Viral Modulation of Host Translation and Implications for Vaccine Development

Translation of mRNAs into protein is an essential mechanism of regulating gene expression—and a step exploited by viruses for their own propagation. In this article, we review mechanisms that govern translation and provide an overview of the translation machinery, discuss some of the components involved in this process, and discuss how viruses modulate host translational controls and implications in vaccine design

Pathobiology of Respiratory Syncytial Virus (RSV).

Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract illness in infants and affects the elderly and the immune-compromised [...]

Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)

Respiratory syncytial virus (RSV) is a major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. Factors attributing to this problem are associated with an incomplete understanding of the mechanisms by which RSV modulates the host cell response to infection. In the present study, we investigate suppressor of cytokine signaling (SOCS)-1 and SOCS3 expression associated with the type I IFN and IFN-stimulated gene (ISG)-15 response following infection of mouse lung epithelial (MLE-15) cells with RSV or RSV mutant viruses lacking the G gene, or NS1 and NS2 gene deletions. Studies in MLE-15 cells are important as this cell line represents the distal bronchiolar and alveolar epithelium of mice, the most common animal model used to evaluate the host cell response to RSV infection, and exhibit morphologic characteristics of alveolar type II cells, a primary cell type targeted during RSV infection. These results show an important role for SOCS1 regulation of the antiviral host response to RSV infection, and demonstrate a novel role for RSV G protein manipulation of SOCS3 and modulation of ISG15 and IFNβ mRNA expression

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter

MicroRNA and Nonsense Transcripts as Putative Viral Evasion Mechanisms

Viral proteins encode numerous antiviral activities to modify the host immunity. In this article, we hypothesize that viral genomes and gene transcripts interfere with host gene expression using passive mechanisms to deregulate host microRNA (miRNA) activity. We postulate that various RNA viruses mimic or block binding between a host miRNA and its target transcript, a phenomenon mediated by the miRNA seed site at the 5′ end of miRNA. Virus-encoded miRNA seed sponges (vSSs) can potentially bind to host miRNA seed sites and prevent interaction with their native targets thereby relieving native miRNA suppression. In contrast, virus-encoded miRNA seed mimics (vSMs) may mediate considerable downregulation of host miRNA activity. We analyzed genomes from diverse RNA viruses for vSS and vSM signatures and found an abundance of these motifs indicating that this may be a mechanism of deceiving host immunity. Employing respiratory syncytial virus and measles virus as models, we reveal that regions surrounding vSS or vSM motifs have features characteristics of pre-miRNA templates and show that RSV viral transcripts are processed into small RNAs that may behave as vSS or vSM effectors. These data suggest that complex molecular interactions likely occur at the host-virus interface. Identifying the mechanisms in the network of interactions between the host and viral transcripts can help uncover ways to improve vaccine efficacy, therapeutics, and potentially mitigate the adverse events that may be associated with some vaccines

Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro

Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC(50) 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC(50) 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC(50) 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes

MicroRNAs affect GPCR and Ion channel genes needed for influenza replication

Influenza virus causes seasonal epidemics and sporadic pandemics resulting in morbidity, mortality, and economic losses worldwide. Understanding how to regulate influenza virus replication is important for developing vaccine and therapeutic strategies. Identifying microRNAs (miRs) that affect host genes used by influenza virus for replication can support an antiviral strategy. In this study, G-protein coupled receptor (GPCR) and ion channel (IC) host genes in human alveolar epithelial (A549) cells used by influenza virus for replication (Orr-Burks et al., 2021) were examined as miR target genes following A/CA/04/09- or B/Yamagata/16/1988 replication. Thirty-three miRs were predicted to target GPCR or IC genes and their miR mimics were evaluated for their ability to decrease influenza virus replication. Paired miR inhibitors were used as an ancillary measure to confirm or not the antiviral effects of a miR mimic. Fifteen miRs lowered influenza virus replication and four miRs were found to reduce replication irrespective of virus strain and type differences. These findings provide evidence for novel miR disease intervention strategies for influenza viruses

A Randomized Exchange Algorithm for Computing Optimal Approximate Designs of Experiments

We propose a class of subspace ascent methods for computing optimal approximate designs that covers both existing as well as new and more efficient algorithms. Within this class of methods, we construct a simple, randomized exchange algorithm (REX). Numerical comparisons suggest that the performance of REX is comparable or superior to the performance of state-of-the-art methods across a broad range of problem structures and sizes. We focus on the most commonly used criterion of D-optimality that also has applications beyond experimental design, such as the construction of the minimum volume ellipsoid containing a given set of data-points. For D-optimality, we prove that the proposed algorithm converges to the optimum. We also provide formulas for the optimal exchange of weights in the case of the criterion of A-optimality. These formulas enable one to use REX for computing A-optimal and I-optimal designs.Comment: 23 pages, 2 figure