Ebola virus outbreaks

Ebola virus outbreaks

Source: BBC News – Summit to discuss Ebola emergency starts

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Outbreak of Ebola Virus Disease in Guinea: Ecology Meets Economy

Ebola in Africa Ebola virus is back – but why?

Ebola virus is back, this time in West Africa, with over 350 cases and a 69% case fatality ratio. The culprit is the Zaire ebolavirus species, the most lethal Ebola virus known, with case fatality ratios up to 90%. The epicenter and site of first introduction is the region of Guéckédou in Guinea’s remote southeastern forest region, spilling over into various other regions of Guinea as well as to neighboring Liberia and Sierra Leone. News of this outbreak engenders three basic questions: (1) What in the world is Zaire ebolavirus doing in West Africa, far from its usual haunts in Central Africa? (2) Why Guinea, where no Ebola virus has ever been seen before? (3) Why now? We’ll have to wait for the outbreak to conclude and more data analysis to occur to answer these questions in detail, and even then we may never know, but some educated speculation may be illustrative – which a new paper (below) provides.

The precise factors that result in an Ebola virus outbreak remain unknown, but a broad examination of the complex and interwoven ecology and socioeconomics may help us better understand what has already happened and be on the lookout for what might happen next, including determining regions and populations at risk. Although the focus is often on the rapidity and efficacy of the short-term international response, attention to these admittedly challenging underlying factors will be required for long-term prevention and control.

Outbreak of Ebola Virus Disease in Guinea: Where Ecology Meets Economy. (2014) PLoS Negl Trop Dis 8(7): e3056. doi:10.1371/journal.pntd.0003056

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10 things you should know about Ebola virus

  1. Montage WHO Ebola virus factsheet
  2. Structure of Ebola virus
  3. How to make a vaccine against Ebola virus?
  4. Like this!
  5. Why some Ebola virus strains are more virulent than others
  6. Ebola virus entry requires a cholesterol transporter
  7. Discovery of an Ebolavirus-like virus in Europe
  8. Ebola has lots of sneaky ways of avoiding the immune system
  9. NHS Choices: Ebola virus threat to the UK is ‘very low’
  10. Are we all going to die? Probably not.
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Influenza Viruses and mRNA Splicing: Doing More with Less

Influenza Viruses During their replication in the nucleus of infected cells, influenza viruses hijack the host splicing machinery to process some of their RNA segments, the M and NS segments. This review provides an overview of the current knowledge gathered on this interplay between influenza viruses and the cellular spliceosome, with a particular focus on influenza A viruses. These viruses have developed accurate regulation mechanisms to reassign the host spliceosome to alter host cellular expression and enable an optimal expression of specific spliced viral products throughout infection.

Influenza virus segments undergoing splicing display high levels of similarity with human consensus splice sites and their viral transcripts show noteworthy secondary structures. Sequence alignments and consensus analyses, along with recently published studies, suggest both conservation and evolution of viral splice site sequences and structure for improved adaptation to the host. This emphasizes the ability of influenza virus to be well adapted to the host’s splicing machinery, and further investigations may contribute to a better understanding of splicing regulation with regard to viral replication, host range, and pathogenesis.

Influenza Viruses and mRNA Splicing: Doing More with Less. (2014) mBio, 5(3), e00070-14

 

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Viruses: Friends, Foes, Change Agents

Cover In contrast to their negative reputation as disease causing agents, some viruses can perform crucial biological and evolutionary functions that help to shape the world we live in today, according to a new free report by the American Academy of Microbiology: Viruses Throughout Life and Time: Friends, Foes, Change Agents.

Viruses participate in essential Earth processes and influence all life forms on the planet, from contributing to biogeochemical cycles, shaping the atmospheric composition, and driving major speciation events. Recent metagenomic studies of viruses have indicated we know very little about the real world of viruses. Almost all published research is about the viruses that cause disease in humans and their domesticated plants and animals. This certainly represents only a very small fraction of the viruses that really exist. It is very important to understand the real world of viruses, as this can inform our basic understanding of life and its origins, as well as major earth phenomena like carbon cycling.

Beyond their pathogenic impact, the report examines in depth the size of the virosphere, the origin of viruses, the overlooked biological and microbial ecological role of viruses, and how these live forms have contributed to evolution. Additional highlights from the report explain how some viruses are commensal organisms or symbionts, their functioning in microbial communities, and their role in maintaining the biosphere. The array of responsibilities taken on by viruses is due to their incredible sequence diversity and genomic plasticity, referred to as “viral dark matter”.

The report concludes by stimulating the readers to think about key questions: “What if viruses had never existed on Earth? Would life have evolved quite differently?” Continued virus research will help to answer these enticing questions.

