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Induction of endoplasmic reticulum stress and unfolded protein response constitutes a pathogenic strategy of group A streptococcus.

Baruch M, Hertzog BB, Ravins M, Anand A, Cheng CY, Biswas D, Tirosh B, Hanski E - Front Cell Infect Microbiol (2014)

Bottom Line: In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host.GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS).GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem (HUJI) Jerusalem, Israel.

ABSTRACT
The connection between bacterial pathogens and unfolded protein response (UPR) is poorly explored. In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host. GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS). By poorly understood pathways, these toxins trigger UPR leading to the induction of the transcriptional regulator ATF4 and consequently to the upregulation of asparagine synthetase (ASNS) transcription leading to production and release of ASN. GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication. We suggest that induction of UPR by GAS and by other bacterial pathogens represent means through which bacterial pathogens gain nutrients from the host, obviating the need to become internalized or inflict irreversible cell damage.

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Related in: MedlinePlus

A model describing the reciprocal relationship between GAS and infected host cell. Upon adherence, GAS delivers the SLO and SLS toxins to the host cell. These toxins induce ER stress causing UPR, which in turn is responsible for the elevated transcription of asns gene through the PERK-eIF2-ATF4 pathway. The enhanced activity of ASNS leads to release of ASN to the culture medium which is sensed by GAS, resulting in reduced transcription of both SLO and SLS. In addition, GAS utilizes the released ASN to enhance its rate of proliferation. Both effects of host ASN on GAS can be inhibited by the addition of bacterial ASNase a widely used chemotherapeutic agent.
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Figure 2: A model describing the reciprocal relationship between GAS and infected host cell. Upon adherence, GAS delivers the SLO and SLS toxins to the host cell. These toxins induce ER stress causing UPR, which in turn is responsible for the elevated transcription of asns gene through the PERK-eIF2-ATF4 pathway. The enhanced activity of ASNS leads to release of ASN to the culture medium which is sensed by GAS, resulting in reduced transcription of both SLO and SLS. In addition, GAS utilizes the released ASN to enhance its rate of proliferation. Both effects of host ASN on GAS can be inhibited by the addition of bacterial ASNase a widely used chemotherapeutic agent.

Mentions: Cyews-Bently et al. showed that GAS induces SLO-mediated ER-stress at low multiplicity of infection (MOI) of keratinocyte cells due to dysregulation of intracellular calcium (Cywes Bentley et al., 2005). In accordance with these findings, it was shown that sil activation occurred at low MOI of intact but not lysed eukaryotic cells, did not required internalization of GAS and was mediated by delivery of SLO and SLS toxins (Baruch et al., 2014). To delineate the cellular process that is triggered by SLO and SLS delivery the involvement of autophagy, apoptosis, and necrosis that are affected by the hemolysin toxins and were shown to be linked to GAS pathogenesis was examined (Baruch et al., 2014). Using mutated mouse embryonic fibroblast cells (MEFs) in combination with various pharmacological agents, the involvement of the indicated cellular processes in sil activation were ruled out. The facts that host cell intactness was essential to observe sil activation and that hemolysin toxins were involved, together with the report that SLO triggers ER stress (Cywes Bentley et al., 2005), hinted at the involvement of the latter process. Indeed, induction of UPR using the ER stressors thapsigargin (TG), and dithiothreitol (DTT) produced a conditioned media capable of activating sil. Furthermore, addition of TG to MEFs-infected by GAS accelerated sil activation (Baruch et al., 2014). During the testing of different eukaryotic cells for the ability to activate sil, it was discovered that ASN per-se is responsible for sil activation (Baruch et al., 2014). This finding together with the fact that asns transcription of host cells is strongly upregulated during UPR through the PERK-eIF2-ATF4 pathway (Figure 1) (Balasubramanian et al., 2013), led to the examination of asns transcription during MEFs infection by GAS. As predicted, it was found that there is a significant increase in asns transcription in GAS-infected MEFs that is dependent on SLO and SLS (Baruch et al., 2014). Taken together, these results supported the model in which delivery of SLO and SLS toxins from GAS to eukaryotic cells during GAS adherence generates ER stress. This in turn leads to UPR, enhanced production of the response regulator ATF4, activation of ASNS and release of ASN to the medium, through a mechanism yet unknown (Figure 2). ASN is than sensed by GAS to activate sil.


Induction of endoplasmic reticulum stress and unfolded protein response constitutes a pathogenic strategy of group A streptococcus.

