STREPSEP

Identification and characterization of targets for the treatment of severe infections caused by Streptococcus pyogenes

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 Obiettivo del progetto (Objective)

'Life-threatening complications from bacterial infections, such as sepsis and septic shock, are the second leading cause of death among patients in non-coronary intensive care units killing up to 146 000 patients each year in Europe. These alarming findings prompted many research groups, to search for novel strategies to treat severe infectious diseases. Many of these approaches are focused on so-called “host effector systems”, since evidence has accumulated that complications from an infection are caused by an over-stimulation of host defense systems that are modulated by bacteria or bacterial products. In severe infections, such as sepsis and septic shock, vascular leakage, increased cytokine levels, and coagulation/fibrinolysis dysfunction are often observed. Thus, the research projects presented in this application focus on the identification and characterization of molecular mechanisms that lead to these complications with a focus on severe infections caused by the human pathogen Streptococcus pyogenes. The results obtained from such investigations could be used for the discovery of novel treatments in infectious diseases.'

Introduzione (Teaser)

Bacterial infections are a major challenge in European hospitals. Novel studies and discoveries are leading to new treatments.

Descrizione progetto (Article)

The second leading cause of death among patients in non-coronary intensive care units is serious complications from bacterial infections, such as sepsis (blood infection) and septic shock. These complications kill up to 146,000 patients each year in Europe, prompting research groups to look for novel ways to treat severe infectious diseases.

Generally, treatment has focused on combating complications caused by an over-stimulation of host defence systems attacked by bacteria. In severe infections such as sepsis and septic shock, vascular leakage, increased cytokine (regulatory protein) levels and coagulation (blood clotting) dysfunction often occur. Medical research has relied on identifying molecular mechanisms that lead to these complications, with particular focus on severe infections caused by the human pathogen Streptococcus pyogenes.

The entirely EU-funded Strepsep project has conducted intense research in this area. It has focused on the contact system, or when blood contacts specific surfaces and initiates coagulation. This mechanism has often been implicated in sepsis and inflammation, in association with Streptococcus pyogenes. In such cases, mice have been shown to suffer from massive tissue damage in the lungs.

The researchers behind Strepsep have produced some positive results in this respect. They found that a certain peptide (amino-acid compound) called HKH20 improved inflammatory reactions caused by the bacteria in sepsis and protected mice from Streptococcus pyogenes. HKH20 prevented tissue damage and bleeding in the lungs, prolonging survival time and increasing overall survival rate.

A complementary part of the treatment focused on neutrophils, known as the frontline defence against infections. Neutrophils are known to engulf microbes and secrete antimicrobials. In recent years, a new mechanism was discovered, that of neutrophil extracellular traps (NETs) which also activate the contact system.

Strepsep also showed that a specific protein from Streptoccocus pyogenes in complex with fibrinogen (a plasma protein), can trigger induction of NETS. This has contributed to developing hypotheses for new drugs and treatments, in combination with the HKH20 finding.

Drugs based on both these findings could have far-reaching health and socio-economic benefits for Europe.