Molecular mechanisms of measles virus entry and exit

Gonçalves Carneiro, Vitor Daniel (2017). Molecular mechanisms of measles virus entry and exit. University of Birmingham. Ph.D.

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Abstract

Measles is a leading cause of mortality in infants in countries with suboptimal vaccination coverage. This disease is caused by a negative-strand RNA virus, measles virus (MeV). Wild-type strains of the virus use two cellular receptors to invade cells and establish infection: the signalling lymphocyte activation molecule f1 (SLAMF1), which is present on certain immune cells, and nectin-4, which is expressed in the lung epithelium. During infection, MeV can spread through the release of virions or by inducing cell-cell fusion. The aim of this thesis is to determine the molecular mechanism underlying viral entry and exit. Herein, I observed that, upon attachment to SLAMF1+ cells, MeV particles induce extensive but transient membrane blebbing and cytoskeleton contraction. MeV entry occurred simultaneously with fluid-uptake and was sensitive to inhibitors of macropinocytosis and cytoskeleton dynamics. In contrast, the cortical actin network restricted the early stages of MeV-induced cell-cell fusion, in RhoGTPases, ezrin and moesin dependent manner. By resolving the proteome of infected cells, conserved phosphorylated residues in the viral haemagglutinin were also shown to impact on dimerization and cell-cell fusion. These results suggest the manipulation of several cellular components and pathways during entry and exit of MeV.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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