Honeybees toil endlessly to make delicious delicious honey, but just like you and me, they have their off days when they don’t feel the buzz. Mites, microrganisms and viruses are enough to put pupa off their pollen, and a sick hive can suffer reduced honey production to full colony collapse. With our vested interest in their well-being, we’ve swotted up on what blights our bees, but whether the unwelcome critters in our managed hives reflect those that bug bumblebees in the wild is less understood. Things I learned from the linked article: 1) there’s some spillover of viruses from our own workers to wild bee populations, with transmission possibly occurring from sharing the same flowers, 2) bee viruses have excellent names – black queen cell virus, deformed wing virus, acute bee paralysis virus, slow bee paralysis virus and sacbrood virus.
If our bees are propagating viruses that later swarm into the wild, birds provide the opposite flight path when it comes to flu.
I think the headline “Wild birds may spread flu virus” is kind of like saying “water flows downhill”, but the article itself is a useful look into how the H5N8 and H7N7 bird flu viruses are travelling around Europe. For instance, ducks on a farm in Yorkshire in the UK may have contracted H5N8 from migratory birds from Russia. How this happens isn’t clear yet, as poultry are kept inside and wouldn’t have mixed with the wild birds.
The guys at the University of Glasgow Centre for Virus Research interview herpesvirologist Professor Peter O’Hare. A great overview of the some of the history, problems and questions associated with those ‘creeping’ viruses of humans. Whilst Peter’s lab do some cool work (this one is a recent favourite – Open Access), he doesn’t include virus latency in his list of big questions in herpesvirology! 😦 For the sake of my fragile little feelings, I’ll assume this is because we’re answering some of the questions, rather than it not being interesting…
This article has been pretty popular online this past week. As Ebola lingers on towards the West African rainy season starting in April, we’re running out of time to aggressively end the outbreak once and for all. This article covers some important points, most notably:
Aggressive contact tracing can now be pursued in areas with few cases. This tactic is very expensive in terms of money and people power, but is the best way to halt further disease spread. However…
…a large proportion of cases in Guinea and Sierra Leone occur in people with no known contact with the sick. In other words, our current surveillance is failing to catch all known cases.
Small individual outbreaks are becoming isolated in different geographical regions, requiring aid work to be mobile rather than relying on bringing the sick to centralised centres. However…
…it’s going to rain soon. A LOT. This is going to hinder all transport in the region.
The virus isn’t gone yet, and if we let it, it’ll probably come back with a vengeance. I’ve not exhausted the important stuff in this piece. Check it out.
The beginnings of an interesting epidemiological detective story here. Recent Measles outbreaks in Quebec can easily be linked to the Disneyland outbreak in the states, but a small cluster of cases in Ontario have come from somewhere else entirely. But where? Measles was eliminated from Canada in the 1990’s, so the virus was likely imported from abroad.
Just goes to show, virus diseases may be extremely rare in your neck of the woods, but in today’s global society, I’d recommend you carry on vaccinating yourself and your family.
Bacteriophage are extremely cool. Every living thing on the planet has its own viruses, and bacteria are no exception. Despite the advent of antibiotics, doctors in the Soviet Union experimented and developed virus preparations to kill common bacterial diseases. Now with the shadow of antibiotic resistance hanging over the globe, people in the West are turning to these plucky ‘bacteria-eaters’ as our future saviours.
It’s not quite as a simple as that though. Bacteriophage (or phage) therapy requires knowing exactly what bug you’re trying to kill. Why? Because bacterial species are incredibly diverse and bacteriophage are highly species-specific. Think about mice and men – both are mammals, but whilst you could send a cat in to remove your mouse problem, sending in a cat to solve your human problem is going to result in more humans and lots of pictures on the internet.
This article gives a great introduction into the successes and failures of individual Western forays into the exciting world of bacteria-exploding viruses.
Parasitoid wasps are nightmarish critters of death and manipulation. For all the times you’ve been stung by a wasp, just be glad it didn’t lay its carnivorous unborn into your still living flesh. Evolution has ‘gifted’ us a huge number of such insects, which happily prey on as large a number of different bugs to both incubate their eggs and eventually provide the newly hatched young with a live-in shelter to eat their way out of.
