhesion to host cells; colonization; impairment of host defenses; and increased bacterial dissemination.”
714
to cause invasive diseases [5] . Nonetheless, GAS M1T1 clone, first detected in the mid-1980s in the USA, has since disseminated worldwide and remains a major cause of severe invasive human infections [6] . To cause such a vast array of human diseases, GAS produces a large repertoire of virulence factors that promote: initial adhesion to host cells; colonization; impairment of host defenses; and increased bacterial dissemination [7] . Factors promoting GAS spreading contain multiple lytic enzymes and toxins, including the poreforming toxins streptolysin O (SLO) and streptolysin S (SLS) [7] . These toxins contributed to the early stages of soft-tissue GAS infections and their activities may be interconnected [8] . In addition, it was reported that SLO dysregulates intracellular calcium in human keratinocytes, causing endoplasmic reticulum (ER) stress [9] . This subsequently leads to mitochondrial depolarization and apoptosis that is followed by cell desquamation and loss of epithelial integrity [9] . The ER is a central organelle for protein biosynthesis, folding and traffic. When the load of proteins exceeds the ER processing capacity, an imbalance is created within the ER and is referred to as ER stress. To alleviate the ER stress and return to proteostasis, a complex signaling cascade, termed the unfolded protein response (UPR), is triggered. At early stages of ER stress, UPR initiates a new gene-expression program aimed to increase the ER capacity of protein folding and to attenuate general protein translation. If however the stress remains unmitigated, UPR will consequently initiate programmed cell death [10] . It is important to indicate here that one of the transcription factors that is involved in the reprograming of gene expression during UPR and starvation stresses is ATF4 [11] . One of the genes whose transcription is stimulated by ATF4 is asparagine synthetase (ASNS), which catalyzes the conversion of aspartate to asparagine (ASN) [11] . While searching for the conditions under which the GAS quorum-sensing locus sil is self-activated, we discovered that the bacterium induces UPR in host cells through which it gains ASN. ASN is subsequently utilized by GAS for enhancing its proliferation rate and altering its gene-expression profile [12] . sil is situated on an mobile genetic element that may have been acquired before GAS speciation and remained present in approximately 20% of GAS clinical isolates [13] . In the GAS M14
Future Microbiol. (2014) 9(6)
serotype, sil controls virulence as was shown using different animal models of human NF [14–16] . Hitherto, we were able to activate sil by providing the bacterium with a minute quantity of synthetic autoinducer peptide SilCR [13] , but we could not find the conditions under which sil is naturally self-activated. Just recently, we discovered that sil is temporarily self-activated in vivo, during the initial stages of soft-tissue infection. Furthermore, we discovered that sil is also activated ex vivo upon adherence to various types of eukaryotic cells [12] . This ex vivo activation is apparent only at low multiplicity of infection (MOI) and cell intactness is crucial, as higher MOI or disruption of eukaryotic cells before GAS infection is detrimental to the activation [12] . sil activation required formation of physical contact between the bacterium and host cells during which delivery of SLO and SLS from the bacterium to host cells occurred [12] . We wished to delineate the cellular process that is triggered by the toxins in host cells and examined the involvement of autophagy, apoptosis and necrosis. These processes are affected by the hemolysin toxins and were shown to be linked to GAS pathogenesis. Using mutated mouse embryonic fibroblast cells (MEFs) in combination with various pharmacological agents, we ruled out the involvement of the indicated cellular processes in sil activation. The fact that host cell intactness was essential to observe sil activation and hemolysins were involved, together with the report that SLO triggers ER stress [9] , hinted at the involvement of the latter. Indeed, induction of UPR using the ER stressors thapsigargin (TG) and dithiothreitol produced conditioned media capable of activating sil. Furthermore, addition of TG to MEFs infected by GAS accelerated sil activation [12] . During testing of different eukaryotic cells for the ability to activate sil, we discovered that ASN, which is present in the rich cell medium F12 but absent in DMEM medium, per se is responsible for sil activation [12] . This finding, taken together with the fact that ASNS transcription of host cells is strongly upregulated during UPR by ATF4 [11] , led us to examine ASNS transcription during MEFs infection by GAS. As predicted, we found that that there is a significant increase in ASNS transcription in GAS-infected MEFs that is dependent on SLO and SLS [12] . Taken together, these results supported the model in which delivery of SLO and SLS toxins from
future science group
Group A streptococcus & host metabolism: virulence influences & potential treatments GAS to eukaryotic cells during GAS adherence generates ER stress. This in turn leads to UPR, production of ATF4, activation of ASNS and release of ASN to the medium. ASN is sensed by GAS to activate sil. To corroborate this model we used asparaginase (ASNase), which is a widely used chemotherapeutic agent [17] . As expected, ASNase obliterated sil activation in vivo and ex vivo, but most fascinatingly also arrested GAS growth [12] . We found that ASNase arrests the growth of GAS irrespective of its serotype or presence/absence of sil. Therefore, we profiled RNA expression of GAS serotype M1T1 after addition of ASNase using RNA sequencing (RNA-seq). We found that 16.7% of GAS genes had a significantly altered expression in the absence versus the presence of ASN. Among others, the transcription of genes involved in GAS replication such as polA and lig was downregulated in ASN absence, while the transcription of genes encoding SLO and SLS was upregulated [12] . Finally, we tested the ability of ASNase to prevent GAS bacteremia and found that ASNase prevented GAS proliferation in whole human blood and in a murine model of human GAS bacteremia [12] . The strategy of GAS to gain ASN from the host may be a central feature of its pathogenesis. It could help GAS to assess its population size that is in close contact with the host cells. It also may reveal to the pathogen the status of its host, whether or not it can sustain more stress to release even more nutrients without progressing
Brown SA, Palmer KL, Whiteley M. Revisiting the host as a growth medium. Nat. Rev. Microbiol. 6(9), 657–666 (2008).
