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On February 3, Liu Xing's research group from the Pasteur Institute of Shanghai, Chinese Academy of Sciences published a research paper entitled Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis in Nature
.
This study is the first to discover and report that the Streptococcus pyogenes GAS virulence factor SpeB triggers skin epithelial cell pyroptosis and inhibits its systemic infection by cleaving and activating GSDMA
.
Group A streptococcus (GAS), also known as Streptococcus pyogenes (Streptococcus pyogenes), is a virulent pathogen widely existing in nature, which can infect the host skin and respiratory mucosa and cause various diseases.
Including scarlet fever, erysipelas, fatal necrotizing fasciitis, toxic shock and sepsis
.
About 700 million people worldwide are infected by it every year (more than 500,000 die from moderate to severe infections)
.
The skin colonization and invasion ability of GAS is closely related to its secreted virulence factors, one of the key virulence factors is streptococcal pyrogenic exotoxin B (SpeB)
.
The clinical severity of GAS infection was significantly negatively correlated with the expression of SpeB, and the specific molecular mechanism was not clear
.
To explore the function of SpeB in GAS invasive infection, the GAS mouse skin infection model was used to compare the pathogenicity of wild-type and different virulence factor-deficient GAS strains
.
The results showed that, compared with the severe purulent and necrotic lesions after infection with wild-type and other virulence factor-deficient strains, no obvious skin ulceration and a significant decrease in neutrophils were observed at the infection site after infection with SpeB-deficient GAS strains.
Mice exhibited more severe systemic infection and death
.
Through GAS infection experiments in primary skin keratinocytes, it was found that compared with other strains, the deletion of GAS SpeB makes it lose the function of inducing pyroptosis-like cell death and promote its systemic infection
.
On this basis, the study used the CRISPR/Cas9 genome-wide knockout screening platform to screen and identify the key protein of SpeB-induced skin epithelial cell pyroptosis: GSDMA, a member of the Gasdermins family, a key executor of inflammatory cell death (pyroptosis).
.
Further, the study analyzed the mechanism of SpeB activation of GSDMA in detail at the molecular level: SpeB specifically cleaves GSDMA (but not other members of the Gasdermins family), generating an N-terminal fragment of about 27kDa and inducing cell pyroptosis; Edman sequencing and mass spectrometry analysis found that SpeB Cleavage of the 246th amino acid of GSDMA; intracellular introduction of purified GSDMA 1-246aa fragment in vitro can directly induce cell pyroptosis; lipid membrane test strips and liposome binding experiments revealed that GSDMA 1-246aa can bind to cell membrane phospholipids and cells containing the corresponding phospholipids.
Liposome binding; liposome leakage experiments demonstrate that GSDMA 1-246aa can form pores on specific liposomes; sequence alignment results show that this cleavage site is conserved in mouse Gsdma1; SpeB-induced Gsdma1 cleavage can induce small Pyroptosis of murine epithelial cells; Gsdma1 cleavage can be detected at the site of GAS infection in mice; knockout of Gsdma1 makes it more sensitive to GAS infection than wild-type mice
.
This study is the first to discover and report that GSDMA molecules (“cannons”) expressed by skin epithelial cells (KCs, “treasure ships”) both serve as exogenous pathogen receptors to recognize Streptococcus pyogenes (GAS, “corsair”) virulence factor SpeB (“hooklock”).
"), at the same time as an immune effector to punch holes in the cell membrane ("barrel") and release inflammatory factors ("gunfire") to cause cell pyroptosis and purulent necrotic lesions of the skin to control further systemic infection by pathogenic bacteria
.
This study revealed a novel mechanism in the body's immune defense response-single protein (GSDMA) as both a pathogen sensor and a host effector, and provided a new clinical treatment for related diseases caused by pathogenic bacteria such as Streptococcus pyogenes infection.
Targets and new ideas
.
Research reveals a novel immune response mechanism against Streptococcus pyogenes infection (schematic drawing: Yu He) Source: Pasteur Institute, Shanghai, Chinese Academy of Sciences
.
