1. Översiktlig projektbeskrivning

Engelsk titel

Fibrinolysis in infections

Sammanfattning av projektet

Hemostatic balance shifts towards coagulation during systemic infections. The most extreme manifestation of such imbalance is disseminated intravascular coagulation (DIC), which leads to multiple organ dysfunction syndrome and death. One of main reasons for systemic fibrin deposition leading to DIC is suppression of fibrinolytic system during infections. Bacterial plasminogen activators and plasminogen adhesins may act as virulence factors by enhancing the invasive capacity of bacteria, which give rise to more severe infection.
Aims: 1) To study the alteration of fibrinolytic process during infections. 2) To characterlize the staphylococcal plasminogen adhesin (spa) and to study the possible role of staphylokinase and spa in staphylococcal infection. 3) To study the possible role of fibrinolytic molecules in host protective immunity and potential interaction between host and bacterial fibrinolytic molecules. 4) To develop new therapeutic strategies against S. aureus infection based on modulating fibrinolytic system.
Preliminary results: We have recently demonstrated that during staphylococcal infection active urokinase levels decreased due to dramatically elevated plasminogen activator inhibitor type-1 (PAI-1). uPA acted as an endogenous antibiotics, thereby alleviating staphylococcal sepsis. We also found that SAK might be responsible for S. aureus evasion from innate immunity by efficient neutralization of bactericidal effect of human antibacterial peptides. SAK also interferes with uPA/uPAR interaction, and neutralizes plasminogen activation activity of uPA. In addition, we demonstrated that SAK is a virulence factor for staphylococcal arthritis using SAK transgenic S.aureus strains.
Significance: To dissect the roles of both bacterial and host fibrinolytic molecules in infectious diseases will help us to understand pathogenesis of life threatening infections. Regulating the hemostatic balance by targeting fibrinolytic system might be potential therapeutic strategy in case of infectious diseases and their complications.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva ämnesområdet

Inlagda MeSH-termer

Animal Experimentation

The use of animals as investigational subjects.

Research

Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. (Webster, 3d ed)

Mice

The common name for the genus Mus.

Fibrinolysis

The natural enzymatic dissolution of FIBRIN.

Staphylococcus

A genus of gram-positive, facultatively anaerobic, coccoid bacteria. Its organisms occur singly, in pairs, and in tetrads and characteristically divide in more than one plane to form irregular clusters. Natural populations of Staphylococcus are membranes of warm-blooded animals. Some species are opportunistic pathogens of humans and animals.

Infection

Invasion of the host organism by microorganisms that can cause pathological conditions or diseases.

Projektets delaktighet i utbildning

Avhandling
D-uppsats / Magisterexamen
C-uppsats / Kandidatexamen
ST-läkarutbildning
Annan utbildning
Ej del i utbildning

3. Processen och projektets redovisning

Pågående aktiviteter

Planering och förberedelse före datainsamling
Datainsamling pågår
Analys av insamlade data pågår
Författande av skriftlig redovisning / publikation pågår
En eller flera publikationer från projektet är publicerade
Slutfört och inget mer görs inom ramen för detta projekt

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2007-02-01

Datum för påbörjande av datainsamling

2008-02-01

Datum då projektet är slutrapporterat

2011-01-31

Publikationer från detta projekt

1. Fibrinolysis is down-regulated in mouse collagen-induced arthritis, but its normalization does not alleviate the course of disease.
   Kwieci Jakub, Josefsson Elisabet, Jin Tao.
   Inflamm Res. 2011:60(11):1021-9.[Source: PubMed®]
   [Links: PMID: 21786185 | DOI länk]
2. Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection.
   Kwieci Jakub, Josefsson Elisabet, Mitchell Jennifer, Higgins Judy, Magnusson Mattias, Foster Timothy, Jin Tao, Bokarewa Maria.
   J Infect Dis. 2010:202(7):1041-9.[Source: PubMed®]
   [Links: PMID: 20726765 | DOI länk]
3. Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis.
   K Marcin, Anäkkälä Nicola, Wang Wanzhong, Lange Stefan, Jonsson Ing-Marie, Tarkowski Andrej, Jin Tao.
   Scand J Infect Dis. 2010:42(5):351-8.[Source: PubMed®]
   [Links: PMID: 20100112 | DOI länk]

Tillämpning av resultat - tidsaspekt (projektledarens bedömning)

Resultaten kommer sannolikt att tillämpas inom 1 år från projektslut.

Tillämpning av resultat - genomslag (projektledarens bedömning)

Internationellt (i flera länder)

Tillämpning av resultat - beskrivning

We have found 1) Inhibition of plasminogen activation significantly aggravates staphylococcal septic arthritis and sepsis. 2)Activation of plasminogen by staphylokinase reduces the severity of Staphylococcus aureus systemic infection. Our results strongly suggest fibrinolytic system plays an important role in S. aureus systemic infection.