2
Cunningham MW. Pathogenesis of group A streptococcal infections. Clin. Microbiol. Rev. 13(3), 470–511 (2000).
3
4
5
Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect. Dis. 5(11), 685–694 (2005). Johansson L, Thulin P, Low DE, NorrbyTeglund A. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin. Infect. Dis. 51(1), 58–65 (2010). McMillan DJ, Dreze PA, Vu T et al. Updated model of group A Streptococcus M proteins based on a comprehensive
future science group
6
7
“The strategy of group A streptococcus to gain asparagine from the host may be a central feature of its pathogenesis. It could help group A streptococcus to assess its population size that is in close contact with the host cells.”
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. worldwide study. Clin. Microbiol. Infect. 19(5), E222–E229 (2013).
References 1
into irreversible cell death. Consequently, these assessments may be used by GAS to regulate the level of virulence factors expression, avoiding destruction of the host before reaching a critical mass, which is necessary to ensure successful deep-tissue invasion. Indeed we found that the expression of SLO and SLS is inversely dependent on ASN level [12] . Interestingly, very recently it was reported that Mycobacterium tuberculosis, which induces ER stress in granulomas during infection in humans [18] , exploits host ASN to assimilate nitrogen and resist acid stress during infection [19] . We propose that M. tuberculosis employs a similar strategy as GAS to gain ASN from the host. In summary, these studies emphasize the tight connection that has evolved during evolution between physiology and virulence. Understanding of this connection at the molecular level should pave the way for development of new ways to control severe human infectious diseases.
Editorial
Maamary PG, Ben Zakour NL, Cole JN et al. Tracing the evolutionary history of the pandemic group A streptococcal M1T1 clone. FASEB J. 26(11), 4675–4684 (2012). Sitkiewicz I, Hryniewicz W. Pyogenic streptococci – danger of re-emerging pathogens. Pol. J. Microbiol. 59(4), 219–226 (2010).
8
Fontaine MC, Lee JJ, Kehoe MA. Combined contributions of streptolysin O and streptolysin S to virulence of serotype M5 Streptococcus pyogenes strain Manfredo. Infect. Immun. 71(7), 3857–3865 (2003).
9
Cywes Bentley C, Hakansson A, Christianson J, Wessels MR. Extracellular group A Streptococcus induces keratinocyte apoptosis by dysregulating calcium signalling. Cell. Microbiol. 7(7), 945–955 (2005).
10 Walter P, Ron D. The unfolded protein
response: from stress pathway to homeostatic regulation. Science 334(6059), 1081–1086 (2011). 11 Balasubramanian MN, Butterworth EA,
Kilberg MS. Asparagine synthetase: regulation by cell stress and involvement in tumor biology. Am. J. Physiol. Endocrinol. Metab. 304(8), e789–e799 (2013). 12 Baruch M, Belotserkovsky I, Hertzog BB
et al. An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell 156(1–2), 97–108 (2014). 13 Belotserkovsky I, Baruch M, Peer A et al.
Functional analysis of the quorum-sensing streptococcal invasion locus (sil). PLoS Pathog. 5(11), e1000651 (2009). 14 Hidalgo-Grass C, Dan-Goor M, Maly A et al.
Effect of a bacterial pheromone peptide on host chemokine degradation in group A
www.futuremedicine.com
715
Editorial Baruch, Hertzog, Ravins, Cheng, Youting & Hanski streptococcal necrotising soft-tissue infections. Lancet 363(9410), 696–703 (2004). 15 Hidalgo-Grass C, Ravins M, Dan-Goor M,
Jaffe J, Moses AE, Hanski E. A locus of group A Streptococcus involved in invasive disease and DNA transfer. Mol. Microbiol. 46(1), 87–99 (2002).
716
16 Kizy AE, Neely MN. First Streptococcus
pyogenes signature-tagged mutagenesis screen identifies novel virulence determinants. Infect. Immun. 77(5), 1854–1865 (2009). 17 Pui CH, Robison LL, Look AT. Acute
lymphoblastic leukaemia. Lancet 371(9617), 1030–1043 (2008).
Future Microbiol. (2014) 9(6)
18 Seimon TA, Kim MJ, Blumenthal A et al.
Induction of ER stress in macrophages of tuberculosis granulomas. PLoS ONE 5(9), e12772 (2010). 19 Gouzy A, Larrouy-Maumus G, Bottai D et al.
Mycobacterium tuberculosis exploits asparagine to assimilate nitrogen and resist acid stress during infection. PLoS Pathog. 10(2), e1003928 (2014).
future science group
