Activation of the contact-phase system on bacterial surfaces—a clue to serious complications in infectious diseases

Herwald, Heiko; Mörgelin, Matthias; Olsén, Arne; Rhen, Mikael; Dahlbäck, Björn; Müller‐Esterl, Werner; Björck, Lars

doi:10.1038/nm0398-298

Cited by 187 publications

(163 citation statements)

References 26 publications

Supporting

Mentioning

156

Contrasting

Order By: Relevance

“…In addition to its role in hemostasis, the blood clotting system plays an important role in host defense against pathogens by stimulating inflammation, fibrin deposition, and possibly other mechanisms (19)(20)(21)(22). In addition, the contact pathway of blood clotting, although dispensable for normal hemostasis, appears to play important roles in kinin generation and host-pathogen interactions (23).…”

Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

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

497

623

View full text Add to dashboard Cite

Inorganic polyphosphate is an abundant component of acidocalcisomes of bacteria and unicellular eukaryotes. Human platelet dense granules strongly resemble acidocalcisomes, and we recently showed that they contain substantial amounts of polyphosphate, which is secreted upon platelet activation. We now report that polyphosphate is a potent hemostatic regulator, accelerating blood clotting by activating the contact pathway and promoting the activation of factor V, which in turn results in abrogation of the function of the natural anticoagulant protein, tissue factor pathway inhibitor. Polyphosphate was also found to delay clot lysis by enhancing a natural antifibrinolytic agent, thrombin-activatable fibrinolysis inhibitor. Polyphosphate is unstable in blood or plasma, owing to the presence of phosphatases. We propose that polyphosphate released from platelets or microorganisms initially promotes clot formation and stability; subsequent degradation of polyphosphate by blood phosphatases fosters inhibition of clotting and activation of fibrinolysis during wound healing.factor V ͉ platelets ͉ tissue factor pathway inhibitor ͉ acidocalcisomes ͉ dense granules P olyphosphate (polyP) is widely distributed in biology, being found in bacteria, fungi, plants, and animals (1). The biologic functions of polyP have been studied most extensively in prokaryotes and unicellular eukaryotes, in which high levels of polyP accumulate in acidic organelles known as acidocalcisomes. PolyP in these organisms can reach chain lengths of several hundred phosphate units. In unicellular organisms, polyP has been shown to play essential roles in stress responses and virulence (1, 2), although its function in higher eukaryotes, including man, has not been extensively investigated. Recently, we reported that dense granules of human platelets strongly resemble acidocalcisomes and contain millimolar levels of polyP (with chain lengths of Ϸ70-75 phosphate units), making acidocalcisomes the only known class of organelle conserved during evolution from bacteria to humans (3). Human platelets each have three to eight dense granules (also called ␦ granules), a type of secretory granule that contains serotonin, ADP, ATP, and PP i in addition to polyP. Patients with dense granule defects exhibit bleeding diatheses, underscoring the role of these secretory granules in hemostasis (4). Platelets contain Ϸ0.74 nmol polyP per 10 8 platelets, which is secreted after stimulation by platelet agonists such as thrombin (3). Therefore, released polyP could readily attain a concentration of 3 M in whole blood, and this could be far higher in platelet-rich thrombi. (Concentrations of polyP are expressed in this paper as phosphate monomer.)The importance of platelets in hemostasis suggested to us that polyP may play an important role in the blood clotting system. In this study, we found that polyP of the size released from activated platelets has a strongly net procoagulant effect, which is exerted at several levels in the clotting͞fibrinolysis system: PolyP activate...

show abstract

Section: Resultsmentioning

confidence: 99%

Polyphosphate modulates blood coagulation and fibrinolysis

Smith

Mutch

Baskar

et al. 2006

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

497

623

View full text Add to dashboard Cite

show abstract

“…Binding assays were performed as previously described (15). Briefly, 200 l of bacterial suspensions were incubated with 25 l (ϳ8 ϫ 10 5 cpm/ml) radioactively labeled protein for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…When injected into animals, curli-expressing bacteria disrupt the coagulation cascade by modulating the contact system and trigger inflammatory reactions by activating inducible nitricoxide synthase (12,15,16). Moreover, it has been observed that E. coli bacteria expressing curli and a mutant strain secreting soluble CsgA stimulate a human macrophage cell line to produce proinflammatory cytokines (17).…”

mentioning

confidence: 99%

The Conversion of Fibrinogen to Fibrin at the Surface of Curliated Escherichia coli Bacteria Leads to the Generation of Proinflammatory Fibrinopeptides

