Vaccinia virus hijacks EGFR signalling to enhance virus spread through rapid and directed infected cell motility

• Published in: Nature microbiology Vol. 4; no. 2; pp. 216 - 225
• Main Authors: Beerli, Corina, Yakimovich, Artur, Kilcher, Samuel, Reynoso, Glennys V., Fläschner, Gotthold, Müller, Daniel J., Hickman, Heather D., Mercer, Jason
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2019; Nature Publishing Group
• Subjects: 13/106; 13/89; 14; 14/63; 14/69; 631/326/596/1746; 631/80/84; 64/60; 96/1; 96/95; ADAM10 Protein - antagonists & inhibitors; ADAM10 Protein - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Biomedical and Life Sciences; Cell Line; Cell Movement - drug effects; Cytopathogenic Effect, Viral - genetics; Enzyme Inhibitors - pharmacology; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Gene Deletion; HeLa Cells; Host-Pathogen Interactions; Humans; Infections; Infectious Diseases; Intercellular Signaling Peptides and Proteins - metabolism; Letter; Life Sciences; MAP kinase; Medical Microbiology; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; Microbiology; Motility; Paracrine signalling; Parasitology; Peptides - deficiency; Peptides - genetics; Peptides - metabolism; RhoA protein; Signal Transduction - drug effects; Smallpox; Vaccinia - metabolism; Vaccinia - pathology; Vaccinia - virology; Vaccinia virus - genetics; Vaccinia virus - growth & development; Vaccinia virus - metabolism; Vaccinia virus - physiology; Viral infections; Viral Proteins - genetics; Viral Proteins - metabolism; Virology; Viruses
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-018-0288-2

Cell motility is essential for viral dissemination
1
. Vaccinia virus (VACV), a close relative of smallpox virus, is thought to exploit cell motility as a means to enhance the spread of infection
1
. A single viral protein, F11L, contributes to this by blocking RhoA signalling to facilitate cell retraction
2
. However, F11L alone is not sufficient for VACV-induced cell motility, indicating that additional viral factors must be involved. Here, we show that the VACV epidermal growth factor homologue, VGF, promotes infected cell motility and the spread of viral infection. We found that VGF secreted from early infected cells is cleaved by ADAM10, after which it acts largely in a paracrine manner to direct cell motility at the leading edge of infection. Real-time tracking of cells infected in the presence of EGFR, MAPK, FAK and ADAM10 inhibitors or with VGF-deleted and F11-deleted viruses revealed defects in radial velocity and directional migration efficiency, leading to impaired cell-to-cell spread of infection. Furthermore, intravital imaging showed that virus spread and lesion formation are attenuated in the absence of VGF. Our results demonstrate how poxviruses hijack epidermal growth factor receptor-induced cell motility to promote rapid and efficient spread of infection in vitro and in vivo.
Following cleavage by ADAM10, the vaccinia virus epidermal growth factor homologue, VGF, promotes infected cell motility at the leading edge of infection and spread of the virus.