Schmaler, Mathias. Staphylococcus aureus lipoproteins - TLR2-mediated activation of innate and adaptive immunity. 2010, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8938
In the first part, we demonstrate the strong cytokine-activating potential of Lpp in murine macrophages, which was associated with the presence of TLR2 in the host. In a systemic infection model, Lpp-TLR2 activation was less contributing to inflammation and S. aureus killing than MyD88-signaling. This indicates that other receptors signaling to MyD88 participate in the antimicrobial response. We further showed in systemic infection that maturation of Lpp facilitates survival of S. aureus in organs due to improved iron acquisition. Studies on growth, uptake, and intracellular storage of iron in vitro confirmed the iron dependence of S. aureus. It is long known, that the immunocompetent host restricts iron in an infection. We show that Lpp enhanced S. aureus growth in the iron-overloaded immunocompetent host, while they were not required in the iron rich environment in the MyD88-deficient host. Interestingly, iron-restricted S. aureus could not profit from Lpp for growth as long as the infected mice were fully immunocompetent. Only in mice deficient in MyD88-dependent inflammation iron-restricted S. aureus used Lpp for growth. In summary, the results in part 1 strongly suggest that Lpp confer a growth and survival advantage although allowing innate immune responses mediated through TLR2-MyD88-signaling.
In the second part, data are presented showing that Lpp released during growth activate TLR2-signaling but engulfment of S. aureus enhances cytokine production. Lpp enhanced phagocytosis by macrophages and intracellular survival of S. aureus. Moreover, Lpp-TLR2-signaling induced cathepsin B-mediated cytotoxicity in macrophages. An effect of Lpp on various interactions of S. aureus with PMN was not found in vitro and in vivo, whereas Lpp enhanced invasion of S. aureus in endothelial cells in vitro. These results point to an additional survival advantage by maturation of Lpp in S. aureus due to improved evasion from extracellular killing, better intracellular survival, and escape from the phagosome.
In the third part, we demonstrate that Lpp-TLR2-MyD88-signaling is important for activation of DCs to induce differentiation of na•ve CD4+ into IFN-g- and IL-17-producing T cells in vitro. Induction of Lpp-TLR2-signaling was also required to promote IFN-g release by na•ve CD8+ T cells. In systemic infection, restimulated spleen T cells produced MyD88-dependent IFN-g and TLR2-MyD88-dependent IL-17. Surprisingly, the presence of B and T cells diminished eradication of S. aureus from organs during early sepsis. These data show that detection of invading S. aureus by DCs leads to the development of adaptive immune responses, which are not always beneficial for eradication of S. aureus.
In the fourth part, the role of other pattern recognition receptors (PRRs) in staphylococcal infection was examined. TLR9 and NOD2, in contrast to IL-1R, had a positive effect on cytokine induction in macrophages and in systemic infection, whereas killing was not affected. In inflammation and bacterial killing during S. aureus infection, TLR2 and TLR9, which both require the MyD88-adaptor, were found to cooperate. These data suggest that concurrent activation of different PRRs elicit a strong antimicrobial defense in response to various molecules of S. aureus.
|Committee Members:||Dehio, Christoph and Arrieumerlou, Cécile|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Infection Biology (Landmann-Suter)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||128|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||19 Feb 2010 14:13|
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