Virus-resistant pigs

FMDV In 2001, an epidemic of foot and mouth disease in the UK resulted in the destruction of over six million livestock, restrictions on international trade, and economic costs in excess of £3 billion. Foot and mouth disease is most common in developing areas of the world, such as parts of Asia, Africa and the Middle East, and an outbreak of the disease in animals raised as food resources in such areas can have a devastating effect on economic growth. Research just published reports the results of experiments on genetically engineered pigs that could have broad implications for the control of the disease.

The virus that causes foot and mouth disease (FMD) comes in seven types, each of which requires a specific vaccine for immunization. The Chinese team focused on a protein called VP1 that is variable across all different FMD viruses. VP1 is part of the virus capsid, a three-dimensional array of proteins that is involved in receptor binding and entry into host cells. The researchers looked for the small RNA that was best able to stop the replication of the FMD virus. They then integrated the gene coding for this small RNA into the genome of single pig cells. FMD virus was almost completely inhibited from growing and dividing inside the cells derived from transgenic pigs.

This work is a proof of concept for the use of RNA interference technology to produce transgenic livestock with increased resistance to virus infection. Although this technology could potentially increase food security, it also faces major challenges since, to date, neither the Food and Drug Administration in the United States nor the European Food Safety Authority have approved genetically engineered animals for human consumption. A global consensus on the regulation of genetically engineered organisms has not been reached and each country adopts policy at a national level. However, the governments in a number of countries – including Argentina, Brazil and China – view transgenic products as a way to resolve food security issues. Such countries have simpler protocols for the approval of transgenic products, which might allow transgenic animals to be approved for human consumption.

Foot and mouth disease: Virus-resistant pigs might help to stem next outbreak. (2015) eLife 4: e09790. doi: 10.7554/eLife.09790

Transgenic shRNA pigs reduce susceptibility to foot and mouth disease virus infection. (2015) eLife 4: e06951. doi: 10.7554/eLife.06951

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Microbial Genomics

Microbial Genomics Microbial Genomics is a new fully open access, online-only journal from the Society for General Microbiology. Increasingly I try only to link to open access journals from MicrobiologyBytes, but I don’t write much about microbial genomics – why is that? Well for one thing it’s not really my area of expertise, but more importantly, the increasingly impenetrable jargon genomics papers are writen in would not be helpful to the sort of general audience who read MicrobiologyBytes. So while I welcome the open access nature of Microbial Genomics … there’s a problem.

What’s missing from the new journal is the sort of expnatory overview good journals are now providing, such as the Author Summary in PLoS Pathogens, or the Significance paragraph in PNAS. The Impact Statements in Microbial Genomics are good, but not quite the same thing. Microbial Genomics may rely on science bloggers to translate its research ghettospeak into language the oublic can understand, but to me, it’s an opportunity missed.

(Of course, I do know how much researchers hate writing these things ;-)

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Repeated infection with malaria makes mosquitoes more dangerous

Mosquito In malaria-endemic regions, humans are often infected repeatedly with the Plasmodium parasite, and the consequences of such multiple infections are under intense study. In contrast, little is known about possible co-infection and its consequences in the Anopheles mosquitoes that transmit the disease. A new study reports that not only can individual mosquitoes accumulate infections from multiple blood feeds, but also that an existing malaria infection makes mosquitoes more susceptible to a second infection, and that infections reach higher densities when another strain is already present.

The researchers set up cages of female Anopheles mosquitoes and allowed them at defined times to feed on mice infected with two different Plasmodium strains. They found that mosquitoes can accumulate mixed strain malaria infections after feeding on multiple hosts, and found that parasites have a greater chance of establishing a secondary infection if another Plasmodium strain is already present in a mosquito. Moreover, the presence of the primary infection facilitated replication of the secondary infection while the first infection developed as normal. This resulted in doubly infected mosquitoes having substantially higher parasite loads. The large parasite numbers do not appear to kill the insects, and as it is expected that mosquitoes carrying more parasites are more likely to transmit malaria to vertebrates, mosquitoes taking multiple infective bites might disproportionally contribute to malaria transmission. This in turn would increase rates of mixed infections in vertebrate (including human) hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains.

