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.
Highlights
Intrinsic, innate, and adaptive arms of host immunity cooperatively supress the replication and spread of invading viral pathogens
We show that at physiologically low multiplicities of infection, PML-nuclear bodies (PML-NBs) rapidly entrap herpes simplex virus 1 (HSV-1) genomes upon nuclear entry. Saturation of this pre-existing intrinsic host defence led to the stable recruitment of the viral DNA (vDNA) pathogen sensor IFI16 to HSV-1 vDNA and the induction of interferon stimulated gene (ISG) expression, an induced innate immune response dependent on the initiation of vDNA replication
Our research identifies dual roles for PML in the sequential regulation of intracellular host immunity during HSV-1 infection, and highlights distinct phases in host immune factor recruitment to infecting viral genomes required for the temporal regulation of intracellular host immune defences during herpesvirus infection
Summary
Innate, and adaptive arms of host immunity cooperatively supress the replication and spread of invading viral pathogens. PRR activation induces downstream signalling events that culminate in the expression of antiviral host genes, principally cytokines (including interferons) and interferon stimulated gene (ISG) products (reviewed in [4,5,6]). This induced innate immune response confers a broadly refractory antiviral state that limits virus propagation and stimulates adaptive immune responses. Many viruses have evolved counter measures to antagonize intrinsic and innate immune defences to promote their efficient propagation and transmission to new hosts
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