Epstein-Barr Virus in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which the body’s immune system is abnormally directed towards the myelin sheaths covering the nerve fibers. What triggers the neuroinflammation and autoimmune destruction of the myelin sheaths remains unknown. However, it is widely accepted that susceptibility depends on a combination of genetic and environmental factors and their interactions. With little chance of influencing genetic predisposition, the importance of identifying risk factors which could be modulated to either prevent the on-set of MS or to ameliorate the course of the disease, is an attractive alternative. An accumulating body of evidence, including our own recent study involving over 1000 MS and non-MS samples, indicates that Epstein-Barr virus (EBV), a common herpesvirus, could be involved. In this chapter, we review the studies linking EBV to MS and propose an explanation by which this common virus could be involved in the pathogenesis of MS

Exosomes and Their Role in Viral Infections

Exosomes are excretory nano-vesicles that are formed by the cell’s endocytic system and shed from the surface of almost all types of cells. These tiny extracellular vesicles, once thought to be “garbage bags for cells,” carry a wide variety of molecules of cellular origin, including proteins, lipids, and RNAs, that are selectively incorporated during the formation of exosomes. Exosomes are now known to play a central role in several important biological processes such as cellular communication, intercellular transfer of bioactive molecules, and immune modulation. Recent advances in the field have shown that a number of animal viruses can exploit the exosomal pathway by incorporating specific cellular or viral factors within exosomes, in order to modulate the cellular microenvironment and influence downstream processes such as host immunity and virus spread. In this chapter, we provide an overview of our current understanding of exosome biogenesis and how this normal physiological process is hijacked by some pathogenic viruses. Viral components that appear to be selectively incorporated into exosomes and the potential role of these exosomes in viral pathogenesis are discussed. Identifying viral signatures in exosomes and their mode of action is fundamental for any future diagnostic and therapeutic strategies for viral infections

Epstein-Barr Virus and miRNAs: Partners in Crime in the Pathogenesis of Multiple Sclerosis?

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS). The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers. These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS. This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS

How Viruses Hijack and Modify the Secretory Transport Pathway

Eukaryotic cells contain dynamic membrane-bound organelles that are constantly remodeled in response to physiological and environmental cues. Key organelles are the endoplasmic reticulum, the Golgi apparatus and the plasma membrane, which are interconnected by vesicular traffic through the secretory transport route. Numerous viruses, especially enveloped viruses, use and modify compartments of the secretory pathway to promote their replication, assembly and cell egression by hijacking the host cell machinery. In some cases, the subversion mechanism has been uncovered. In this review, we summarize our current understanding of how the secretory pathway is subverted and exploited by viruses belonging to Picornaviridae, Coronaviridae, Flaviviridae, Poxviridae, Parvoviridae and Herpesviridae families

Complete genome sequence of Vibrio gazogenes PB1: an estuarine bacterium capable of producing prodigiosin from starch or cellulose

Vibrio is a genus of gram-negative, rod-shaped, motile bacteria commonly found in saltwater. One species in particular, Vibrio gazogenes PB1, sourced from an estuarine environment, is known to produce the secondary metabolite, prodigiosin. This high-value compound has potential uses as an antibiotic, a fungicide, and an anti-cancer agent. To further explore its metabolic and genetic features for biotechnological purposes, the complete genome sequence of V. gazogenes PB1 was determined by Illumina and Pacbio sequencing. Two chromosomes were assembled with a mean coverage of 293x. Chromosome 1 is 3.5 Mbp in size with 45.3% GC content and chromosome 2 is 1.2 Mbp in size with 45.1% GC content. The entire genome harbours 4178 genes, of which 3988 are protein-coding and 114 are RNA-coding. A total of 55 virulence-related genes, 38 antimicrobial resistance genes, 48 transposase sequences, 2 intact prophage regions, and 10 genomic islands were present within the genome. Six genes associated with the degradation of cellulose and starch were also identified within the genome. Four of them were strongly up-regulated, as confirmed by RT-qPCR, thus providing strong evidence for their involvement in starch and cellulose degradation. Quite importantly, we demonstrate for the first time that starch and cellulose is associated with the synthesis of prodigiosin in a native prodigiosin-producing bacterium. The prodigiosin titres obtained in the presence of cellulose were on par with glucose as the carbon source which lends further support in the use of V. gazogenes PB1 as a biotechnological host for prodigiosin production

Pandemic (H1N1) 2009, Abu Dhabi, United Arab Emirates, May 2009–March 2010

To ascertain characteristics of pandemic (H1N1) 2009 virus infection, we reviewed medical records for all suspected or confirmed cases reported in Abu Dhabi during May 2009–March 2010. Overall case-fatality rate was 1.4/100,000 population. Most patients who died had ≥1 risk factor, and female decedents were considerably younger than male decedents

Induction of interferon-stimulated genes on the IL-4 response axis by Epstein-Barr virus infected human b cells; relevance to cellular transformation.