 

Existing Infection Facilitates Establishment and Density of Malaria Parasites in Their Mosquito Vector. (2015) PLoS Pathog 11(7): e1005003. doi: 10.1371/journal.ppat.1005003
Very little is known about how vector-borne pathogens interact within their vector and how this impacts transmission. Here we show that mosquitoes can accumulate mixed strain malaria infections after feeding on multiple hosts. We found that parasites have a greater chance of establishing and reach higher densities if another strain is already present in a mosquito. Mixed infections contained more parasites but these larger populations did not have a detectable impact on vector survival. Together these results suggest that mosquitoes taking multiple infective bites may disproportionally contribute to malaria transmission. This will increase rates of mixed infections in vertebrate hosts, with implications for the evolution of parasite virulence and the spread of drug-resistant strains. Moreover, control measures that reduce parasite prevalence in vertebrate hosts will reduce the likelihood of mosquitoes taking multiple infective feeds, and thus disproportionally reduce transmission. More generally, our study shows that the types of strain interactions detected in vertebrate hosts cannot necessarily be extrapolated to vectors.

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All Good Things

Woodlouse Some observant microbiologists have noticed that microbiologybytes.com is no more. That doesn’t mean that MicrobiologyBytes is going away, only that this is its home now. The content now called MicrobiologyBytes has moved “home” (URL) four times since I created it in the mid 1990’s. It will probably move home again in the future – it’s already set up base camps in Twitter, Facebook, Tumblr and Google+, none of which existed when the idea was created. The Internet has changed a great deal since the grandaddy of MicrobiologyBytes was born in ’95. The Internet will continue to change in future, and MicrobiologyBytes will change with it.

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Why poliovirus replication has been studied for more than 50 years

A 21st Century Perspective of Poliovirus Replication

It’s very rare to find a long term prospective on any science topic being published in scientific journals. There are few authors who are capable of writing them well and little credit for doing so in a world obsessed with novelty. That makes this short article in PLoS Pathogens all the more valuable and all the more worth while reading.

A 21st Century Perspective of Poliovirus Replication. (2015) PLoS Pathog 11(6): e1004825. doi: 10.1371/journal.ppat.1004825

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Plant virus replication and movement

Plasmodesmata Because plant cells are not identical to animal cells, plant viruses are significantly different from animal viruses in several ways.

Plant viruses replicate and then move between cells through plasmodesmata, gatable channels in the walls of adjoining cells. Although the process of virus movement can be complex and requires support by the coordinated activity of several virus-and host-encoded proteins, many viruses achieve their movement with the help of classical, virus-encoded movement proteins that bind nucleic acids and target and dilate plasmodesmata.

Replication and movement are structurally and functionally linked processes and occur in association with the cytoskeleton and motor proteins. Plant viruses may exploit mechanisms of endogenous macromolecular trafficking for movement. Plant viruses depend on interactions with cellular proteins and membranes to support the formation of membrane-associated, multifactorial protein:nucleic acid complexes for replication and movement. To enhance these processes, viruses assemble and replicate in membrane-associated complexes that may develop into “virus factories” or “viroplasms” in which viral components and host factors required for replication are concentrated.

 

Plant virus replication and movement. (2015) Virology, 479, 657-671. doi: 10.1016/j.virol.2015.01.025
Replication and intercellular spread of viruses depend on host mechanisms supporting the formation, transport and turnover of functional complexes between viral genomes, virus-encoded products and cellular factors. To enhance these processes, viruses assemble and replicate in membrane-associated complexes that may develop into “virus factories” or “viroplasms” in which viral components and host factors required for replication are concentrated. Many plant viruses replicate in association with the cortical ER-actin network that is continuous between cells through plasmodesmata. The replication complexes can be highly organized and supported by network interactions between the viral genome and the virus-encoded proteins. Intracellular PD targeting of replication complexes links the process of movement to replication and provides specificity for transport of the viral genome by the virus-encoded movement proteins. The formation and trafficking of replication complexes and also the development and anchorage of replication factories involves important roles of the cortical cytoskeleton and associated motor proteins.

