LASSA VIRUS RECEPTOR

The interaction of Lassa virus with its cellular receptor alpha-dystroglycan

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 Obiettivo del progetto (Objective)

'The arenavirus Lassa fever virus (LFV) causes a severe viral hemorrhagic fever in humans with over 300, 000 infections and thousands of deaths annually. Fatal LFV infection is characterized by marked immunosuppression of the patient, resulting in uncontrolled viral infection with progressive hemorrhagic disease and shock. Since death occurs in absence of a significant anti-viral immune response, the fatal disease is caused by virus-induced changes in host cell function, rather than immunopathology. The analysis of the virus-host cell interaction is therefore of great importance to understand this disease and to develop novel therapeutic strategies. Binding of a virus to its cellular receptor(s) is not only the first step of virus infection but represents also a promising target for therapeutic intervention. The cellular receptor of LFV is alpha-dystroglycan (alpha-DG), an important cell surface receptor for proteins of the extracellular matrix (ECM). Based on the pivotal importance of alpha-DG for normal host cell biology, the interaction of LFV with its receptor is of particular interest regarding virus-cell interaction and viral pathogenesis. Using a combination of biochemical and cell biological techniques we will investigate the role of the virus-receptor interaction for infection and viral pathogenesis. Since alpha-DG is involved in cellular signal transduction, we will investigate the impact of virus binding on receptor-mediated signaling in the host cell. In a next step, we will address the role of virus-induced receptor signaling for virus infection and its consequences for the host cell. Our recent studies showed that expression of the envelope glycoprotein (GP) of LFV in cells results in down-regulation of functional alpha-DG. In the present project, we will investigate the impact of this “virus-receptor interference” on the function of vascular endothelial cells, which play a key role in the pathogenesis of Lassa hemorrhagic fever.'

Introduzione (Teaser)

Lassa virus is the most important human pathogen among a big family of arenaviruses. It brings about severe viral hemorrhagic fever and is the cause of death for some 300 000 people each year.

Descrizione progetto (Article)

Death from Lassa virus (LASV) infection happens without any antiviral immune response having taken place. This means the disease kills humans by attacking host cell functioning on the strength of the virus itself, rather than eliciting an (ineffective) immune response.

The interaction of Lassa virus with its cellular receptor alpha-dystroglycan' (Lassa virus receptor) is a project that has set out to understand more about this disease by analysing the interaction between a virus and its host cells. The first step of virus infection takes place when a virus binds to its cellular receptor(s). Improved understanding of how this happens may highlight how the process can be a promising target for therapeutic intervention.

Alpha-dystroglycan (alpha-DG), crucial to normal cell functioning, is the cellular receptor for LASV. Lassa virus receptor partners have already shown that alpha-DG's involvement in cellular signalling results in the recruitment of cellular proteins that are found on the MAP kinase (MEK/ERK) signalling pathway. Specifically, these are the adaptor protein grb2 and the protein kinase MEK1. Further tests on signalling showed that LASV binding disrupted activation of the MEK/ERK pathway via beta1-integrins. These integrin subunits are receptors spanning the plasma membrane that mediate attachment between a cell and surrounding material.

Other Lassa virus receptor studies have so far shown that the protein kinase inhibitors staurosporin and genistein effectively block LASV entry. Also, a first screening of protein kinases associated with DG and LASV binding and entry revealed several candidates that actually reduced infection with LASV. One of these is the phosphoinositide-3 kinase (PI3K). Others are still undergoing validation.

The Lassa virus receptor project has succeeded in its first aim and revealed the major impact that LASV binding has on DG-mediated signalling in the host cell. Considering the alteration in normal signalling crosstalk between DG and beta1-integrins, project partners believe this signalling equilibrium is what may contribute to development of this deadly disease. This line of discovery is bound to help in future efforts to develop novel therapeutic strategies.