 

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Gene editing eradicates HIV-1

CRISPR More than three decades after the discovery of HIV, AIDS remains a major public health problem affecting greater than 35.3 million people worldwide. Current antiretroviral therapy fails to eradicate HIV infection, partly due to the persistence of virus reservoirs. A new paper just published shows that RNA-guided HIV-1 genome cleavage by Cas9 CRISPR technology has shown promising efficacy in disrupting the HIV-1 genome in latently infected cells, suppressing virus gene expression and replication, and immunizing uninfected cells against HIV-1 infection. These properties may provide a viable path toward a permanent cure for AIDS, and provide a means to vaccinate against other pathogenic viruses. Given the ease and rapidity of Cas9/guide RNA development, personalized therapies for individual patients with HIV-1 variants might be developed quickly.

Comment: In spite of the breezy optimism of this paper (and this is progress), the work described has only been carried out on cultured cells in vitro. It is not clear whether or how easily it will be to replicate this finding in animals, and we’re still along way away from clinical trials which will be needed to show if this approach works in HIV-infected people.

 

RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. PNAS USA July 21, 2014, doi: 10.1073/pnas.1405186111
AIDS remains incurable due to the permanent integration of HIV-1 into the host genome, imparting risk of viral reactivation even after antiretroviral therapy. New strategies are needed to ablate the viral genome from latently infected cells, because current methods are too inefficient and prone to adverse off-target effects. To eliminate the integrated HIV-1 genome, we used the Cas9/guide RNA (gRNA) system, in single and multiplex configurations. We identified highly specific targets within the HIV-1 LTR U3 region that were efficiently edited by Cas9/gRNA, inactivating viral gene expression and replication in latently infected microglial, promonocytic, and T cells. Cas9/gRNAs caused neither genotoxicity nor off-target editing to the host cells, and completely excised a 9,709-bp fragment of integrated proviral DNA that spanned from its 5′ to 3′ LTRs. Furthermore, the presence of multiplex gRNAs within Cas9-expressing cells prevented HIV-1 infection. Our results suggest that Cas9/gRNA can be engineered to provide a specific, efficacious prophylactic and therapeutic approach against AIDS.

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Mosquitoes infected with Wolbachia more likely to transmit West Nile virus

Wolbachia Mosquitoes infected with the bacteria Wolbachia are more likely to become infected with West Nile virus and more likely to transmit the virus to humans, according to a new paper.

Previous research has shown that Wolbachia – a genus of bacteria that live in insects – renders mosquitoes resistant to pathogen infection, preventing the mosquitoes from infecting humans with the pathogens. As a result, researchers are currently releasing Wolbachia-infected mosquitoes into the wild as part of a strategy to control Dengue virus. They also are investigating Wolbachia as a possible control strategy for malaria.

Expecting to find that Wolbachia would block infection by West Nile virus in the same way that it blocks Dengue virus, injected the Wolbachia into adult female Culex tarsalis mosquitoes, allowed them to grow, then fed the mosquitoes a meal of blood infected with West Nile virus. Wolbachia infection did not block West Nile virus in the mosquito, instead these mosquitoes had significantly higher West Nile virus infection rates seven days after they were fed the infected blood. Wolbachia infection allowed the mosquitoes to become infected with West Nile virus faster than the controls.

These results point to a previously unforeseen complication – the possibility that mosquitoes rendered resistant to one pathogen by Wolbachia infection might become better vectors of an alternative pathogen. The team also found that West Nile virus enhancement in the Wolbachia-infected mosquitoes occurred in conjunction with the suppression of genes associated with the mosquitoes’ anti-viral immune response.

This is the first study to demonstrate that Wolbachia can enhance a human pathogen in a mosquito. The results suggest that caution should be used when releasing Wolbachia-infected mosquitoes into nature to control vector-borne diseases of humans.

 

Wolbachia Enhances West Nile Virus (WNV) Infection in the Mosquito Culex tarsalis. (2014) PLoS Negl Trop Dis 8(7): e2965. doi:10.1371/journal.pntd.0002965
Novel strategies are required to control mosquitoes and the pathogens they transmit. One attractive approach involves maternally inherited endosymbiotic Wolbachia bacteria. After artificial infection with Wolbachia, many mosquitoes become refractory to infection and transmission of diverse pathogens. We evaluated the effects of Wolbachia (wAlbB strain) on infection, dissemination and transmission of West Nile virus (WNV) in the naturally uninfected mosquito Culex tarsalis, which is an important WNV vector in North America. After inoculation into adult female mosquitoes, Wolbachia reached high titers and disseminated widely to numerous tissues including the head, thoracic flight muscles, fat body and ovarian follicles. Contrary to other systems, Wolbachia did not inhibit WNV in this mosquito. Rather, WNV infection rate was significantly higher in Wolbachia-infected mosquitoes compared to controls. Quantitative PCR of selected innate immune genes indicated that REL1 (the activator of the antiviral Toll immune pathway) was down regulated in Wolbachia-infected relative to control mosquitoes. This is the first observation of Wolbachia-induced enhancement of a human pathogen in mosquitoes, suggesting that caution should be applied before releasing Wolbachia-infected insects as part of a vector- borne disease control program.