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New eBooks on viruses

Books Do we still need books, or has the Internet philosophy of “small pieces loosely joined” killed them? Overall, the market for books is not buoyant and is being nibbled away by video, games, mobile phone messenger apps, and of course, Facebook (like it or not). But do we still need books? When I wrote the latest edition of Principles of Molecular Virology, I wrote in the preface:

In the age of the Internet, why would anyone write a textbook about virology?

(If you’re interested, the answer is here.)

But Principles of Molecular Virology is an old fashioned paper book, although you can also get an old fashioned eBook version if you want one. Edward Rybicki and Russell Kightley have written two “modern” eBooks, which you can read onscreen, or use the images and interactive graphics in them via a digital projector or TV screen in talks and lectures:

Both of these short book are beautifully produced and illustrated and you can buy them via the links above, but to read them you’ll need Apple’s iBooks app on iPad, iPhone or Macintosh. But the question keeps nagging at me, Do we still need books? And if we do, are these the books we need?

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How to wipe out polio and keep it that way

Poliovirus Science poised to eliminate polio from the planet but a new study shows that the job won’t be over when the last case of the disease is recorded.

Thanks to global vaccination efforts, poliovirus is on the brink of worldwide eradication. However, achieving eradication and preventing re-emergence requires intimate knowledge of how the virus persists. In order to understand a system that is complicated by heavy human intervention, such as vaccination, it is important to establish a baseline by studying that system in the absence of intervention. Historical epidemics that predate the use of vaccines can be used to disentangle the epidemiology of disease from vaccine effects. Using historical polio data from large-scale epidemics in the USA, mathematical models were used to track poliovirus and to reconstruct the millions of unobserved sub-clinical infections that propagated the disease. This identified why polio epidemics are explosive and seasonal, and why they vary geographically. These analyses show that the historical expansion of polio is straightforwardly explained by the demographic “baby boom” during the postwar period rather than improvements in hygiene. Researchers were also able to demonstrate that poliovirus persisted primarily through symptomless individuals, and that in the event of local virus extinction, infection was reintroduced from other geographic locations.

Disease transmission models show that silent transmission of poliovirus could continue for more than three years with no reported cases. To ensure that the disease is truly eradicated, aggressive surveillance programs and vaccination campaigns must continue in endemic countries for years after the last reported case. Once we’ve eradicated polio – or think we’ve eradicated polio – we probably should intensify the environmental surveillance to make sure the virus is not just lurking under the hood at very low levels. Polio eradication is about eradicating the virus, it’s not about eradicating the disease paralytic poliomyeltis.

Unraveling the Transmission Ecology of Polio. (2015) PLoS Biol 13 (6): e1002172. doi: 10.1371/journal. pbio.1002172
Sustained and coordinated vaccination efforts have brought polio eradication within reach. Anticipating the eradication of wild poliovirus (WPV) and the subsequent challenges in pre- venting its re-emergence, we look to the past to identify why polio rose to epidemic levels in the mid-20th century, and how WPV persisted over large geographic scales. We analyzed an extensive epidemiological dataset, spanning the 1930s to the 1950s and spatially repli- cated across each state in the United States, to glean insight into the drivers of polio’s his- torical expansion and the ecological mode of its persistence prior to vaccine introduction. We document a latitudinal gradient in polio’s seasonality. Additionally, we fitted and validat- ed mechanistic transmission models to data from each US state independently. The fitted models revealed that: (1) polio persistence was the product of a dynamic mosaic of source and sink populations; (2) geographic heterogeneity of seasonal transmission conditions ac- count for the latitudinal structure of polio epidemics; (3) contrary to the prevailing “disease of development” hypothesis, our analyses demonstrate that polio’s historical expansion was straightforwardly explained by demographic trends rather than improvements in sanitation and hygiene; and (4) the absence of clinical disease is not a reliable indicator of polio trans- mission, because widespread polio transmission was likely in the multiyear absence of clinical disease. As the world edges closer to global polio eradication and continues the strategic withdrawal of the Oral Polio Vaccine (OPV), the regular identification of, and rapid response to, these silent chains of transmission is of the utmost importance.

