Projekt

Role CCR7-ligands in virus-induced chronic CNS inflammation and demyelination

Abgeschlossen · 2013 bis 2013

Art
Grundlagenforschung
Reichweite
Monozentrisch am KSSG
Bereiche
Status
Abgeschlossen
Start
2013
Ende
2013
Finanzierungsart
Andere
Schlagwörter (Tags)
Virus infection, Multiple Sclerosis
Projektpartner
Prof. Ingo Bechmann, Institute of Anatomy, University of Leipzig
Kurzbeschreibung/Zielsetzung

Background: Epidemiological studies indicate that onset and progression of multiple sclerosis (MS) critically depends on environmental factors, including infectious agents. Experimental infections with neurotropic viruses can precipitate MS-like pathological tissue responses and can hence mirror all aspects of the neurodegenerative processes associated with MS, i.e. persistent inflammatory responses with activation/destruction of glia cells, demyelination, and axonal death. Infection with the neurotropic mouse hepatitis virus (MHV) is well-suited to understand the basic mechanisms underlying both acute virus-induced CNS pathologies and those factors that determine chronic disease. The constitutive chemokines CCL19 and CCL21, i.e. the ligands of the chemokine receptor 7 (CCR7), are critical regulators of immune homeostasis and activation. Importantly, these chemokines are constitutively expressed in the CNS and their expression is significantly elevated in MS patients. However, it has remained elusive whether and how these chemokines contribute to virus-driven inflammatory processes in the CNS that lead to demyelination.
Working hypothesis: Based on our preliminary results from MHV CNS infection in mice lacking either CCR7 on all cells or the CCR7 ligands selectively in secondary lymphoid organs, we postulate that CCR7 ligands expressed in the CNS critically determine the outcome of virus-mediated CNS inflammation.
Specific aims: The major aim of this study is to determine to which extent and by which mechanisms CCR7 ligands produced in the CNS contribute to the control of MHV-mediated CNS inflammation. To characterize the immunological and molecular processes involved in virus-mediated demyelination following MHV infection, we will use a novel T cell receptor transgenic mouse model that has been developed in our laboratory. CD8+ T cells of TCR-S mice recognize a MHV spike protein-derived peptide and hence facilitate the detection of antigen presentation and immune activation processes in lymph nodes and the CNS. Here, CCR7-deficient or CCR7-proficient TCR-S cells will be adoptive transferred into mice that lack the expression of CCR7-ligands specifically in lymph nodes (plt/plt mice) or into wild-type controls. Since the CCR7 ligand CCL21 binds also to the chemokine receptor CXCR3, we will cross TCR-S mice onto the CXCR3-deficient background and use adoptive transfer into plt/plt vs wild-type mice. Subsequent CNS-restricted infection with MHV will reveal the impact of CNS-derived CCR7 ligands on the activation, differentiation and migration patterns of MHV-specific T cells.
Significance and implications of the planned work: On the basis of our preliminary results, we can predict that the experiments planned in this project will help to clarify to which extent CNS-derived CCR7 ligands impinge on MHV-driven demyelinating CNS disease. Should the effects of CNS-derived CCR7 ligands be profoundly involved in the development of chronic inflammatory lesions within the CNS, we will embark to an extended project with selective ablation of CCR7 ligands and other inflammatory mediators in different CNS cell populations. Hence, the support requested from the MS society will not only facilitate finalization of a study that has been initiated by a promising young scientist in our laboratory, but will also pave the way for a new project that will help to clarify fundamental aspects of the pathogenesis of this virus-driven MS-like disease.