Functional and structural identification of peptidoglycan part structures involved in thrombospondin-1 mediated adherence of Gram-positive bacteria to host cells

• Applicants: Professor Dr. Sven Hammerschmidt; Professor Dr. Ulrich Zähringer
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2008 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 64038601

Peptidoglycan (PG, murein) is an essential exoskeleton needed to withstand the internal cytoplasmic turgor (osmotic) pressure in both Gram-negative as well as Gram-positive bacteria. It consists of oligo-(GlcNAc-MurNAc)glycan strands that are cross-linked by short peptides to form a complex three-dimensional scaffold (murein) that surrounds and stabilizes the bacterial cytoplasmic membrane. Studies in our laboratory show that Gram-positive bacteria such as Streptococcus pneumoniae, S. pyogenes and Staphylococcus aureus engage the human glycoprotein and lectin thrombospondin-1 (TSP-1) as a molecular sensor, thereby promoting adherence of the bacteria to host cells. We could demonstrate that purified soluble PG natural part structures from S. aureus inhibits TSP-1 mediated Gram-positive bacterial adherence, indicating that TSP-1 recognizes the PG of the bacteria. Based on these data we plan to explore the role of PG structures for TSP-1 mediated interactions on the basis of a structure-function relationship in more detail. In our planned studies we will combine the capacity of synthetic chemistry, analytical and structural chemistry and biochemical/immunological studies to explore the minimal PG part structure which shows bioactivity in TSP-1 mediated adherence of bacteria to host cells. We will use purified and completely analyzed natural PG moieties as well as synthetic PG moieties and according to the biological activity chemically modified PG structures in our infection assays. It is anticipated that the combination of purified PG structures on the one side as well as functionally designed synthetic PG part structures will provide new insights into the biological function of PG. On a long term goal it is expected that these findings have an impact for the development of newer strategies against colonization by Gram-positive bacteria and will finally lead to newer strategies against Gram-positive sepsis.

• DFG Programme: Research Grants