Phosphoinositide-3 Kinase-Akt Pathway Controls Cellular Entry of Ebola Virus

PLoS Pathogens

Mohammad F. Saeed¹  Alexander N. Freiberg¹  Robert A. Davey²  Michael R. Holbrook³  Andrey A. Kolokoltsov³ 

[1] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America;Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America;Western Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Research, University of Texas Medical Branch, Galveston, Texas, United States of America

关键词: Ebola virus;    Luciferase;    Endocytosis;    Vesicular stomatitis virus;    Cell signaling;    Membrane fusion;    Membrane trafficking;    Viral entry;   

DOI  :  10.1371/journal.ppat.1000141

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY