Posts Tagged ‘virus’

Larger body size – less retroviruses?

Friday, July 18th, 2014

Retrovirus replication Retroviruses have been invading mammalian genomes for over 100 million years, leaving traces known as endogenous retroviruses (ERVs). Early genome sequencing studies revealed a marked difference in the activity of retroviruses among species, with humans largely containing inactive lineages of ERVs, while the mouse contains numerous lineages of active ERVs. A new paper explores the hypothesis that life history traits determine the activity of ERVs in mammalian genomes, and shows that larger mammals have fewer ERV copies over recent evolutionary time (the last 10 million years) compared to smaller mammals. This association is determined by body size independently of any confounding variables.

A mathematical model that shows that ERV abundance in genomes decreases with larger body size and increases with horizontal transmission. Retroviral integration can cause cancer, and our analysis suggests that larger bodied animals control ERV replication in order to postpone cancer until a post-reproductive age. This is in line with a long-standing observation that cancer rates do not fluctuate among mammals of different body size, a phenomenon known as Peto’s paradox, and opens up the possibility that larger animals have evolved mechanisms to limit ERV activity.

Larger animals exert greater control over ERV proliferation. This could be due to the evolution of mechanisms capable of limiting retroviral activity and consequently limiting the incorporation of ERVs in the genome. Such mechanisms could involve the enhancement of innate or adaptive responses to retroviruses, or perhaps epigenetic regulation is more potent in larger mammals. An intriguing alternative is that the effect is indirect via an improved immune surveillance – some genes involved in pattern recognition for defence against pathogens such as viruses are also involved in controlling cancers. Antiviral genes are the result of a continuous and ancient arms race between viruses and their hosts, and elucidating their roles in controlling cancer across animals of different body size could provide insights into cancer susceptibility.

 

Larger Mammalian Body Size Leads to Lower Retroviral Activity. (2014) PLoS Pathog 10(7): e1004214. doi:10.1371/journal.ppat.1004214
Retroviruses have been infecting mammals for at least 100 million years, leaving descendants in host genomes known as endogenous retroviruses (ERVs). The abundance of ERVs is partly determined by their mode of replication, but it has also been suggested that host life history traits could enhance or suppress their activity. We show that larger bodied species have lower levels of ERV activity by reconstructing the rate of ERV integration across 38 mammalian species. Body size explains 37% of the variance in ERV integration rate over the last 10 million years, controlling for the effect of confounding due to other life history traits. Furthermore, 68% of the variance in the mean age of ERVs per genome can also be explained by body size. These results indicate that body size limits the number of recently replicating ERVs due to their detrimental effects on their host. To comprehend the possible mechanistic links between body size and ERV integration we built a mathematical model, which shows that ERV abundance is favored by lower body size and higher horizontal transmission rates. We argue that because retroviral integration is tumorigenic, the negative correlation between body size and ERV numbers results from the necessity to reduce the risk of cancer, under the assumption that this risk scales positively with body size. Our model also fits the empirical observation that the lifetime risk of cancer is relatively invariant among mammals regardless of their body size, known as Peto’s paradox, and indicates that larger bodied mammals may have evolved mechanisms to limit ERV activity.

 

Mosquitoes infected Wolbachia more likely to transmit West Nile virus

Friday, July 11th, 2014

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.

 

A synthetic antibody with broad antiviral activity

Friday, June 27th, 2014

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.

 

Crossing the species barrier

Friday, June 20th, 2014

The number of pathogens known to infect humans is ever increasing. Whether such increase reflects improved surveillance and detection or actual emergence of novel pathogens is unclear. Nonetheless, infectious diseases are the second leading cause of human mortality and disability-adjusted life years lost worldwide. On average, three to four new pathogen species are detected in the human population every year. Most of these emerging pathogens originate from nonhuman animal species.

Zoonotic pathogens represent approximately 60% of all known pathogens able to infect humans. Their occurrence in humans relies on the human-animal interface, defined as the continuum of contacts between humans and animals, their environments, or their products. The human-animal interface has existed since the first footsteps of the human species and its hominin ancestors 6–7 million years ago, promoting the prehistoric emergence of now well-established human pathogens. These presumably include pathogens with roles in the origin of chronic diseases, such as human T-lymphotropic viruses and Helicobacter pylori, as well as pathogens causing major crowd diseases, such as the smallpox and measles viruses and Bordetella pertussis. Since prehistory, the human-animal interface has continued to evolve and expand, ever allowing new pathogens to access the human host and cross species barriers.

Crossing the Interspecies Barrier: Opening the Door to Zoonotic Pathogens. (2014) PLoS Pathog 10(6): e1004129. doi:10.1371/journal.ppat.1004129

Crossing the species barrier

Virus ecology

Thursday, June 5th, 2014

Viruses Nothing wildly new here, but rather a nice overview of viruses from an ecological rather than a disease perspective.