 

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Honing in on enteric fever

Salmonella typhimurium Enteric fever (typhoid), affects about 22 million people and causes about 200,000 deaths every year, according to conservative estimates. Enteric fever is spread by bacteria belonging to the Salmonella genus, with two sub-species – Salmonella Typhi and Salmonella Paratyphi A – being responsible for most cases of the disease. And although the number of cases of enteric fever has fallen significantly over recent decades, there is a clear need for a diagnostic test for Salmonella that is rapid, affordable and accurate. It is important to be able to distinguish between enteric fever caused by Salmonella Typhi and enteric fever caused by Salmonella Paratyphi A in order to ensure that the correct drugs are prescribed and to combat the development of antibiotic resistance.

The application of metabolomics is relatively new in infectious diseases research compared to the application of genomics and proteomics. Despite this, screening the metabolome in blood plasma has identified useful prognostic profiles of several diseases, including sepsis. One of the major benefits of this technique is that it utilizes a pattern of biomarkers (that is, the various metabolites), as opposed to relying on just one host biomarker, as has been the focus of previous approaches.

A new paper in eLife applies this promising new approach to this challenge. Instead of trying to detect Salmonella in the blood during infection, they used a technique called metabolomics. The basic idea of this approach is that infection leads to metabolic changes, such that a person with enteric fever (or any infection) could have a profile of metabolites in their blood that is different to the metabolite profile of a healthy person. The challenge, therefore, is to identify a ‘metabolic fingerprint’ that can be used to detect enteric fever with high levels of sensitivity and specificity.

 

eLife: Host-pathogen interactions: Honing in on enteric fever

 

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A synthetic antibody with broad antiviral activity

Antibody Most strategies for developing virus-resistant transgenic cells and animals are based on the concept of virus-derived resistance, in which dysfunctional virus-derived products are expressed to interfere with the pathogenic process of the virus in transgenic cells or animals. However, these viral protein targeting approaches are limited because they only target specific viruses and are susceptible to viral mutations.

A new paper describes a novel strategy that targets the viral genome rather than virus gene products to generate virus-resistant transgenic cells and animals. A synthetic mini antibody (3D8 scFv), which has both DNase and RNase activities, was expressed in HeLa cells and transgenic mice. The authours found that the transgenic cells and mice acquired complete resistance to two DNA viruses and showed delayed onset of disease symptoms.

The antiviral effects against DNA viruses demonstrated in this study were caused by (1) DNase activity of the antibody in the nucleus, which inhibited DNA replication or RNA transcription and (2) antibody RNase activity in the cytoplasm, which blocked protein translation. This strategy might allow control of a broad spectrum of viruses, including viruses uncharacterized at the molecular level, regardless of their genome type or variations in gene products.

 

A Nucleic-Acid Hydrolyzing Single Chain Antibody Confers Resistance to DNA Virus Infection in HeLa Cells and C57BL/6 Mice. (2014) PLOS Pathog 10(6): e1004208. doi:10.1371/journal.ppat.1004208
Viral protein neutralizing antibodies have been developed but they are limited only to the targeted virus and are often susceptible to antigenic drift. Here, we present an alternative strategy for creating virus-resistant cells and animals by ectopic expression of a nucleic acid hydrolyzing catalytic 3D8 single chain variable fragment (scFv), which has both DNase and RNase activities. HeLa cells (SCH7072) expressing 3D8 scFv acquired significant resistance to DNA viruses. Virus challenging with Herpes simplex virus (HSV) in 3D8 scFv transgenic cells and fluorescence resonance energy transfer (FRET) assay based on direct DNA cleavage analysis revealed that the induced resistance in HeLa cells was acquired by the nucleic acid hydrolyzing catalytic activity of 3D8 scFv. In addition, pseudorabies virus (PRV) infection in WT C57BL/6 mice was lethal, whereas transgenic mice (STG90) that expressed high levels of 3D8 scFv mRNA in liver, muscle, and brain showed a 56% survival rate 5 days after PRV intramuscular infection. The antiviral effects against DNA viruses conferred by 3D8 scFv expression in HeLa cells as well as an in vivo mouse system can be attributed to the nuclease activity that inhibits viral genome DNA replication in the nucleus and/or viral mRNA translation in the cytoplasm. Our results demonstrate that the nucleic-acid hydrolyzing activity of 3D8 scFv confers viral resistance to DNA viruses in vitro in HeLa cells and in an in vivo mouse system.

 

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