“Mike?!” you yell, “Why are you ruining our brains forever with this? Where are the viruses?!”
Worry not, viruses are at work here. In fact, this article deals with just one such virus story (I’ll save the other for a later write-up).
In brief, because you should dive into the linked article:
Wasp injects ladybird (ladybug) with an egg. Ladybird carries around egg, which later hatches and eats its way out of the ladybird. Wasp wraps itself in a cocoon to develop into an adult and the still living (but presumably now-porous) ladybird guards the cocoon from predators. Why? Because a virus, named D. coccinellae Paralysis Virus, or DcPV, that lives in the wasps and their eggs, infects the brain of ladybirds and turns them into zombie guards. Nature. You are scary.
OK, let’s get serious. A report into what we know about Ebola transmission has been published this week, and the media has leapt on to the authors’ opinion that the virus might spread by air as well as by contact. I don’t see a problem with the media’s interpretation of the report: the news seems to be carrying the salient points made by the piece. But the fact of the matter is that the evidence to back up aerosol transmission of Ebola just isn’t there. We know that people get infected when they come into close contact with the very sick and/or dying: people leaking virus-laden fluid into their immediate surrounding environment.
The possibility of transmission of virus cast into the air by the coughing sick – possible, but paling in comparison to the aforementioned infectious fluid – does not match up to the fear of a ‘Hollywood-style’ virus epidemic. The sick spread the virus to one or two people by close contact, they do not infect dozens by lacing the air with virus particles.
Could the virus evolve to use a different route of transmission though? Suddenly infecting through the air rather than by contact? No. A scene in the movie Outbreak, in which scientists crowd around an electron microscope image of an Ebola-like virus, before and after the “evolution of hair-like molecules” which “enable the virus to spread through the air” is firmly lodged in fiction (for the record, despite being objectively terrible, that movie is ace).
This topic is deserving of full articles to explain this reasoning and the outbreak as it stands, and so I defer to two:
Finally, because choice of language is more important than we think, a small piece on ditching the term ‘pathogen’. This article isn’t virus-centric, but that’s really the point. We focus on the bugs – the “pathogens” – when we research disease, because we hold them up as the reason for the illness. But in reality, disease isn’t a one-way street. Our immune systems are often responsible for most of the damage done to us during infection, and some people can be asymptomatically infected with viruses, bacteria or fungi, when others become desperately ill.
The term pathogen isn’t going anywhere, but if we think about the pathology of infection a little more holistically, perhaps we’ll make better progress eliminating it.
The tempo of publishing to the site is a little lower than I want at the moment. While I’ll always publish the weekly links, I’ll return to longer writing when stuff ‘behind the scenes’ has calmed down a bit. Now is one of those times, but a more normal service should resume shortly. For this week, I’ve a report, a video and a podcast to feed your audio-visual thirst for virology:
News of Ebola’s ‘death’ may have been greatly exaggerated – including by yours truly. For the second consecutive week in a row the number of new cases has risen in all three afflicted countries. We’ll have to pay careful attention to disease trends from here on. Extinguishing the last embers of this outbreak may require even more water than anticipated.
Ever looked at a 3D reconstruction of a virus particle and found the whole thing boringly static? No me neither, BUT this video demonstrates just how fluid a poliovirus particle in motion may be. The second half of the video looks behind the curtain of such simulations. No wizards here (well, not magic ones anyway…), just massive supercomputer CPU arrays. It’s all really cool (literally and figuratively).
I’ll admit, I generally think of (and refer to) virus capsids as protein shells – but rigid and brittle these particles are not. Perhaps coats is a better metaphor, something protective but allowing for motion.
Speaking of language and its careful use, I only just got around to listening to the linked episode of This Week in Virology, featuring guest Paul Duprex of the National Emerging Infectious Diseases Institute in Boston. The episode focuses upon the debate surrounding so-called “gain of function” experiments. A previous example of such an experiment would be the adaption of influenza to transmit between ferrets, in order to understand the mechanics of virus evolution and transmission in new hosts.
Proponents of such work say it’s necessary to understand and combat the results of phenomena occuring in wild flu infections. Opponents suggest that such work may create new pandemic viruses that would endanger global human health if they were accidentally released. Given the nature of the debate, the rhetoric is being horribly ratcheted up by those against this work.
