Teicoplanin-resistant S. aureus present a thickened cell wall, and thus may have an impact on virulence and on host response. We plan to study the effect of glycopeptide resistance on innate immune response in vitro in polymorphonuclear leukocytes and in vivo in three mouse infection models.
Background
Antibiotic resistance in Staphylococcus aureus has become a global problem. Glycopeptides are the last antibiotics of choice for treating methicillin-resistant S. aureus. Recently strains with low-level glycopeptide resistance were found in patients, albeit this resistance appears instable in the absence of drugs. Several yet unknown genes participate in glycopeptide resistance, which is characterized by a thickened cell wall, due to altered peptidoglycan turnover. These features may have an impact on virulence of teicoplanin-resistant S.aureus and on host response, which mirrors virulence. Host response to cell wall components of S.aureus depends on the pattern recognition receptors Toll-like receptor 2 (TLR2) and Nod2. These receptors are activated by peptidoglycan and muramyldipeptide respectively.
Aim
We are interested into the impact of glycopeptide resistance on host response to S.aureus and its mechanism. 1. We compare teicoplanin-resistant and – sensitive S. aureus with regard to their susceptibility towards phagocytosis and killing by leukocytes in vitro. We use cells from mice and men with or witout the defense molecules Toll-like receptor 2 and Nod2 to know role of these molecules in defense against S.aureus. 2. We follow teicoplanin-resistant strains without and with teicoplanin pressure in three mouse infection models, a local foreign body, a catheter abscess and a systemic infection with liver abscesses. We measure bacterial load, we assess cell wall properties and host response to these bacteria . This will allow defining conditions of maintenance and loss of teicoplanin resistance in vivo, the accompanying cell wall changes, as well as the mechanism of the host response to glycopeptide resistant S.aureus. 3. We search for spontaneous appearance of teicoplanin-resistant S. aureus from infections with teicoplanin-sensitive strains in vivo, and characterize the host response to resistant clones.
Significance
The aim is to know the virulence of and host response to teicoplanin-sensitive and resistant S. aureus and to study the balance between resistance and virulence under different conditions in vivo. Further, the unravelling of the role of TLR2 and Nod2 in defense against S. aureus helps to identifying adjuvant host molecules for therapies under conditions, when S.aureus cannot be eradicated.
