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Third-party-funded project

Title:
Molecular basis of measles virus induced immunosuppression

Project management at the University of Würzburg:

Abstract:
The generalised immunosuppression during and for weeks after acute measles is the major cause of the high morbidity and mortality rates associated with this disease worldwide. The inability to expand in response to polyclonal and antigen-specific stimulation seen with peripheral blood lymphocytes from patients ex vivo is considered as a hallmark of measles virus (MV)-induced immunosuppression. As the frequency of infected lymphocytes and monocytes is extremely low, indirect mechanisms such as production of soluble inhibitory mediators, sensitisation for apoptosis or surface contact dependent negative signaling to T cells are likely to be crucial. We have shown that surface contact with the MV glycoprotein complex consisting of the H and the proteolytically activated F protein (expressed on infected cells, virions or cells transfected to express these proteins) is necessary and sufficient to induce a state of unresponsiveness in an excess amount of uninfected lymphocytes both in vitro and in vivo. This occurs independent of cellular fusion but rather by direct negative signaling to T cells by as yet unknown receptors. Aiming to define this particular interaction on a molecular level, our focus is 1) to characterise immunosuppressive domains within the F/H complex, 2) to identify the receptor(s), and 3) the signaling pathways involved. As we have shown, F/H contacted T cells reveal a classical arrest in the late G1 phase of the cell cycle, and this is associated with deregulations of cell cycle control proteins on the level of both expression and activity. Addressing intracellular pathways involved, we found that activation of signaling pathways crucial for cell cycle entry of T cells are inhibited. Evidently, however, g/d T cells are able to expand in the presence of the inhibitory F/H complex when the latter is expressed on B cells or dendritic cells. Insight into the mechanisms of this particular resistance will reveal important informations on potential intracellular resistance mechanisms.

Key words:
    Measles virus
    Immunosuppression
    Glycoproteins
    Receptors
    T cell signaling
    g/d T cells

Projekt period: from 1.1998 to 12.2003

Publications: