Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regula...Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.展开更多
Invasive infection caused by Streptococcus pyogenes emm89 strains has been increasing in several countries linked to a recently emergent clade of emm89 strains,designated clade 3.In Japan,the features of emm89 S.pyoge...Invasive infection caused by Streptococcus pyogenes emm89 strains has been increasing in several countries linked to a recently emergent clade of emm89 strains,designated clade 3.In Japan,the features of emm89 S.pyogenes strains,such as clade classification,remains unknown.In this study,we collected emm89 strains isolated from both streptococcal toxic shock syndrome(STSS)(89 STSS isolates)and noninvasive infections(72 non-STSS isolates)in Japan from 2011 to 2019,and conducted wholegenome sequencing and comparative analysis,which resulted in classification of a large majority into clade 3 regardless of disease severity.In addition,invasive disease-associated factors were found among emm89 strains,including mutations of control of virulence sensor,and absence of the hylP1 gene encoding hyaluronidase.These findings provide new insights into genetic features of emm89 strains.展开更多
基金supported in part by Marie Skłodowska-Curie actions Intra-European Fellowships(MC-IEF-329520)The Naito Foundation,The Takeda Science Foundation,and the US National Institutes of Health(R01-AI145325)。
文摘Autophagy serves an innate immune function in defending the host against invading bacteria,including group A Streptococcus(GAS).Autophagy is regulated by numerous host proteins,including the endogenous negative regulator calpain,a cytosolic protease.Globally disseminated serotypeM1T1 GAS strains associated with high invasive disease potential express numerous virulence factors and resist autophagic clearance.Upon in vitro infection of human epithelial cell lines with representative wild-type GAS M1T1 strain 5448(M1.5448),we observed increased calpain activation linked to a specific GAS virulence factor,the interleukin-8 protease SpyCEP.Calpain activation inhibited autophagy and decreased capture of cytosolic GAS in autophagosomes.In contrast,the serotype M6 GAS strain JRS4(M6.JRS4),which is highly susceptible to host autophagy-mediated killing,expresses low levels of SpyCEP and does not activate calpain.Overexpression of SpyCEP in M6.JRS4 stimulated calpain activation,inhibited autophagy,and significantly decreased bacterial capture in autophagosomes.These paired loss-and gain-of-function studies reveal a novel role for the bacterial protease SpyCEP in enabling GAS M1 evasion of autophagy and host innate immune clearance.
基金AMED(Grant numbers:JP19fk0108044,JP19fm0208007)Japanese Society for the Promotion of Science(JSPS)KAKENHI(Grant numbers:19H03825,20K18474)。
文摘Invasive infection caused by Streptococcus pyogenes emm89 strains has been increasing in several countries linked to a recently emergent clade of emm89 strains,designated clade 3.In Japan,the features of emm89 S.pyogenes strains,such as clade classification,remains unknown.In this study,we collected emm89 strains isolated from both streptococcal toxic shock syndrome(STSS)(89 STSS isolates)and noninvasive infections(72 non-STSS isolates)in Japan from 2011 to 2019,and conducted wholegenome sequencing and comparative analysis,which resulted in classification of a large majority into clade 3 regardless of disease severity.In addition,invasive disease-associated factors were found among emm89 strains,including mutations of control of virulence sensor,and absence of the hylP1 gene encoding hyaluronidase.These findings provide new insights into genetic features of emm89 strains.
