How Group A
 Streptococcus
 Circumvents Host Phagocyte Defenses

Kwinn, Laura A; Nizet, Victor

doi:10.2217/17460913.2.1.75

Cited by 62 publications

(49 citation statements)

References 85 publications

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“…Although Th17 responses to other bacteria and fungi were reported (27), a link to induction of specific cytokines by these microbes has not been established. IL-6 is an inflammatory cytokine commonly induced by a variety of pathogens, including Lm (28,29). Experiments here show that GAS elicits TGF-β1-dependent secretion of IL-17 and a dominant Th17 response, whereas Lm fails to induce TGF-β1 and only induces a weak Th17 response, suggesting that TGF-β1 is the decisive signal for Th17 differentiation.…”

Section: Discussionmentioning

confidence: 64%

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Wang¹,

Dileepan²,

Briscoe³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

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Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-β1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-β1 induction on the Tcell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-β1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-β1 and IL-6 production, signals required for promotion of a Th17 immune response. As predicted, IL-17, the Th17 signature cytokine, was induced in a TGF-β1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. mice. These experiments link specific induction of TGF-β1 by a bacterial infection to an in vivo Th17 immune response and show that this cellular response is sufficient for protection against GAS. The association of a Th17 response with GAS infection reveals a potential mechanism for destructive autoimmune responses in humans.

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Section: Discussionmentioning

confidence: 64%

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Wang¹,

Dileepan²,

Briscoe³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

118

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“…The pathogenesis of S pyogenes infection is a complex multifactorial process, and diverse host systems are involved. [10][11][12] For instance, S pyogenes can counteract phagocytosis, complement activity, antibody recognition, and antimicrobial peptides. S pyogenes infection also involves important interactions with the host hemostasis system, and the bacteria have been shown to bind to and modulate the function of several important factors involved in coagulation and fibrinolysis: fibrinogen, 13,14 coagulation factors, 15 plasminogen, 16,17 and platelets.…”

Section: Introductionmentioning

confidence: 99%

Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis

Shannon

Rydengård

Schmidtchen

et al. 2010

Blood

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Streptococcus pyogenes is a significant bacterial pathogen in humans. In this study, histidine-rich glycoprotein (HRG), an abundant plasma protein, was found to kill S pyogenes. Furthermore, S pyogenes grew more efficiently in HRG-deficient plasma, and clots formed in this plasma were significantly less effective at bacterial entrapment and killing. HRG-deficient mice were strikingly more susceptible to S pyogenes infection. These animals failed to control the infection at the local subcutaneous site, and abscess formation and inflammation were diminished compared with control animals. As a result, bacterial dissemination occurred more rapidly in HRG-deficient mice, and they died earlier and with a significantly higher mortality rate than control animals.HRG-deficient mice supplemented with purified HRG gave the same phenotype as control animals, demonstrating that the lack of HRG was responsible for the increased susceptibility. The results demonstrate a previously unappreciated role for HRG as a regulator of inflammation and in the defense at the local site of bacterial infection. (Blood. 2010;116(13):2365-2372) IntroductionHistidine-rich glycoprotein (HRG) is an abundant plasma protein synthesized in the liver and also stored in the ␣-granules of platelets, from which it is released on activation. 1 The protein has a diverse array of ligands, including heparin, plasminogen, immunoglobulin, thrombospondin, and fibrinogen. 2 The diversity of ligands probably contributes to the fact that new activities are regularly attributed to HRG in vitro, whereas a definitive biologic function in vivo has been difficult to identify. Based on in vitro studies, HRG has been reported to modulate angiogenesis, 3 phagocytosis, 4 and complement function 5 and to be antibacterial. 6 HRG is negatively charged at physiologic pH but becomes positively charged at low pH or in the presence of zinc. Several the reported biologic effects have also been shown to be dependent on pH or zinc, suggesting that HRG may be a sensitive adaptor molecule to changing environments. 7 The generation of HRG-knockout mice has facilitated the search for the biologic function of HRG. These animals were viable with no apparent abnormalities, but ex vivo studies demonstrated a mild dysregulation of hemostasis with effects on plasma-clotting factors and platelets, and in vivo HRG seemed to have both anticoagulant and antifibrinolytic properties. 8 Recently, it has been shown that HRG-deficient animals have diminished antifungal activity in vivo. 9 In the present study, we have assessed the role of HRG in response to a pathologic situation (ie, bacterial infection). Streptococcus pyogenes is a significant human bacterial pathogen responsible for both superficial and invasive infection. The pathogenesis of S pyogenes infection is a complex multifactorial process, and diverse host systems are involved. [10][11][12] For instance, S pyogenes can counteract phagocytosis, complement activity, antibody recognition, and antimicrobial peptides. S pyogenes infection al...

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“…C3b plays a central role in the innate immune response to bacterial infection, and opsonization of bacteria with C3b facilitates neutrophil phagocytosis. GAS have evolved numerous strategies to minimize complement deposition at the bacterial cell surface, including expression of M protein [18]. The presence of M6 and M49 at the GAS cell surface has been linked to protection from C3b-mediated phagocytosis [19], while fibrinogen and factor H binding by certain M serotypes has been shown to block C3b deposition at the bacterial cell surface [18].…”

Section: Discussionmentioning

confidence: 99%

“…GAS have evolved numerous strategies to minimize complement deposition at the bacterial cell surface, including expression of M protein [18]. The presence of M6 and M49 at the GAS cell surface has been linked to protection from C3b-mediated phagocytosis [19], while fibrinogen and factor H binding by certain M serotypes has been shown to block C3b deposition at the bacterial cell surface [18]. To date, over 200 different M protein types have been identified, and M protein function is highly diverse [20].…”

Section: Discussionmentioning

confidence: 99%

Plasmin(ogen) Acquisition by Group A Streptococcus Protects against C3b-Mediated Neutrophil Killing

Taylor

Tsatsaronis

et al. 2013

J Innate Immun

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The globally significant human pathogen group A Streptococcus (GAS) sequesters the host protease plasmin to the cell surface during invasive disease initiation. Recent evidence has shown that localized plasmin activity prevents opsonization of several bacterial species by key components of the innate immune system in vitro. Here we demonstrate that plasmin at the GAS cell surface resulted in degradation of complement factor C3b, and that plasminogen acquisition is associated with a decrease in C3b opsonization and neutrophil-mediated killing in vitro. Furthermore, the ability to acquire cell surface plasmin(ogen) correlates directly with a decrease in C3b opsonization, neutrophil phagocytosis, and increased bacterial survival in a humanized plasminogen mouse model of infection. These findings demonstrate that localized plasmin(ogen) plays an important role in facilitating GAS escape from the host innate immune response and increases bacterial virulence in the early stages of infection.

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How Group A Streptococcus Circumvents Host Phagocyte Defenses

Cited by 62 publications

References 85 publications

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Histidine-rich glycoprotein promotes bacterial entrapment in clots and decreases mortality in a mouse model of sepsis

Plasmin(ogen) Acquisition by Group A <b><i>Streptococcus</i></b> Protects against C3b-Mediated Neutrophil Killing

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