What Ecologists Can Tell Virologists. Annual Review of Microbiology, first posted online on May 16, 2014. doi: 10.1146/annurev-micro-091313-103436

I pictured myself as a virus…and tried to sense what it would be like. — Jonas Salk

Ecology as a science evolved from natural history, the observational study of the interactions of plants and animals with each other and their environments. As natural history matured, it became increasingly quantitative, experimental, and taxonomically broad. Focus diversified beyond the Eukarya to include the hidden world of microbial life. Microbes, particularly viruses, were shown to exist in unfathomable numbers, affecting every living organism. Slowly viruses came to be viewed in an ecological context rather than as abstract, disease-causing agents. This shift is exemplified by an increasing tendency to refer to viruses as living organisms instead of inert particles. In recent years, researchers have recognized the critical contributions of viruses to fundamental ecological processes such as biogeochemical cycling, competition, community structuring, and horizontal gene transfer. This review describes virus ecology from a virus’s perspective. If we are, like Jonas Salk, to imagine ourselves as a virus, what kind of world would we experience?

 

 

A new drug against MERS?

Friday, May 30th, 2014

MERS virus Before the emergence of the highly pathogenic severe acute respiratory syndrome-associated coronavirus (SARS-CoV) in 2003 only two circulating human coronaviruses (HCoVs), HCoV- 229E and HCoV-OC43 causing relatively mild common cold-like respiratory tract infections, were known, and coronaviruses have not been regarded as significant threat for human health. Now, more than ten years later, the emergence of another highly pathogenic coronavirus of zoonotic origin, the Middle East respiratory syndrome coronavirus (MERS-CoV) points to the need for effective drugs against coronaviruses. Viruses such as coronaviruses that replicate in the host cell cytoplasm have evolved to employ host cell-derived membranes to compartmentalize genome replication and transcription. Specifically for positive-stranded RNA viruses, accumulating knowledge concerning the involvement, rearrangement and requirement of cellular membranes for RNA synthesis specify the establishment of the viral replicase complex at host cell-derived membranes as an evolution- ary conserved and essential step in the early phase of the viral life cycle.

A new paper in PLoS Pathogens describe a small molecule inhibitor of coronavirus replication that specifically targets this membrane-bound RNA replication step and has broad antiviral activity against number of diverse coronaviruses including highly pathogenic SARS-CoV and MERS-CoV. Since resistance mutations appear in an integral membrane-spanning component of the coronavirus replicase complex, and since all positive stranded RNA viruses have very similar membrane-spanning or membrane-associated replicase components implicated in anchoring the viral replication complex to host cell-derived membranes, the data suggests that the membrane-bound replication step of the viral life cycle is a novel, vulnerable, and druggable target for antiviral intervention of a wide range of RNA virus infections.

Of course clinical trials are needed before such drugs could be used, so we’re still years away from this approach being put into practce. Just in time for the next emergent coronavirus maybe?

 

Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus. (2014) PLoS Pathog 10(5): e1004166. doi:10.1371/journal.ppat.1004166
Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

 

Oncolytic virotherapy – in pets?

Friday, May 16th, 2014

Oncolytic viruses Oncolytic virotherapy – using viruses to treat cancer – is a hot topic. Earlier this week the media was reporting a new clinical trial where researchers seeming cured multiple myeloma in one patient by giving her a huge dose of measles vaccine (NHS Choices: Measles virus used to treat bone marrow cancer). But cancer is among the top fatal diseases in domestic and feral dogs and cats too. Incidence of canine or feline cancer ranges from 1% to 2% and cancer currently accounts for about half of the deaths of domestic animals older than 10 years. The most common forms of cancer in dogs and cats are skin, lymphoma, mammary, bone, connective tissue, and oral cancers. The traditional and established methods for pet cancer treatment include surgery, radiation therapy, chemotherapy, hyperthermia and photodynamic therapy. However, the available treatment options for pets with advanced-stage disease are limited and the prognosis for such animals is very poor.

The first clinical studies with vaccinia and adenovirus for canine cancer therapy are underway and data on clinical effectiveness is awaited. As for oncolytic virotherapy of human cancers, the most important challenges for the successful clinical use of OVs in veterinary practice are reduction of viral toxicity, optimization of virus delivery to tumor, and enhancement of viral spread throughout the tumor mass. So will it catch on?

