1. Översiktlig projektbeskrivning

Engelsk titel

Staphylococcus aureus surface proteins: their role in virulence and their potential as vaccine candidates

Sammanfattning av projektet

Syfte
Detta projekts syfte är att få mer kunskap om S. aureus-ytproteinernas roll vid infektion, och att hitta vaccinkandidater mot denna bakterie.

Bakgrund
Systemiska S. aureus-infektioner är allvarliga kliniska tillstånd som är svåra att behandla, inte minst på grund av den ständiga uppkomsten och spridningen av antibiotikaresistenta bakteriestammar. Det finns fortfarande inget vaccin mot S. aureus. Reumatoid artrit (RA) är en riskfaktor för septisk artrit. S. aureus är den vanligaste orsaken till septisk artrit. För utveckling av ett S. aureus-vaccin skulle det vara värdefullt att känna till vilka ytproteiner som är nyckelaktörer i sjukdomsutvecklingen.

Metod
Vi har tidigare visat att flera av S. aureus ytproteiner är virulensfaktorer i modeller för sepsis och septisk artrit, till exempel ytproteinet clumping factor A (ClfA). I detta projekt kommer vi att kunna studera om bakteriella ytproteiners interaktion med värdkomponenter har någon betydelse för bakteriens virulens. S. aureus-mutanter där ytproteinets bindningsställe för värdkomponenten är förstört kommer att användas. Vår första studie föreslår att ClfA:s förmåga att binda fibrinogen är avgörande för patogenesen vid allvarlig S. aureus-infektion.
Vi kommer att leta efter vaccinkandidater bland ytproteiner som interagerar med värden, och som är virulensfaktorer. Vi kommer också att använda proteinsegment som finns på flera olika ytproteiner hos S. aureus. Ett immunsvar mot en sådan proteinbit skulle alltså kunna riktas mot mer än ett sorts ytprotein. Jag har tidigare beskrivit ett sådant proteinsegment, Sdr B-repeat, som finns i fyra olika S. aureus-ytproteiner.
Slutligen används vaccinkandidaterna i modeller för sepsis och septisk artrit, för att se om de kan skydda mot sjukdomsutveckling.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva ämnesområdet

Inlagda MeSH-termer

Arthritis, Infectious

Arthritis caused by BACTERIA; RICKETTSIA; MYCOPLASMA; VIRUSES; FUNGI; or PARASITES.

Sepsis

Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by HYPOTENSION despite adequate fluid infusion, it is called SEPTIC SHOCK.

Amino Acids

Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.

Animals

Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain Eukarya.

Antigens, Bacterial

Substances elaborated by bacteria that have antigenic activity.

Binding Sites

The reactive parts of a macromolecule that directly participate in its specific combination with another molecule.

Cloning, Molecular

The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.

Coagulase

Enzymes that cause coagulation in plasma by forming a complex with human PROTHROMBIN. Coagulases are produced by certain STAPHYLOCOCCUS and YERSINIA PESTIS. Staphylococci produce two types of coagulase: Staphylocoagulase, a free coagulase that produces true clotting of plasma, and Staphylococcal clumping factor, a bound coagulase in the cell wall that induces clumping of cells in the presence of fibrinogen.

Complement C3b

The larger fragment generated from the cleavage of COMPLEMENT C3 by C3 CONVERTASE. It is a constituent of the ALTERNATIVE PATHWAY C3 CONVERTASE (C3bBb), and COMPLEMENT C5 CONVERTASES in both the classical (C4b2a3b) and the alternative (C3bBb3b) pathway. C3b participates in IMMUNE ADHERENCE REACTION and enhances PHAGOCYTOSIS. It can be inactivated (iC3b) or cleaved by various proteases to yield fragments such as COMPLEMENT C3C; COMPLEMENT C3D; C3e; C3f; and C3g.

Disease Models, Animal

Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.

Female

Fibrinogen

Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products.

Humans

Members of the species Homo sapiens.

Iron

A metallic element found in certain minerals, in nearly all soils, and in mineral waters. It has the atomic symbol Fe, atomic number 26, and atomic weight 55.85. It is an essential constituent of hemoglobin, cytochrome, and other components of respiratory enzyme systems. Its chief functions are in the transport of oxygen to tissue (hemoglobin) and in cellular oxidation mechanisms. Depletion of iron stores may result in iron-deficiency anemia. Iron is used to build up the blood in anemia. (From Dorland, 27th ed)

Neutrophils

Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes.

Phagocytosis

The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells (PHAGOCYTES).

Receptors, Cell Surface

Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.

Recombinant Proteins

Proteins prepared by recombinant DNA technology.

Staphylococcal Infections

Infections with bacteria of the genus STAPHYLOCOCCUS.

Staphylococcus aureus

Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications.

Virulence

The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenic capacity of an organism is determined by its VIRULENCE FACTORS.

Amino Acid Substitution

The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.

Mutation, Missense

A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)

Mice

The common name for the genus Mus.

Virology

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)

2006-05-29

Datum för påbörjande av datainsamling

2006-05-29

Datum då projektet är slutrapporterat

2010-12-31

Publikationer från detta projekt

1. Staphylococcus aureus host cell invasion and virulence in sepsis is facilitated by the multiple repeats within FnBPA.
   Edwards Andrew, Potts Jennifer, Josefsson Elisabet, Massey Ruth.
   PLoS pathogens 2010:6[Source: User]
2. Immune evasion by Staphylococcus aureus conferred by iron-regulated surface determinant protein IsdH.
   Visai Livia, Yanagisawa Naoko, Josefsson Elisabet, Tarkowski Andrej, Pezzali Ilaria, Rooijakkers Suzan H M, Foster Timothy J, Speziale Pietro.
   Microbiology (Reading, Engl.) 2009:155:667-79.[Source: PubMed®]
   [Links: PMID: 19246738 | DOI länk]
3. The Staphylococcus aureus response to unsaturated long chain free fatty acids: survival mechanisms and virulence implications.
   Kenny John G, Ward Deborah, Josefsson Elisabet, Jonsson Ing-Marie, Hinds Jason, Rees Huw H, Lindsay Jodi A, Tarkowski Andrej, Horsburgh Malcolm J.
   PLoS ONE 2009:4(2):e4344.[Source: PubMed®]
   [Links: PMID: 19183815 | DOI länk]
4. Fibrinogen binding sites P336 and Y338 of clumping factor A are crucial for Staphylococcus aureus virulence.
   Josefsson Elisabet, Higgins Judy, Foster Timothy J, Tarkowski Andrej.
   PLoS ONE 2008:3(5):e2206.[Source: PubMed®]
   [Links: PMID: 18493318 | DOI länk]
5. In vivo sortase A and clumping factor A mRNA expression during Staphylococcus aureus infection.
   Josefsson Elisabet, Kubica Malgorzata, Mydel Piotr, Potempa Jan, Tarkowski Andrej.
   Microb Pathog. 2008:44(2):103-10.[Source: PubMed®]
   [Links: PMID: 17890045 | DOI länk]

Tillämpning av resultat - tidsaspekt (projektledarens bedömning)

Resultaten kommer sannolikt att tillämpas inom 5 år från projektslut.

Tillämpning av resultat - genomslag (projektledarens bedömning)

Internationellt (i flera länder)