Whilst sometimes wishing it had a bit more teeth, I appreciate both Paul Duprex’s defence of the work and his calls for the return to reasoned debate, because there’s one to be had. To quote: “if it’s a fight, no one’s gonna win”. I think he’s probably right.
Measles virus is in the news recently for all the wrong reasons, but how can the virus make such a roaring comeback in developed countries if vaccination campaigns slip? The answer: it is insanely contagious. And it needs to be – once you’ve had the virus you are immune for life – so if susceptible humans are around to be infected, the virus needs to get at them to survive and continue spreading. The article also touches on a cool thought that seems paradoxical to how well the virus can spread: because it can only infect people and not animals, it’s a great candidate for eradication from the planet.
When it comes to transmission between hosts, measles is at the ‘hit-and-run’ end of the spectrum: infect human and get out before the immune system kills every last one of you. On the complete opposite end of the spectrum we have endogenous retroviruses.
Retroviruses, like HIV, bury themselves in your DNA. Every time an infected cell divides into two, you get twice as many copies of virus. But when such viruses get into sperm or egg cells, things get weird. If the infected sperm or egg goes on the make a new lifeform, every cell in the new life’s body will contain of copy of the virus! Surely this must be rarity, right? Nope. In human beings, this has probably occurred more than 30 times. But as the article concludes, apes (including humans), may have finally had enough of picking up these stowaways.
For a third story, this week saw a ‘great’ example of the science media hype machine in action, not helped by the study authors’ press release one bit. Here are 5 tweets from Stephen Curry regarding both the study and one example of an accompanying news report that deftly summarised the article I had planned to write this week. Curses.
That PNAS paper on how RNA viruses package their genomes is a nice piece of work (1/n) http://t.co/hPqCqBgHo7
Excellent news reported in the New York Times today – Ebola drug trial is halted due to lack of patients. The quicker this virus leaves the West African region alone, the better. But this news is also a somber reflection on drug and vaccine development. As I wrote before, medical trials in countries with declining disease are doomed to fail. You cannot work out if a treatment works if you don’t have the patients to treat.
Before I go any further, I’ll reiterate: of course it’s excellent news that this horrendous virus is finally leaving the people of Liberia alone (and soon Guinea and Sierra Leone). But when the virus comes back in the future1, having new and effective weapons against it could prevent outbreaks happening again at this scale.
Before the 2014 outbreak in West Africa, news of Ebola vaccines was confined to the academic literature. Once the outbreak was in full force we finally decided to pay attention and fire up the drug pipeline. We needed candidate vaccines and drugs ready to go into the field at the beginning.
I admit the example of ZMapp, an experimental antibody cocktail against Ebola, was such a drug candidate. ZMapp was shown to protect rhesus macaques against the virus (albeit during the outbreak) and saw action in the field. The fact that the drug is so difficult to make in large quantities was probably tolerated by its manufacturers because the world had never seen such a large Ebola outbreak. Either way, we still don’t definitively know if it works in people because too few received it.
This newest drug trial closure is different. We’ve known about this one – Brincidofovir – for some time. Brincidofovir is a potent DNA virus growth inhibitor. It’s currently being stockpiled by the U.S. to counteract a smallpox bioterrorism threat. The fact that it works against Ebola in dishes of cells is an oddity (Ebola has a genome made of RNA, not DNA) that we don’t understand. But we know it works.
I’m not angered by the failings of the current trials. Logistics and manufacturing mean that responding to such an unforeseen virus outbreak without a whole bunch of candidate drugs was always going to prove difficult.
But we need to be ready next time. We don’t have time to run the compulsory safety trials while the virus is raging. We need a list of potential drugs and vaccines that we already know are safe in humans. Only then can we ethically test whether they work during the timeframe of an outbreak. And this preparation should also apply to other emerging virus diseases.
If we fail next time, then there’ll be reason to be angry.