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Virus Commuters

USA Travel In increasingly mobile modern societies, long-distance transmission can rapidly spread pathogens. A new study suggests that both airline and commuter road travel influence flu virus distribution in the continental USA.

When viruses invade naïve host populations and are propagated predominantly by local transmission, we expect to observe wave-like spread across geographic space. As viruses evolve rapidly, because of their high mutation rate, these wave-like patterns of local transmission (from person-to-person and village-to-village) should generate wave-like patterns of genetic variation where the geographic distance between locations and the genetic distance between variants is positively correlated. In today’s world, however, transmission patterns are more complicated, as human pathogens also travel by road, rail, and air. To examine how genetic variation correlates with spatial distribution in a highly mobile society, scientists explored whether measures of distance defined by airline and commuter transportation networks can explain the population genetic structure of seasonal influenza viruses within the USA.

Analyzing the travel networks, the researchers calculated that during the flu season, approximately 1.6 million people travel along the interstate aviation network per day, and that most US states are well connected to most other states. More people (over 3.8 million) travel daily across the interstate ground travel commuter network, but the vast majority of connections here occur between neighboring states, and more so in the Eastern than in the Western USA.

They conclude that while recent findings have shown that the aviation network plays an important role in the world-wide transmission of seasonal influenza, their results suggest that when population structure is detectable, it is the commuter network that is of greater importance at more regional scales. Discussing the public health implications, the researchers say that the detection of network structure implies that patterns of epidemic spread are, to some extent, predictable and point out that the absence of predictability is problematic for the design of containment strategies, since it suggests that the annual seasonal spread of influenza within countries is highly variable and depends heavily on chance events.

The Role of Human Transportation Networks in Mediating the Genetic Structure of Seasonal Influenza in the United States. (2015) PLoS Pathog 11(6): e1004898. doi: 10.1371/journal.ppat.1004898
Recent studies have demonstrated the importance of accounting for human mobility net- works when modeling epidemics in order to accurately predict spatial dynamics. However, little is known about the impact these movement networks have on the genetic structure of pathogen populations and whether these effects are scale-dependent. We investigated how human movement along the aviation and commuter networks contributed to intra-sea- sonal genetic structure of influenza A epidemics in the continental United States using spa- tially-referenced hemagglutinin nucleotide sequences collected from 2003–2013 for both the H3N2 and H1N1 subtypes. Comparative analysis of these transportation networks re- vealed that the commuter network is highly spatially-organized and more heavily traveled than the aviation network, which instead is characterized by high connectivity between all state pairs. We found that genetic distance between sequences often correlated with dis- tance based on interstate commuter network connectivity for the H1N1 subtype, and that this correlation was not as prevalent when geographic distance or aviation network con- nectivity distance was assessed against genetic distance. However, these patterns were not as apparent for the H3N2 subtype at the scale of the continental United States. Finally, although sequences were spatially referenced at the level of the US state of collection, a community analysis based on county to county commuter connections revealed that com- muting communities did not consistently align with state geographic boundaries, emphasiz- ing the need for the greater availability of more specific sequence location data. Our results highlight the importance of utilizing host movement data in characterizing the underlying ge- netic structure of pathogen populations and demonstrate a need for a greater understanding of the differential effects of host movement networks on pathogen transmission at various spatial scales.

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