Platelets and their immunomodulatory roles during Streptococcus pyogenes infection

Sinead Hurley

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

400 Nedladdningar (Pure)


Sepsis and invasive bacterial infection is a major cause of human disease and death worldwide. Streptococcus pyogenes is one of the major pathogens responsible for bacterial infections, which range from mild to severe and life threatening conditions. S. pyogenes contains a cell wall anchored M protein, which is an important virulence factor that can interact with many cells of the immune system. One of the smallest and most rapidly responding cells in our bloodstream are platelets and they are a main focus for the studies presented in this thesis and have been investigated.
The overall aim of this thesis was to delineate and understand the role of platelets, neutrophils and endothelial cells in response to bacterial infection and sepsis pathogenesis in both in vitro and in vivo model systems.
Platelets can bind to neutrophils, resulting in the formation of heterotypic complexes, however the function of neutrophils within these complexes has not been described. In paper I, we investigated platelet-neutrophil complexes (PNCs) generated in response to thrombin, a key factor involved in coagulation and compared these to complexes formed in response to S. pyogenes M1 protein. We determined that platelet dependent neutrophil activation occurs in response to thrombin, while S. pyogenes M1 protein compromised neutrophil functions by a platelet-dependent mechanism. In addition, this was dependent on donor specific IgG against M1 protein. This paper highlights the modulation of neutrophil function by platelets during inflammation and infection.
In paper II, platelet aggregation and platelet-leukocyte complex formation was investigated in whole blood in response to S. pyogenes bacteria. Platelet aggregation occurred and heterotypic complexes were formed between activated platelets and neutrophils and monocytes. Platelet dependent activation of these leukocytes was observed and bacteria were associated with the platelet and leukocyte complexes. The platelet aggregates remained stable over time, were viable and did not disaggregate. Taken together this study provides new insights into the role of platelets and heterotypic complex formation for bacterial survival in blood.

In papers III and IV, the contribution of platelets and the kinetics of platelet activation during invasive S. pyogenes infection were investigated in vivo in a mouse model. We demonstrated that during a bacterial infection thrombocytopenia, neutrophil activation and platelet-neutrophil complex formation occurs.
The acute pro-inflammatory response to the infection and diminished bacterial dissemination in platelet-depleted animals indicated that platelets contribute to the immune response. In paper IV we determined that monitoring platelet activation, particularly PNC formation might provide prognostic information during the progression of sepsis. Platelet activation occurred and aggregated platelets accumulated in the liver at the late stages of sepsis.
In paper V, we investigated the effect of the S. pyogenes M1 protein on endothelial cells in vitro using two cell lines. We have demonstrated that M1 protein binds to endothelial cells, increases endothelial cell vascular permeably in a TLR-2 and Rho kinase dependent manner and generates limited cytokine release. This may reflect an innate immune recognition of the bacterial protein, however increased vascular permeability and vascular leakage has also been reported to contribute to the pathogenesis of streptococcal infection.
Collectively, this thesis has revealed multiple strategies for S. pyogenes to modulate the host immune response during invasive bacterial infection by interacting directly and indirectly with platelets, neutrophils, monocytes and endothelial cells.
Tilldelande institution
  • Infektionsmedicin
  • Shannon, Oonagh, handledare
  • Nordenfelt, Pontus, handledare
  • Herwald, Heiko, handledare
Tilldelningsdatum2016 mars 31
ISBN (tryckt)978-91-7619-256-6
StatusPublished - 2016

Bibliografisk information

Defence details

Date: 2016-03-31
Time: 09:15
Place: Belfragesalen, BMC D15, Klinikgatan 32, Lund.

External reviewer(s)

Name: Kerrigan, Steven W.
Title: Dr.
Affiliation: [unknown]


Ämnesklassifikation (UKÄ)

  • Mikrobiologi inom det medicinska området


Utforska forskningsämnen för ”Platelets and their immunomodulatory roles during Streptococcus pyogenes infection”. Tillsammans bildar de ett unikt fingeravtryck.

Citera det här