Abstract
The phosphoinositide-3 kinase (PI3K) pathway regulates diverse cellular activities related to cell growth, migration, survival, and vesicular trafficking. It is known that Ebola virus requires endocytosis to establish an infection. However, the cellular signals that mediate this uptake were unknown for Ebola virus as well as many other viruses. Here, the involvement of PI3K in Ebola virus entry was studied. A novel and critical role of the PI3K signaling pathway was demonstrated in cell entry of Zaire Ebola virus (ZEBOV). Inhibitors of PI3K and Akt significantly reduced infection by ZEBOV at an early step during the replication cycle. Furthermore, phosphorylation of Akt-1 was induced shortly after exposure of cells to radiation-inactivated ZEBOV, indicating that the virus actively induces the PI3K pathway and that replication was not required for this induction. Subsequent use of pseudotyped Ebola virus and/or Ebola virus-like particles, in a novel virus entry assay, provided evidence that activity of PI3K/Akt is required at the virus entry step. Class 1A PI3Ks appear to play a predominant role in regulating ZEBOV entry, and Rac1 is a key downstream effector in this regulatory cascade. Confocal imaging of fluorescently labeled ZEBOV indicated that inhibition of PI3K, Akt, or Rac1 disrupted normal uptake of virus particles into cells and resulted in aberrant accumulation of virus into a cytosolic compartment that was non-permissive for membrane fusion. We conclude that PI3K-mediated signaling plays an important role in regulating vesicular trafficking of ZEBOV necessary for cell entry. Disruption of this signaling leads to inappropriate trafficking within the cell and a block in steps leading to membrane fusion. These findings extend our current understanding of Ebola virus entry mechanism and may help in devising useful new strategies for treatment of Ebola virus infection.
Highlights
Ebola virus, a member of the family Filoviridae, is an emerging infectious agent that causes severe and often fatal hemorrhagic fever in humans and nonhuman primates
While it is known that the cell must engulf the virus by the process of endocytosis, we know little about how the virus triggers this event
The findings indicated that Zaire Ebola virus (ZEBOV) induces activation of phosphoinositide-3 kinase (PI3K) pathway prior to or during entry and that activity of class 1A PI3Ks is critical for entry into host cells
Summary
A member of the family Filoviridae, is an emerging infectious agent that causes severe and often fatal hemorrhagic fever in humans and nonhuman primates. Especially those caused by Zaire Ebola virus (ZEBOV), mortality rates close to 90% have been reported [1]. As with many enveloped viruses, entry of ZEBOV into cells likely involves virus particles binding to host cell receptor(s), followed by endocytosis and trafficking through vesicular compartments, and fusion of the virus membrane to that of the endocytic vesicle. This results in release of the viral nucleocapsid into the cytoplasm where the subsequent steps of the replication cycle take place [3]. An important aspect of ZEBOV entry involves endocytic trafficking into the cell
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