Persson¹,

Russell

Mörgelin

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The inflammatory response to bacterial infection is the result of a complex interplay between bacterial products and host effector systems, such as the immune and complement systems. Here we show that Escherichia coli bacteria expressing fibrous surface proteins, known as curli, assemble and activate factors of the human coagulation cascade at their surface. As a result of this interaction, fibrinogen is converted to fibrin and fibrinogen-derived peptides, termed fibrinopeptides, are generated. The molecular mechanisms behind the bacteria-induced formation of fibrinopeptides were investigated and shown to be triggered by the activation of the contact system, also known as the kallikrein/kinin system or the intrinsic pathway of coagulation. Samples containing fibrinopeptides generated by the interaction between bacteria and plasma were injected into animals and the inflammatory response was monitored. We found that this treatment provoked an infiltration of white blood cells, and the induction of the proinflammatory cytokine MCP-1 at the inflamed site. Our results therefore demonstrate that activation of the coagulation system at the bacterial surface contributes to the pathophysiology of bacterial infectious diseases.

show abstract

“…Agf fibers are fimbrial organelles that bind Congo red and soluble fibronectin (14), contact phase proteins (31), and promote adhesion to the mouse small intestinal epithelial cells (23). As the mutation responsible for the altered agf expression was unknown, we used a transposon mapping approach to identify the locus responsible.…”

Section: Mapping a Locus Associated With Agfa Fimbrial Expression Andmentioning

confidence: 99%

Polynucleotide phosphorylase is a global regulator of virulence and persistency in Salmonella enterica

Clements

Eriksson

Thompson

et al. 2002

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

Self Cite

154

133

View full text Add to dashboard Cite

For many pathogens, the ability to regulate their replication in host cells is a key element in establishing persistency. Here, we identified a single point mutation in the gene for polynucleotide phosphorylase (PNPase) as a factor affecting bacterial invasion and intracellular replication, and which determines the alternation between acute or persistent infection in a mouse model for Salmonella enterica infection. In parallel, with microarray analysis, PNPase was found to affect the mRNA levels of a subset of virulence genes, in particular those contained in Salmonella pathogenicity islands 1 and 2. The results demonstrate a connection between PNPase and Salmonella virulence and show that alterations in PNPase activity could represent a strategy for the establishment of persistency.T he species Salmonella enterica is a classic example of the facultative intracellular pathogen that can cause acute and persistent infections (1-4). Typhoid fever is a serious manifestation of systemic salmonellosis in humans and involves an estimated 16.6 million new cases per year (2) with between 2% and 5% of the cases developing into the carrier state (3, 4).Much of the knowledge of salmonellosis pathogenesis comes from work on the murine salmonellosis model (1, 5), and this model has been used to define bacterial virulence factors (1, 6, 7). An important virulence trait of Salmonella is its ability to invade and grow within host cells, and many of the genetic determinants essential for these processes have been well characterized (8-11). Invasion of epithelial cells requires the expression of a type III secretion apparatus, which translocates effector proteins from the bacterium to the host cell, inducing the cell to internalize the bacteria by bacterial-mediated endocytosis (8,11). Proteins involved in this process are encoded by a large cluster of genes collectively termed Salmonella pathogenicity island 1 (SPI 1). The ability to grow intracellularly, once internalized within the host cell, requires the coordinate expression of additional sets of virulence factors (6), such as SPI 2 (1, 10).Although chronic carriage of Salmonella is recognized as a significant complication that facilitates spread of the disease (2) and predisposes victims to additional clinical conditions (12, 13) the mechanism underlying persistency has remained poorly understood. We discovered the link between polynucleotide phosphorylase (PNPase) and chronic infection while characterizing a mutant of Salmonella typhimurium that was defective in its expression of virulence-associated AgfA fimbriae and known to establish persistent infection in BALB͞c mice (14). Materials and Methods Mapping and Sequencing of MC2 Mutation.A random Tn10camd insertion library from S. typhimurium 14028 (22) was transduced into MC1 by P22 transduction selecting for chloramphenicolresistant colonies. Transductants were pooled and used to propagate phage KB1, which was then used to transduce MC2. Chloramphenicol-resistant colonies were screened for agf expression on Congo red pla...

show abstract

Activation of the contact-phase system on bacterial surfaces—a clue to serious complications in infectious diseases

Cited by 187 publications

References 26 publications

Polyphosphate modulates blood coagulation and fibrinolysis

Polyphosphate modulates blood coagulation and fibrinolysis

The Conversion of Fibrinogen to Fibrin at the Surface of Curliated Escherichia coli Bacteria Leads to the Generation of Proinflammatory Fibrinopeptides

Polynucleotide phosphorylase is a global regulator of virulence and persistency in Salmonella enterica

Contact Info

Product

Resources

About