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. Intrinsic and innate immunity act to restrict the replication of many clinically important viral pathogens. However, the temporal regulation of these two arms of host immunity during virus infection remains poorly defined. A key aspect in the regulation of these intracellular immune defences during herpesvirus infection is the rapid recruitment of constitutively expressed immune regulators to infecting viral genomes. Here we show that at physiologically low multiplicities of infection, PML-NBs rapidly entrap HSV-1 genomes upon nuclear entry. Saturation of this pre-existing intrinsic host defence led to the stable recruitment of the vDNA pathogen sensor IFI16 to HSV-1 vDNA and the induction of ISG expression, an induced innate immune response dependent on the initiation of vDNA replication. Importantly, both intrinsic and innate arms of host immunity required PML, the principle scaffolding protein of PML-NBs. 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.

Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global threat to human population. The numbers of cases and deaths due to COVID-19 are escalating daily, putting health care systems worldwide under tremendous pressure. Policymakers in the affected countries have adopted varying strategies to deal with this crisis. As a result, the current COVID-19 status in terms of number of cases and deaths hugely varies between countries. The Gulf Cooperation Council (GCC) countries have managed to limit the massive spread of the infection among their populations by implementing proactive plans and timely decisions in response to COVID-19 outbreak; measures taken included suspension of flights, closure of educational institutes, curfew and lockdown of major cities, and provision of free-of-charge healthcare to patients. This review summarizes the COVID-19 status as of 18 May 2020 and highlights prevention and control measures applied in the GCC countries.

Monkeypox virus (MPXV) is a member of the Orthopoxvirus genus and the Poxviridae family, which instigated a rising epidemic called monkeypox disease. Proteinases are majorly engaged in viral propagation by catalyzing the cleavage of precursor polyproteins. Therefore, proteinase is essential for monkeypox and a critical drug target. In this study, high-throughput virtual screening (HTVS) and molecular dynamics simulation were applied to detect the potential natural compounds against the proteinase of the monkeypox virus. Here, 32,552 natural products were screened, and the top five compounds were selected after implementing the HTVS and molecular docking protocols in series. Gallicynoic Acid F showed the minimum binding score of −10.56 kcal/mole in the extra precision scoring method, which reflected the highest binding with the protein. The top five compounds showed binding scores ≤−8.98 kcal/mole. These compound complexes were tested under 100 ns molecular dynamics simulation, and Vaccinol M showed the most stable and consistent RMSD trend in the range of 2 Å to 3 Å. Later, MM/GBSA binding free energy and principal component analysis were performed on the top five compounds to validate the stability of selected compound complexes. Moreover, the ligands Gallicynoic Acid F and H2-Erythro-Neopterin showed the lowest binding free energies of −61.42 kcal/mol and −61.09 kcal/mol, respectively. Compared to the native ligand TTP-6171 (ΔG_Bind = −53.86 kcal/mol), these two compounds showed preferable binding free energy, suggesting inhibitory application against MPXV proteinase. This study proposed natural molecules as a therapeutic solution to control monkeypox disease.

When host cells are invaded by viruses, they deploy multifaceted intracellular defense mechanisms to control infections and limit the damage they may cause. Host intracellular antiviral immunity can be classified into two main branches: (i) intrinsic immunity, an interferon (IFN)-independent antiviral response mediated by constitutively expressed cellular proteins (so-called intrinsic host restriction factors); and (ii) innate immunity, an IFN-dependent antiviral response conferred by IFN-stimulated gene (ISG) products, which are (as indicated by their name) upregulated in response to IFN secretion following the recognition of pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs). Recent evidence has demonstrated temporal regulation and specific viral requirements for the induction of these two arms of immunity during herpes simplex virus type 1 (HSV-1) infection. Moreover, they exert differential antiviral effects to control viral replication. Although they are distinct from one another, the words "intrinsic" and "innate" have been interchangeably and/or simultaneously used in the field of virology. Hence, the aims of this review are to (1) elucidate the current knowledge about host intrinsic and innate immunity during HSV-1 infection, (2) clarify the recent advances in the understanding of their regulation and address the distinctions between them with respect to their induction requirements and effects on viral infection, and (3) highlight the key roles of the viral E3 ubiquitin ligase ICP0 in counteracting both aspects of immunity. This review emphasizes that intrinsic and innate immunity are temporally and functionally distinct arms of host intracellular immunity during HSV-1 infection; the findings are likely pertinent to other clinically important viral infections.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a more severe strain of coronavirus (CoV) that was first emerged in China in 2019. Available antiviral drugs could be repurposed and natural compounds with antiviral activity could be safer and cheaper source of medicine for SARS-CoV-2. 78 natural antiviral compounds database was identified from literature and virtual screening technique was applied to identify potential 3-chymotrypsin-like protease (3CLpro) inhibitors. Molecular docking studies were conducted to analyze the main protease (3CLpro) and inhibitors interactions with key residues of active site of target protein (PDB ID: 6LU7), active site constitute the part of active domain I and II of 3CLpro. 10 compounds with highest dock score were subjected to calculate ADMET parameters to figure out drug-likeness. Molecular dynamic (MD) simulation of the selected lead was performed by Amber simulation package to understand the conformational changes in docked complex. MD simulations analysis (RMSD, RMSF, Rg, BF, HBs, and SASA plots) of lead bounded with 3CLpro, hence revealed the important structural turns and twists during MD simulations from 0 to 100 ns. MM-PBSA/GBSA methods has also been applied for the estimation binding free energy (BFE) of the selected lead-complex. The present study has identified lead compound “Forsythoside A” an active extract of Forsythia suspense as SARS-CoV-2 3CLpro inhibitor that can block the viral replication and translation. Structural analysis of target protein and lead compound performed in this study could contribute to the development of potential drug against SARS-CoV-2 infection.