This study is the first to discover and report that the Streptococcus pyogenes GAS virulence factor SpeB triggers skin epithelial cell pyroptosis and inhibits its systemic infection by cleaving and activating GSDMA
.
Group A streptococcus (GAS), also known as Streptococcus pyogenes (Streptococcus pyogenes), is a virulent pathogen widely existing in nature, which can infect the host skin and respiratory mucosa and cause various diseases.
Including scarlet fever, erysipelas, fatal necrotizing fasciitis, toxic shock and sepsis
.
About 700 million people worldwide are infected by it every year (more than 500,000 die from moderate to severe infections)
.
The skin colonization and invasion ability of GAS is closely related to its secreted virulence factors, one of the key virulence factors is streptococcal pyrogenic exotoxin B (SpeB)
.
The clinical severity of GAS infection was significantly negatively correlated with the expression of SpeB, and the specific molecular mechanism was not clear
.
To explore the function of SpeB in GAS invasive infection, the GAS mouse skin infection model was used to compare the pathogenicity of wild-type and different virulence factor-deficient GAS strains
.
The results showed that, compared with the severe purulent and necrotic lesions after infection with wild-type and other virulence factor-deficient strains, no obvious skin ulceration and a significant decrease in neutrophils were observed at the infection site after infection with SpeB-deficient GAS strains.
Mice exhibited more severe systemic infection and death
.
Through GAS infection experiments in primary skin keratinocytes, it was found that compared with other strains, the deletion of GAS SpeB makes it lose the function of inducing pyroptosis-like cell death and promote its systemic infection
.
On this basis, the study used the CRISPR/Cas9 genome-wide knockout screening platform to screen and identify the key protein of SpeB-induced skin epithelial cell pyroptosis: GSDMA, a member of the Gasdermins family, a key executor of inflammatory cell death (pyroptosis).
.
Further, the study analyzed the mechanism of SpeB activation of GSDMA in detail at the molecular level: SpeB specifically cleaves GSDMA (but not other members of the Gasdermins family), generating an N-terminal fragment of about 27kDa and inducing cell pyroptosis; Edman sequencing and mass spectrometry analysis found that SpeB Cleavage of the 246th amino acid of GSDMA; intracellular introduction of purified GSDMA 1-246aa fragment in vitro can directly induce cell pyroptosis; lipid membrane test strips and liposome binding experiments revealed that GSDMA 1-246aa can bind to cell membrane phospholipids and cells containing the corresponding phospholipids.
Liposome binding; liposome leakage experiments demonstrate that GSDMA 1-246aa can form pores on specific liposomes; sequence alignment results show that this cleavage site is conserved in mouse Gsdma1; SpeB-induced Gsdma1 cleavage can induce small Pyroptosis of murine epithelial cells; Gsdma1 cleavage can be detected at the site of GAS infection in mice; knockout of Gsdma1 makes it more sensitive to GAS infection than wild-type mice
.
This study is the first to discover and report that GSDMA molecules (“cannons”) expressed by skin epithelial cells (KCs, “treasure ships”) both serve as exogenous pathogen receptors to recognize Streptococcus pyogenes (GAS, “corsair”) virulence factor SpeB (“hooklock”).
"), at the same time as an immune effector to punch holes in the cell membrane ("barrel") and release inflammatory factors ("gunfire") to cause cell pyroptosis and purulent necrotic lesions of the skin to control further systemic infection by pathogenic bacteria
.
This study revealed a novel mechanism in the body's immune defense response-single protein (GSDMA) as both a pathogen sensor and a host effector, and provided a new clinical treatment for related diseases caused by pathogenic bacteria such as Streptococcus pyogenes infection.
Targets and new ideas
.
Research reveals a novel immune response mechanism against Streptococcus pyogenes infection (schematic drawing: Yu He) Source: Pasteur Institute, Shanghai, Chinese Academy of Sciences