Epstein-Barr virus (EBV) is an oncogenic virus that is associated with the pathogenesis of several human lymphoid malignancies, including Hodgkin's lymphoma. Infection of normal resting B cells with EBV results in activation to lymphoblasts that are phenotypically similar to those generated by physiological stimulation with CD40L plus IL-4. One important difference is that infection leads to the establishment of permanently growing lymphoblastoid cell lines, whereas CD40L/IL-4 blasts have finite proliferation lifespans. To identify early events which might later determine why EBV infected blasts go on to establish transformed cell lines, we performed global transcriptome analyses on resting B cells and on EBV and CD40L/IL-4 blasts after 7 days culture. As anticipated there was considerable overlap in the transcriptomes of the two types of lymphoblasts when compared to the original resting B cells, reflecting common changes associated with lymphocyte activation and proliferation. Of interest to us was a subset of 255 genes that were differentially expressed between EBV and CD40L/IL-4 blasts. Genes which were more highly expressed in EBV blasts were substantially and significantly enriched for a set of interferon-stimulated genes which on further in silico analyses were found to be repressed by IL-4 in other cell contexts and to be up-regulated in micro-dissected malignant cells from Hodgkin's lymphoma biopsies when compared to their normal germinal center cell counterparts. We hypothesized that EBV and IL-4 were targeting and discordantly regulating a common set of genes. This was supported experimentally in our B cell model where IL-4 stimulation partially reversed transcriptional changes which follow EBV infection and it impaired the efficiency of EBV-induced B cell transformation. Taken together, these data suggest that the discordant regulation of interferon and IL-4 pathway genes by EBV that occurs early following infection of B cells has relevance to the development or maintenance of an EBV-associated malignancy

Quantifying risks and interventions that have affected the burden of lower respiratory infections among children younger than 5 years : an analysis for the Global Burden of Disease Study 2017

Background Despite large reductions in under-5 lower respiratory infection (LRI) mortality in many locations, the pace of progress for LRIs has generally lagged behind that of other childhood infectious diseases. To better inform programmes and policies focused on preventing and treating LRIs, we assessed the contributions and patterns of risk factor attribution, intervention coverage, and sociodemographic development in 195 countries and territories by drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) LRI estimates. Methods We used four strategies to model LRI burden: the mortality due to LRIs was modelled using vital registration data, demographic surveillance data, and verbal autopsy data in a predictive ensemble modelling tool; the incidence of LRIs was modelled using population representative surveys, health-care utilisation data, and scientific literature in a compartmental meta-regression tool; the attribution of risk factors for LRI mortality was modelled in a counterfactual framework; and trends in LRI mortality were analysed applying changes in exposure to risk factors over time. In GBD, infectious disease mortality, including that due to LRI, is among HIV-negative individuals. We categorised locations based on their burden in 1990 to make comparisons in the changing burden between 1990 and 2017 and evaluate the relative percent change in mortality rate, incidence, and risk factor exposure to explain differences in the health loss associated with LRIs among children younger than 5 years. Findings In 2017, LRIs caused 808 920 deaths (95% uncertainty interval 747 286-873 591) in children younger than 5 years. Since 1990, there has been a substantial decrease in the number of deaths (from 2 337 538 to 808 920 deaths; 65.4% decrease, 61.5-68.5) and in mortality rate (from 362.7 deaths [3304-392.0] per 100 000 children to 118.9 deaths [109.8-128.3] per 100 000 children; 67.2% decrease, 63.5-70.1). LRI incidence dedined globally (32.4% decrease, 27.2-37.5). The percent change in under-5 mortality rate and incidence has varied across locations. Among the risk factors assessed in this study, those responsible for the greatest decrease in under-5 LRI mortality between 1990 and 2017 were increased coverage of vaccination against Haemophilus influenza type b (11.4% decrease, 0.0-24.5), increased pneumococcal vaccine coverage (6.3% decrease, 6.1-6.3), and reductions in household air pollution (8.4%, 6 8-9.2). Interpretation Our findings show that there have been substantial but uneven declines in LRI mortality among countries between 1990 and 2017. Although improvements in indicators of sociodemographic development could explain some of these trends, changes in exposure to modifiable risk factors are related to the rates of decline in LRI mortality. No single intervention would universally accelerate reductions in health loss associated with LRIs in all settings, but emphasising the most dominant risk factors, particularly in countries with high case fatality, can contribute to the reduction of preventable deaths