Projects / Programmes
Mechanisms of TLR4 signalling of different pathogenic bacteria
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| B510 |
Biomedical sciences |
Infections |
bacterial infection, sepsis, pathogenic bacteria, lipopolysaccharide, innate immunity, Toll-like receptor 4, cell signaling
Researchers (2)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
06628 |
PhD Roman Jerala |
Biochemistry and molecular biology |
Head |
2005 - 2007 |
1,190 |
| 2. |
21426 |
PhD Mateja Manček Keber |
Pharmacy |
Researcher |
2005 - 2007 |
159 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
21,007 |
Abstract
A wide variety, but nevertheless limited, number of bacterial components are capable of stimulating innate immune response through activation of 10 Toll-like receptors. LPS from gram-negative bacteria is one of the most potent stimulants, whose potency depends on its structure. Some pathogenic bacteria exploit this phenomenon and use LPS modifications as important virulent factor for escaping the human immune system surveillance. Innate immune response to LPS is mediated through oligomerization of MD-2/TLR4 complex. Recent data show that besides LPS-MD-2/TLR4 interaction also TLR4-TLR4 interactions are important for signalling. We will prepare TLR4 mutants by insertion of flexible linkers between selected domains of TLR4 in order to identify the region which inhibits constitutive activity of TLR4 and which couples LPS binding to receptor association and initiation of signalling. Binding of LPS to MD-2/TLR4 complex activates two parallel signalling pathways depending on the chemotype of LPS, specific for different pathogenic bacteria. Activation of the MyD88-dependent pathway leads to the synthesis of proinflammatory cytokines, important for stimulation and mobilisation of cells (neutrophils, monocytes, macrophages) to the site of infection. MyD88-independent pathway involving TRIF adaptor leads to the synthesis of IFN-which in turn triggers activation of a distinct set of genes. We plan to achieve better understanding of the pathogenesis of some of the pathogenic bacteria that invade host cells (e.g. Yersinia pestis, Brucella abortus, Salmonella spp.,…) and the mechanisms they employ to avoid recognition by the innate immune receptors by answering to the questions: First, is there an LPS-dependent difference in activation of each of the two pathways regarding macrophages and epithelial cells (in macrophages MD-2/TLR4 is expressed on the cell surface, but on tissues, constantly exposed to environmental or comensal bacteria, e.g. intestinal, lung epithelial cells this complex is expressed intracellularly, thus preventing undesirable excessive activation.) and Second, is the endocytosis of LPS required for the activation of MyD88-independent pathway. We expect to confirm the hypothesis that activation of this signalling pathway is more important in cells, resisting intracellular bacterial infection. Understanding mechanisms of this action is highly important for development of improved antiinfective treatment.