Baruch M, Hertzog BB, Ravins M, Anand A, Cheng CY, Biswas D, Tirosh B, Hanski E - Front Cell Infect Microbiol (2014)

A model describing the reciprocal relationship between GAS and infected host cell. Upon adherence, GAS delivers the SLO and SLS toxins to the host cell. These toxins induce ER stress causing UPR, which in turn is responsible for the elevated transcription of asns gene through the PERK-eIF2-ATF4 pathway. The enhanced activity of ASNS leads to release of ASN to the culture medium which is sensed by GAS, resulting in reduced transcription of both SLO and SLS. In addition, GAS utilizes the released ASN to enhance its rate of proliferation. Both effects of host ASN on GAS can be inhibited by the addition of bacterial ASNase a widely used chemotherapeutic agent.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4120759&req=5

Figure 2: A model describing the reciprocal relationship between GAS and infected host cell. Upon adherence, GAS delivers the SLO and SLS toxins to the host cell. These toxins induce ER stress causing UPR, which in turn is responsible for the elevated transcription of asns gene through the PERK-eIF2-ATF4 pathway. The enhanced activity of ASNS leads to release of ASN to the culture medium which is sensed by GAS, resulting in reduced transcription of both SLO and SLS. In addition, GAS utilizes the released ASN to enhance its rate of proliferation. Both effects of host ASN on GAS can be inhibited by the addition of bacterial ASNase a widely used chemotherapeutic agent.
Mentions: Cyews-Bently et al. showed that GAS induces SLO-mediated ER-stress at low multiplicity of infection (MOI) of keratinocyte cells due to dysregulation of intracellular calcium (Cywes Bentley et al., 2005). In accordance with these findings, it was shown that sil activation occurred at low MOI of intact but not lysed eukaryotic cells, did not required internalization of GAS and was mediated by delivery of SLO and SLS toxins (Baruch et al., 2014). To delineate the cellular process that is triggered by SLO and SLS delivery the involvement of autophagy, apoptosis, and necrosis that are affected by the hemolysin toxins and were shown to be linked to GAS pathogenesis was examined (Baruch et al., 2014). Using mutated mouse embryonic fibroblast cells (MEFs) in combination with various pharmacological agents, the involvement of the indicated cellular processes in sil activation were ruled out. The facts that host cell intactness was essential to observe sil activation and that hemolysin toxins were involved, together with the report that SLO triggers ER stress (Cywes Bentley et al., 2005), hinted at the involvement of the latter process. Indeed, induction of UPR using the ER stressors thapsigargin (TG), and dithiothreitol (DTT) produced a conditioned media capable of activating sil. Furthermore, addition of TG to MEFs-infected by GAS accelerated sil activation (Baruch et al., 2014). During the testing of different eukaryotic cells for the ability to activate sil, it was discovered that ASN per-se is responsible for sil activation (Baruch et al., 2014). This finding together with the fact that asns transcription of host cells is strongly upregulated during UPR through the PERK-eIF2-ATF4 pathway (Figure 1) (Balasubramanian et al., 2013), led to the examination of asns transcription during MEFs infection by GAS. As predicted, it was found that there is a significant increase in asns transcription in GAS-infected MEFs that is dependent on SLO and SLS (Baruch et al., 2014). Taken together, these results supported the model in which delivery of SLO and SLS toxins from GAS to eukaryotic cells during GAS adherence generates ER stress. This in turn leads to UPR, enhanced production of the response regulator ATF4, activation of ASNS and release of ASN to the medium, through a mechanism yet unknown (Figure 2). ASN is than sensed by GAS to activate sil.

Bottom Line: In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host.GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS).GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Molecular Genetics, Faculty of Medicine, The Hebrew University of Jerusalem (HUJI) Jerusalem, Israel.

ABSTRACT
The connection between bacterial pathogens and unfolded protein response (UPR) is poorly explored. In this review we highlight the evidence showing that group A streptococcus (GAS) induces endoplasmic reticulum (ER) stress and UPR through which it captures the amino acid asparagine (ASN) from the host. GAS acts extracellularly and during adherence to host cells it delivers the hemolysin toxins; streptolysin O (SLO) and streptolysin S (SLS). By poorly understood pathways, these toxins trigger UPR leading to the induction of the transcriptional regulator ATF4 and consequently to the upregulation of asparagine synthetase (ASNS) transcription leading to production and release of ASN. GAS senses ASN and alters gene expression profile accordingly, and increases the rate of multiplication. We suggest that induction of UPR by GAS and by other bacterial pathogens represent means through which bacterial pathogens gain nutrients from the host, obviating the need to become internalized or inflict irreversible cell damage.

Show MeSH
Related in: MedlinePlus