Viral immune modulators perturb the human molecular network by common and unique strategies.

Viruses must enter host cells to replicate, assemble and propagate. Because of the restricted size of their genomes, viruses have had to evolve efficient ways of exploiting host cell processes to promote their own life cycles and also to escape host immune defence mechanisms. Many viral open reading frames (viORFs) with immune-modulating functions essential for productive viral growth have been identified across a range of viral classes. However, there has been no comprehensive study to identify the host factors with which these viORFs interact for a global perspective of viral perturbation strategies. Here we show that different viral perturbation patterns of the host molecular defence network can be deduced from a mass-spectrometry-based host-factor survey in a defined human cellular system by using 70 innate immune-modulating viORFs from 30 viral species. The 579 host proteins targeted by the viORFs mapped to an unexpectedly large number of signalling pathways and cellular processes, suggesting yet unknown mechanisms of antiviral immunity. We further experimentally verified the targets heterogeneous nuclear ribonucleoprotein U, phosphatidylinositol-3-OH kinase, the WNK (with-no-lysine) kinase family and USP19 (ubiquitin-specific peptidase 19) as vulnerable nodes in the host cellular defence system. Evaluation of the impact of viral immune modulators on the host molecular network revealed perturbation strategies used by individual viruses and by viral classes. Our data are also valuable for the design of broad and specific antiviral therapies.

Pre-clinical modeling of CCR5 knockout in human hematopoietic stem cells by zinc finger nucleases using humanized mice.

Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4(+) T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies.

Unexpected roles for DEAD-box protein 3 in viral RNA sensing pathways.

Detection of viral nucleic acid within infected cells is essential to an effective anti-viral response. The retinoic acid-inducible gene-I-like receptors (RLR) form part of the virus detection repertoire and are critically important in sensing viral RNA in the cytoplasm. Efforts continue to define the signalling components downstream of RLR that are required to induce type I IFN (IFN-alpha and promoter stimulator-1) after viral infection. One surprising finding was that the Asp-Glu-Ala-Asp box helicase DEAD/H Box 3 (DDX3), known for some time to have a number of roles in cellular RNA regulation in the nucleus, has a role in the RLR cytoplasmic signalling pathway involved in promoter stimulator-1 induction. In this issue of the European Journal of Immunology, an article reports an additional distinct positive role for DDX3 in the RLR RNA sensing pathway. This further emphasises the importance of DDX3 in anti-viral immunity, and is consistent with the idea that viruses target DDX3 for immune evasion.

Participation of the hospitals in the Republic of Ireland in international research over more than a decade: a bibliometric analysis.

BACKGROUND: This study provides an accurate awareness of the present situation of health research in Irish hospitals both public and private. We aimed to analyze factors that may influence it and provide recommendations for active steps to improve the current situation of Irish health research based on our findings. METHODS: We performed a bibliometric analysis to assess qualitatively and quantitatively the publications from Ireland over a period between 2007 and 2018. We also investigated the associated variables with the quality of research. Furthermore, we conducted a Joinpoint analysis to see the trends in Irish research over these years. RESULTS: From 12,828 included peer-reviewed articles, the average citation count per article was 19.98. Furthermore, we showed that a higher impact factor (IF) and institutions number, present per article, were significantly associated with more citations. Also, the publication count and the mean IF showed an increase over the years according to the Joinpoint analysis. Moreover, the oncology research had the highest output, followed by pediatrics, then neurology while the specialties with least publications were ear, nose, and throat (ENT), urology, plastic surgery, and dentistry. Additionally, cardiovascular, obstetrics and gynecology, oncology, pediatrics, pulmonology, dermatology, ophthalmology, dentistry, and radiology research showed an increased publication count trend in recent years. While anesthesiology, ENT, general surgery, gastroenterology and hepatology, infection and tropical medicine, nephrology, neurology, orthopedics, plastic surgery, and urology showed a decrease in the publications trend. CONCLUSIONS: Our findings may serve as a useful approach to benchmark scientific output from hospitals and guide the future allocation of research spending.

Modulation of innate immune signalling pathways by viral proteins.

In recent years an explosion of information on the various strategies viruses employ to penetrate and hijack the host cell has led to an increased understanding of both viruses themselves and the host immune response. Despite their simplicity viruses have evolved a number of strategies to not only evade the host immune response but also modulate immune signalling to favour their replication and survival within the cell. The innate immune response provides the host with an early reaction against viruses. This response relies heavily upon the recognition of pathogen-associated molecular patterns (PAMPs) by a number of host pattern recognition receptors (PRRs), leading to activation of innate signalling pathways and altered gene expression. In this chapter we outline the signalling pathways that respond to viral infection and the various methods that viruses utilize to evade detection and modulate the innate immune response to favour their survival.