Distinct temporal roles for the promyelocytic leukaemia (PML) protein in the sequential regulation of intracellular host immunity to HSV-1 infection

Alandijany, T., Roberts, A. P.E., Conn, K. L., Loney, C., McFarlane, S., Orr, A. and Boutell, C. (2018) Distinct temporal roles for the promyelocytic leukaemia (PML) protein in the sequential regulation of intracellular host immunity to HSV-1 infection. PLoS Pathogens, 14(1), e1006769. (doi:10.1371/journal.ppat.1006769) (PMID:29309427) (PMCID:PMC5757968)

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Abstract

Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2’-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions. Following viral genome entry into the nucleus, PML-nuclear bodies (PML-NBs) rapidly entrapped viral DNA (vDNA) leading to a block in viral replication in the absence of the viral PML-NB antagonist ICP0. This pre-existing intrinsic host defence to infection occurred independently of the vDNA pathogen sensor IFI16 (Interferon Gamma Inducible Protein 16) and the induction of interferon stimulated gene (ISG) expression, demonstrating that vDNA entry into the nucleus alone is not sufficient to induce a robust innate immune response. Saturation of this pre-existing intrinsic host defence during HSV-1 ICP0-null mutant infection led to the stable recruitment of PML and IFI16 into vDNA complexes associated with ICP4, and led to the induction of ISG expression. This induced innate immune response occurred in a PML-, IFI16-, and Janus-Associated Kinase (JAK)-dependent manner and was restricted by phosphonoacetic acid, demonstrating that vDNA polymerase activity is required for the robust induction of ISG expression during HSV-1 infection. Our data identifies dual roles for PML in the sequential regulation of intrinsic and innate immunity to HSV-1 infection that are dependent on viral genome delivery to the nucleus and the onset of vDNA replication, respectively. These intracellular host defences are counteracted by ICP0, which targets PML for degradation from the outset of nuclear infection to promote vDNA release from PML-NBs and the onset of HSV-1 lytic replication.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Orr, Mrs Anne and Boutell, Dr Chris and Loney, Mr Colin and Conn, Dr Kristen and Roberts, Dr Ashley and McFarlane, Mr Steven and Alandijany, Thamir Abdulaziz A
Creator Roles:
Alandijany, T.Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing – original draft, Writing – review and editing
Roberts, A. P.E.Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Visualization, Writing – original draft, Writing – review and editing
Conn, K. L.Conceptualization, Methodology, Supervision, Writing – review and editing
Loney, C.Investigation, Methodology
McFarlane, S.Investigation, Supervision
Orr, A.Investigation, Supervision
Boutell, C.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review and editing
Authors: Alandijany, T., Roberts, A. P.E., Conn, K. L., Loney, C., McFarlane, S., Orr, A., and Boutell, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2018 Alandijany et al.
First Published:First published in PLoS Pathogens 14(1):e1006769
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656521The role of ubiquitin and ubiquitin-like proteins during viral infectionChris BoutellMedical Research Council (MRC)MC_UU_12014/5MVLS III - CENTRE FOR VIRUS RESEARCH

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