Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

Sumitomo, Tomoko; Nakata, Masao; Higashino, Miharu; Yamaguchi, M.; Kawabata, Shigetada

doi:10.1038/srep20069

Cited by 45 publications

(30 citation statements)

References 48 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…E-cadherin promoted the cell-to-cell adhesion and integrity of the epithelial barrier, and, accordingly, GAS translocation across epithelial monolayers was suppressed by the knockout of slo or nga. Sumitomo et al have reported that streptolysin S and a cysteine protease contribute to bacterial translocation by perhaps directly destabilizing intercellular junction proteins such as E-cadherin [39,42,44]. Our data suggest that invading GAS may support the translocation of extracellular GAS and may facilitate invasion into deeper tissues.…”

Section: Discussionmentioning

confidence: 54%

Intracellular Group AStreptococcusinduces Golgi fragmentation to impair host defenses through Streptolysin O and NAD-glycohydrolase

Nozawa

Iibushi

Toh

et al. 2020

Preprint

View full text Add to dashboard Cite

Group A Streptococcus (GAS; Streptococcus pyogenes) is a major human pathogen that causes streptococcal pharyngitis, skin and soft-tissue infections, and life-threatening conditions such as streptococcal toxic-shock syndrome. During infection, GAS not only invades diverse host cells, but also injects effector proteins such as NAD-glycohydrolase (Nga) into the host cells through a streptolysin O (SLO)-dependent mechanism without invading the cells; Nga and SLO are two major virulence factors that are associated with increased bacterial virulence. Here, we have shown that the invading GAS induces fragmentation of the Golgi complex and inhibits anterograde transport in the infected host cells through the secreted toxins SLO and Nga. GAS infection-induced Golgi fragmentation required both bacterial invasion and SLO-mediated Nga translocation into the host cytosol. The cellular Golgi network is critical for the sorting of surface molecules and thus is essential for epithelial barrier integrity and the immune response of macrophages to pathogens. In epithelial cells, inhibition of anterograde trafficking by invading GAS and Nga resulted in the redistribution of E-cadherin to the cytosol and an increase in bacterial translocation across the epithelial barrier. Moreover, in macrophages, interleukin-8 secretion in response to GAS infection was found to be suppressed by intracellular GAS and Nga. Our findings reveal a previously undescribed bacterial invasion-dependent function of Nga as well as a previously unrecognized GAS-host interaction that is associated GAS pathogenesis.ImportanceTwo prominent virulence factors of GAS, SLO and Nga, have been established to be linked to enhanced pathogenicity of prevalent GAS strains. Recent advances show that SLO and Nga are important for intracellular survival of GAS in epithelial cells and macrophages. Here, we found that invading GAS disrupt the Golgi complex in host cells by SLO and Nga. We showed that GAS-induced Golgi fragmentation requires bacterial invasion into host cells, SLO pore-formation activity, and Nga NADase activity. GAS-induced Golgi fragmentation resulted in the impairment of epithelial barrier and chemokine secretion in macrophages. This immune inhibition property of SLO and Nga by intracellular GAS indicates that the invasion of GAS is associated with virulence exerted by SLO and Nga.

show abstract

Section: Discussionmentioning

confidence: 54%

Intracellular Group AStreptococcusinduces Golgi fragmentation to impair host defenses through Streptolysin O and NAD-glycohydrolase

Nozawa

Iibushi

Toh

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…GAS infection studies in animals have provided strong evidence that GAS has the ability to manipulate the host fibrinolytic system at many levels [88,89]. On one hand, hijacking the host Plg/Plm on the bacterial surface has provided an energy-efficient strategy to break down the fibrin network during dissemination [55,57,90], and this is achieved with the aid of PAM. Using GAS strains which express both SK2b and PAM genes, it was shown that inactivation of either genes significantly reduces virulence [59].…”

Section: Resultsmentioning

confidence: 99%

Toward Better Understanding on How Group AStreptococcusManipulates Human Fibrinolytic System

Quek

Whisstock²,

Law

2020

Staphylococcus and Streptococcus

View full text Add to dashboard Cite

Group A Streptococcus pyogenes (GAS) is a human pathogen that commonly causes superficial infections such as pharyngitis, but can also lead to systemic and fatal diseases. GAS infection remains to be a major threat in regions with insufficient medical infrastructures, leading to half a million deaths annually worldwide. The pathogenesis of GAS is mediated by a number of virulence factors, which function to facilitate bacterial colonization, immune evasion, and deep tissue invasion. In this review, we will discuss the mechanism of molecular interaction between the host protein and virulence factors that target the fibrinolytic system, including streptokinase (SK), plasminogen-binding group A streptococcal M-like protein (PAM), and streptococcal inhibitor of complement (SIC). We will discuss our current understanding, through structural studies, on how these proteins manipulate the fibrinolytic system during infection.

show abstract

“…Association and dissociation reactions of GP96 to pneumococcal Ali proteins were analyzed using a BIAcore optical biosensor (BIAcore X-100 system, GE Healthcare Life Sciences), as previously described 48 . Briefly, recombinant GP96 (20 g ml -1 in 10 mM sodium acetate, pH 4) was covalently immobilized on a CM5 sensor chip using an Amine coupling kit (GE Healthcare immobilized bacterial surface proteins for 90 minutes at 37ºC.…”

Section: Surface Plasmon Resonance Analysismentioning

confidence: 99%

GP96 drives exacerbation of secondary bacterial pneumonia following influenza A virus infection

Sumitomo

Nakata

Nagase

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Influenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperon GP96 on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin αV, with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96, as well as addition of RGD peptide. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract.

show abstract

Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions

Cited by 45 publications

References 48 publications

Intracellular Group AStreptococcusinduces Golgi fragmentation to impair host defenses through Streptolysin O and NAD-glycohydrolase

Intracellular Group AStreptococcusinduces Golgi fragmentation to impair host defenses through Streptolysin O and NAD-glycohydrolase

Toward Better Understanding on How Group AStreptococcusManipulates Human Fibrinolytic System

GP96 drives exacerbation of secondary bacterial pneumonia following influenza A virus infection

Contact Info

Product

Resources

About