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@article{Schmidt:2015:10.1128/JVI.01950-15,
author = {Schmidt, N and Hennig, T and Serwa, RA and Marchetti, M and O'Hare, P},
doi = {10.1128/JVI.01950-15},
journal = {Journal of Virology},
pages = {11107--1115},
title = {Remote activation of host cell DNA synthesis in uninfected cells signalled by infected cells in advance of virus transmission.},
url = {http://dx.doi.org/10.1128/JVI.01950-15},
volume = {89},
year = {2015}
}

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TY  - JOUR
AB  - Viruses modulate cellular processes and metabolism in diverse ways but these are almost universally studied in the infected cell itself. Here we study spatial organisation of DNA synthesis during multi-round transmission of herpes simplex virus (HSV) using pulse-labelling with ethynyl-nucleotides and cycloaddition of azide-fluorophores. We report a hitherto unknown and unexpected outcome of virus-host interaction. Consistent with current understanding during single step growth cycle, HSV suppresses host DNA synthesis and promotes virus DNA synthesis in spatially segregated compartments within the cell. In striking contrast, during progressive rounds of infection initiated at a single cell, we observe that infection induces a clear and pronounced stimulation of cellular DNA replication in remote uninfected cells. This induced DNA synthesis was observed in hundreds of uninfected cells at the extended border, outside the perimeter of the progressing infection. Moreover using pulse chase analysis we show that this activation is maintained, resulting in a propagating wave of host DNA synthesis continually in advance of infection. As the virus reaches and infects these activated cells, host DNA synthesis was then shut off and replaced with virus DNA synthesis. Using non-propagating viruses or conditioned medium we demonstrate a paracrine effector of uninfected cell DNA synthesis in remote cells continually in advance of infection. These findings have significant implications, likely with broad applicability, for our understanding of the ways virus infection manipulates cell processes not only in the infected cell itself but also now in remote uninfected cells, as well as for mechanisms governing host DNA synthesis. IMPORTANCE: We show that during infection initiated by a single particle with progressive cell-cell virus transmission (i.e., the normal situation), HSV induces host DNA synthesis in uninfected cells, mediated by a virus induced paracrine effector. The field ha
AU  - Schmidt,N
AU  - Hennig,T
AU  - Serwa,RA
AU  - Marchetti,M
AU  - O'Hare,P
DO  - 10.1128/JVI.01950-15
EP  - 1115
PY  - 2015///
SN  - 1098-5514
SP  - 11107
TI  - Remote activation of host cell DNA synthesis in uninfected cells signalled by infected cells in advance of virus transmission.
T2  - Journal of Virology
UR  - http://dx.doi.org/10.1128/JVI.01950-15
UR  - http://hdl.handle.net/10044/1/25917
VL  - 89
ER  -

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