 

Oncolytic Virotherapy of Canine and Feline Cancer. Viruses 2014, 6(5), 2122-2137; doi:10.3390/v6052122
Cancer is the leading cause of disease-related death in companion animals such as dogs and cats. Despite recent progress in the diagnosis and treatment of advanced canine and feline cancer, overall patient treatment outcome has not been substantially improved. Virotherapy using oncolytic viruses is one promising new strategy for cancer therapy. Oncolytic viruses (OVs) preferentially infect and lyse cancer cells, without causing excessive damage to surrounding healthy tissue, and initiate tumor-specific immunity. The current review describes the use of different oncolytic viruses for cancer therapy and their application to canine and feline cancer.

 

 

Further delay before the end of smallpox virus?

Friday, May 2nd, 2014

Smallpox vaccine Variola, the virus that causes smallpox, is on the agenda of the upcoming meeting of the World Health Assembly (WHA), the governing body of the World Health Organization. The decision to be made is whether the last known remaining live strains of the virus should be destroyed. An international group of scientists argue in an opinion piece published on May 1st in PLOS Pathogens that the WHA should not choose destruction, because crucial scientific questions remain unanswered and important public health goals unmet.

Smallpox was declared eradicated in 1980, the only human pathogen for which successful eradication has been achieved to date. Since then, limited research focusing on diagnostic, antiviral and vaccine development, under close direction and oversight, has continued in two high-security laboratories – one in Russia and one in the US – the only places that are known still to have live variola strains. The justification for this research is that smallpox might re-appear via intentional release. Indeed, recent advances in synthetic biology make the possibility of re-creating the live virus from scratch more plausible.

Summarizing the focus and the achievements of the research on live variola over the past several decades, the authors of the PLOS Pathogens article mention several new smallpox vaccines (the ones widely used prior to eradication would not meet today’s stricter safety standards for routine use) and two new drug candidates that, based on research so far, appear to be promising antivirals against the virus that causes smallpox. However, both of these drug candidates have not yet been licensed for use against the disease. “Despite these considerable advances, they argue that “the research agenda with live variola virus is not yet finished”.

Are We There Yet? The Smallpox Research Agenda Using Variola Virus. (2014) PLoS Pathog 10(5): e1004108. doi:10.1371/journal.ppat.1004108

Should Remaining Stockpiles of Smallpox Virus Be Destroyed?

 

A global network of researchers? Not really – small worlds.

Thursday, April 17th, 2014

As science evolves, important scientific achievements require the collaborative effort of an increasing number of researchers. The study of patterns of scientific collaboration allows us to gain further understanding of innovation and knowledge production. Scientific collaboration networks have been the subject of growing interest in the past few years. Collaborative scientific publications have a long history. The first collaborative research paper was published in 1665 in the Philosophical Transactions of the Royal Society. To date, the most multi-authored scientific paper was published in 2010, when 3,222 researchers from 32 different countries contributed to a study of charged-particle multiplicities performed in the Large Hadron Collider at CERN.

A new study finds that the United States was the country with the largest number of international collaborations, particularly with South Africa, Uganda and Brazil. The high global clustering coefficient coupled with a short average distance between nodes suggests a “small-world phenomenon” among HIV and HPV researchers. Researchers from high-income countries seem to have a high number of research collaborations among them and to cluster together in densely connected communities, particularly those from the US. There is a large well-connected community, which encompasses 70% of researchers, and other much smaller communities, including the UK.

Small worlds

International Scientific Collaboration in HIV and HPV: A Network Analysis. (2014) PLoS ONE 9(3): e93376. doi:10.1371/journal.pone.0093376
Research endeavours require the collaborative effort of an increasing number of individuals. International scientific collaborations are particularly important for HIV and HPV co-infection studies, since the burden of disease is rising in developing countries, but most experts and research funds are found in developed countries, where the prevalence of HIV is low. The objective of our study was to investigate patterns of international scientific collaboration in HIV and HPV research using social network analysis. Through a systematic review of the literature, we obtained epidemiological data, as well as data on countries and authors involved in co-infection studies. The collaboration network was analysed in respect to the following: centrality, density, modularity, connected components, distance, clustering and spectral clustering. We observed that for many low- and middle-income countries there were no epidemiological estimates of HPV infection of the cervix among HIV-infected individuals. Most studies found only involved researchers from the same country (64%). Studies derived from international collaborations including high-income countries and either low- or middle-income countries had on average three times larger sample sizes than those including only high-income countries or low-income countries. The high global clustering coefficient (0.9) coupled with a short average distance between researchers (4.34) suggests a “small-world phenomenon.” Researchers from high-income countries seem to have higher degree centrality and tend to cluster together in densely connected communities. We found a large well-connected community, which encompasses 70% of researchers, and 49 other small isolated communities. Our findings suggest that in the field of HIV and HPV, there seems to be both room and incentives for researchers to engage in collaborations between countries of different income-level. Through international collaboration resources available to researchers in high-income countries can be efficiently used to enroll more participants in low- and middle-income countries.