Virus Entry: Open Sesame
Mark Marsh and Ari Helenius. Cell 124: 729-740 (2006)

Abstract: Detailed information about the replication cycle of viruses and their interactions with host organisms is required to develop strategies to stop them.  Cell biology studies, live-cell imaging, and systems biology have started to illuminate the multiple and subtly different pathways that animal viruses use to enter host cells. These insights are revolutionizing our understanding of endocytosis and the movement of vesicles within cells. In addition, such insights reveal new targets for attacking viruses before they can usurp the host-cell machinery for replication.
A Superhighway to Virus Infection
Urs F. Greber and Michael Way. Cell 124: 741–754 (2006)

Abstract: Microtubule-mediated transport of macromolecules and organelles (also known as ‘‘cargo’’) is essential for cells to function. Deficiencies in cytoplasmic transport are frequently associated with severe diseases and syndromes. Cytoplasmic transport also provides viruses with the means to reach their site of replication and is the route for newly assembled progeny to leave the infected cell. This parasitic relationship of viruses with the host cytoskeleton provides an excellent basis for cell biologists to unlock the secrets of cytoplasmic transport and unravel mechanisms of disease. Recent advances in live cell imaging and computational tracking of fluorescently labeled viruses are now revealing how complex the movements of single viruses are in infected cells. This review focuses on microtubule-based motility of viruses and highlights the mechanisms regulating cytoplasmic transport.
Lessons from Genetics: Interpreting Complex Phenotypes in RNAi Screens
Raphael Sacher, Lilli Stergiou and Lucas Pelkmans.
Current Opinion in Cell Biology  20: 483-489 (2008)

Abstract: Mammalian cell biology is witnessing a new era in which cellular processes are explained through dynamic networks of interacting cellular components. In this fast-pacing field, where image-based RNAi screening is
taking a central role, there is a strong need to improve ways to capture such interactions in space and time. Cell biologists traditionally depict these events
by confining themselves to the level of a single cell, or to many population-averaged cells. Similarly, classical geneticists observe and interpret phenotypes
in a single organism to delineate signaling processes, but have also described genetic phenomena in populations of organisms. The analogy in the two approaches inspired us to draw parallels with, and take lessons from concepts
in classical genetics.
Vaccinia Virus Uses Macropinocytosis and Apoptotic Mimicry to Enter
Host Cells
Jason Mercer and Ari Helenius. Science 320: 531 (2008)

Abstract: Viruses employ many different strategies to enter host cells. Vaccinia virus, a prototype poxvirus, enters cells in a pH-dependent fashion. Live cell imaging showed that fluorescent virus particles associated with and moved along filopodia to the cell body, where they were internalized after inducing the extrusion of large transient membrane blebs. p21-activated kinase 1 (PAK1) was activated by the virus, and the endocytic process had the general characteristics of macropinocytosis. The induction of blebs, the endocytic event, and infection
were all critically dependent on the presence of exposed phosphatidylserine in
the viral membrane, which suggests that vaccinia virus uses apoptotic mimicry
to enter cells.
A One-Sided Signal
Gregory D. Fairn and Sergio Grinstein. Science 320: 458-460 (2008)

Abstract: Changes in the distribution of a lipid within the plasma membrane affect normal cell function and virus infection.
Simian Virus 40 Depends on ER Protein Folding and Quality Control Factors for Entry into Host Cells
Mario Schelhaas, Johan Malmström, Lucas Pelkmans, Johannes Haugstetter, Lars Ellgaard, Kay Grünewald and Ari Helenius. Cell 131: 516-29 (2007)

Abstract: Cell entry of Simian Virus 40 (SV40) involves caveolar/lipid raft-mediated endocytosis, vesicular transport to the endoplasmic reticulum (ER), translocation into the cytosol, and import into the nucleus. We analyzed the effects of ER-associated processes and factors on infection and on isolated viruses and found that SV40 makes use of the thiol-disulfide oxidoreductases, ERp57 and PDI, as well as the retrotranslocation proteins Derlin-1 and Sel1L. ERp57 isomerizes specific interchain disulfides connecting the major capsid protein, VP1, to a crosslinked network of neighbors, thus uncoupling about 12 of 72 VP1 pentamers. Cryo-electron tomography indicated that loss of interchain disulfides coupled with calcium depletion induces selective dissociation of the 12 vertex pentamers, a step likely to mimic uncoating of the virus in the cytosol. Thus, the virus utilizes the protein folding machinery for initial uncoating before exploiting the ER-associated degradation machinery presumably to escape from the ER lumen into the cytosol.
Population Context Determines Cell-to-Cell Variability in Endocytosis and Virus Infection
Bernard Snijder, Raphael Sacher, Pauli Rämö, Eva-Maria Damm, Prisca Liberali, and Lucas Pelkmans. Nature 461(7263): 520-3 (2009)

Abstract: Single-cell heterogeneity in cell populations arises from a combination of intrinsic and extrinsic factors. This heterogeneity has been measured for gene transcription, phosphorylation, cell morphology and drug perturbations, and used to explain various aspects of cellular physiology. In all cases, however, the causes of heterogeneity were not studied. Here we analyse, for the first time, the heterogeneous patterns of related cellular activities, namely virus infection, endocytosis and membrane lipid composition in adherent human cells. We reveal correlations with specific cellular states that are defined by the population context of a cell, and we derive probabilistic models that can explain and predict most cellular heterogeneity of these activities, solely on the basis of each cell's population context. We find that accounting for population-determined heterogeneity is essential for interpreting differences between the activity levels of cell populations. Finally, we reveal that synergy between two molecular components, focal adhesion kinase and the sphingolipid GM1, enhances the population-determined pattern of simian virus 40 (SV40) infection. Our findings provide an explanation for the origin of heterogeneity patterns of cellular activities in adherent cell populations.		  
     
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