Endocarditis Pathogen Promotes Vegetation Formation by Inducing Intravascular Neutrophil Extracellular Traps Through Activated Platelets
Background—Endocarditis-inducing streptococci form multi-layered biofilms in complex with aggregated platelets on injured heart valves. But host factors that interconnect and entrap these bacteria-platelet aggregates to promote vegetation formation were unclear.
Methods and Results—In a Streptococcus mutans endocarditis rat model, we identified layers of neutrophil extracellular traps (NETs) interconnecting and entrapping bacteria-platelet aggregates inside vegetation that could be reduced significantly in size along with diminished colonizing bacteria by prophylaxis with intravascular DNase I alone. The combination of activated platelets and specific IgG-adsorbed bacteria are required to induce the formation of NETs through multiple activation pathways. Bacteria play key roles in coordinating the signaling through spleen tyrosine kinase, Src family kinases, phosphatidylinositol-3-kinase, and p38 mitogen-activated protein kinase pathways to up-regulate the expression of P-selectin in platelets, while inducing reactive oxygen species-dependent citrullination in the arm of neutrophils. NETs in turn serve as the scaffold to further enhance and entrap bacteria-platelet aggregate formation and expansion.
Conclusions—NETs promote and expand vegetation formation through enhancing and entrapping bacteria-platelet aggregates on the injured heart valves.
- Received May 29, 2014.
- Revision received November 11, 2014.
- Accepted December 10, 2014.