Platelets promote bacterial dissemination in a mouse model of streptococcal sepsis

Kahn, Fredrik; Hurley, Sinead; Shannon, Oonagh

doi:10.1016/j.micinf.2013.05.003

Cited by 36 publications

(44 citation statements)

References 23 publications

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“…This provided us with a unique opportunity to study the role of direct platelet-bacteria interactions during invasive infection. Mouse platelets will not become aggregated in response to bacterial pathogens that utilize an IgG-dependent mechanism of platelet activation, such as GAS (Kahn et al, 2013). Importantly, we confirmed that platelet activation and thrombocytopenia occurred during invasive GGS infection, verifying that our model exhibits important hallmarks of invasive human infection.…”

Section: Discussionsupporting

confidence: 69%

“…The direct contribution of FOG to bacterial dissemination and pathogenesis of infection was not investigated in our animal model, since the focus of our hypothesis was the contribution of platelet activation and aggregation to the pathogenesis of GGS infection. Platelets have been reported to contribute to the pathogenesis of GAS infection in an animal model (Kahn et al, 2013); however, platelets have also been proposed to protect in an animal model of sepsis (de Stoppelaar et al, 2014;Xiang et al, 2013). Interestingly, studies of human sepsis patients indicate that antiplatelet therapy is beneficial for the outcome of invasive infection (Winning et al, 2009;Otto et al, 2013;Akinosoglou & Alexopoulos, 2014).…”

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confidence: 99%

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Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

2016

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Platelets have been reported to become activated in response to bacteria and this is proposed to contribute to the acute response to bacterial infection. In the present study, we investigated platelet aggregation in response to group G streptococci (GGS) in vitro in healthy human donors and in vivo in a mouse model of streptococcal sepsis. Platelet aggregation by GGS was dependent on the bacterial surface protein FOG and engagement of the platelet fibrinogen receptor; however, it was independent of IgG and the platelet Fc receptor. Platelets exerted no antibacterial effects on the bacteria, and aggregates formed were markedly unstable, allowing bacteria to rapidly return to the plasma and grow post-aggregation. Thrombocytopenia and platelet activation occurred during invasive infection with GGS, and platelets were demonstrated to contribute to bacterial dissemination during infection. These findings reveal an important role for bacteria-platelet interactions during the pathogenesis of streptococcal infection.

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Section: Discussionsupporting

confidence: 69%

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confidence: 99%

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

2016

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“…The ability of S. pyogenes to bind fibrinogen is associated with enhanced bacterial survival in blood (28,29). Importantly, we have recently demonstrated that platelets contribute to the dissemination of S. pyogenes in a mouse model of streptococcal sepsis (30); however, the direct role of bacterium-mediated platelet activation cannot be addressed in this murine model, since mouse platelets lack the Fc receptor required to mediate platelet aggregation in response to the bacteria.…”

Section: Discussionmentioning

confidence: 96%

Platelet Activation by Streptococcus pyogenes Leads to Entrapment in Platelet Aggregates, from Which Bacteria Subsequently Escape

et al. 2014

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Platelet activation and aggregation have been reported to occur in response to a number of Gram-positive pathogens. Here, we show that platelet aggregates induced by Streptococcus pyogenes were unstable and that viable bacteria escaped from the aggregates over time. This was not due to differential activation in response to the bacteria compared with physiological activators. All the bacterial isolates induced significant platelet activation, including integrin activation and alpha and dense-granule release, at levels equivalent to those induced by potent physiological platelet activators that induced stable aggregates. The ability to escape the aggregates and to resist the antibacterial effects of platelets was dependent on active protein synthesis by the bacteria within the aggregate. We conclude that S. pyogenes bacteria can temporarily cover themselves with activated platelets, and we propose that this may facilitate survival of the bacteria in the presence of platelets.

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“…Platelets and prothrombotic blood coagulation factors can play harmful roles in sepsis when they fuel pathogen-driven coagulopathy that results in thromboembolic tissue damage, often with a fatal outcome. Aberrations in platelet activity may further complicate sepsis by binding and disseminating bacteria throughout the bloodstream (16,17) or by contributing to granzyme B-mediated killing of splenocytes (18). Regulation of glycoprotein homeostasis by the AMR has been imperceptible to multiple studies of genomic variation and transcriptional outputs, reflecting posttranslational and enzymatic processes that modulate metabolism and which are increasingly linked to the origins of common diseases and syndromes (19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

Grewal

Aziz

Uchiyama

et al. 2013

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

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The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.

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Platelets promote bacterial dissemination in a mouse model of streptococcal sepsis

Cited by 36 publications

References 23 publications

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

Group G streptococci mediate fibrinogen-dependent platelet aggregation leading to transient entrapment in platelet aggregates

Platelet Activation by Streptococcus pyogenes Leads to Entrapment in Platelet Aggregates, from Which Bacteria Subsequently Escape

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

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