The virus is thought to persist in insectivorous bats in the wild. When a virus persists in an animal reservoir, the only way to effectively eliminate it is to vaccinate or kill enough of that species. Both are extremely difficult and undesirable courses of action. With the virus persistent in bats, there is always the potential for human infection in the future.↩
The story of poverty, population density and a deadly pathogen. Whilst more about Freetown, Sierra Leone than the Ebola virus, this is one of those articles that blossoms understanding in the minds of those fortunate enough to be on the other side of the planet. The virus is fascinating and deadly, but it’s the human side of the equation that is by far the most complicated. The photography is really great here too, but just a warning that some photos early on in the article are harrowing.
It’s an absolute truism: yes, it’s mutating because it’s a virus. Connor Bamford slams the recent lazy headlines about the virus mutating with a comprehensive explanation of what we mean by mutation, what the likely consequences of this are, why you shouldn’t worry about it and why we need to continue tackling Ebola as we currently are.
A virus to keep on the radar: the snappily named Enterovirus D68. The circulation of this virus increased in the US last year, coincident with strange cases of fever, respiratory illness and paralysis in children and young adults. There is no smoking gun connecting the virus to these cases of paralysis at the moment, so why mention them in the same breath?
The most important reason is the timing of the cases – the virus could be isolated from some of the people suffering from sudden onset paralysis – but correlation is not causation, and assuming the virus is responsible could prevent us treating people if it’s not actually the cause. The second reason suspicion is being cast on the virus is due to our history with one of its close relatives – Poliovirus.
Taken together – animals need vaccine development, children around the world cannot get access to vaccines, and – to be plain – idiots in the US are ignoring an effective vaccine to measles, allowing for outbreaks of the disease.
GlaxoSmithKline have announced that 300 doses of an experimental Ebola vaccine are on their way to Monrovia, Liberia. The rapidly developed vaccine has gone through phase one trials in 200 healthy volunteers across the globe to test its safety. Having passed this test it will now enter phase two trials in Liberia to test whether the vaccine is actually effective at preventing Ebola infection and disease.
How will this work?
To test vaccines, healthy people are either given the vaccine or a dummy shot. Those two groups are then followed over the course of months to record the number of individuals that go on to catch the virus or develop the disease. If fewer people in the vaccinated group catch Ebola virus than the dummy group, then we can conclude that it works. Obviously, nobody wants anyone to get Ebola in the first place (this is why we’re trying to develop vaccines, after all), but it’s necessary to tell if the vaccine is an effective tool against the virus.1
As a result, the success of the experiment is dependent upon a significant proportion of the studied people coming into contact with the virus. If nobody catches Ebola, you can’t tell whether the vaccine works. You then have nothing to aid those at extremely high risk of disease, such as family members of the already sick, or medical workers.
By all means, these vaccines cannot come too soon. If they are effective, we will have a powerful weapon against a virus that will strike again in the future.2 And clearly, the decision to send these doses to Liberia is months in the planning, it didn’t get decided overnight.
But is sending the vaccine to Liberia actually going to tell us whether the vaccine works?
A senior health minister from the Liberian government has today announced that there are just five Ebola cases left in the country. This is fantastic news and a real testament to both the national and international response to the outbreak. While not every Ebola case may be officially diagnosed in a country, the fact that new cases have been reduced to single digit numbers suggests a virus on the way out.
Taking the CDC’s cumulative case numbers (.csv download) (which can be viewed without download here) and plotting the number of cases per month, it’s quite clear where the Ebola outbreak is headed:
Ebola cases per month (CDC figures). These data are complete up to January 21st 2015.
The virus is outta here, with cases dropping in every country (note, the January data are up until the 21st, not the end of the month). Most importantly, we can see that Sierra Leone is really the final bastion of the disease. If we want to test the efficacy of this GlaxoSmithKline vaccine, and be potentially3 ready to contain future outbreaks with it, surely it would be reasonable to retarget our efforts to Sierra Leone? While the logistics of this aren’t trivial, should we be sending a trial vaccine to a country where the chance of catching the virus is rapidly plummeting to zero? We may as well send the country thousands of sterile syringes, they’d be more useful.
To be clear, the studied group are not then purposefully exposed to the virus to test the vaccine. Individuals already thought to be at a risk of infection, such as medical workers, are included in the study.↩
The virus is thought to persist in insectivorous bats in the wild. When a virus persists in an animal reservoir, the only way to effectively eliminate it is to vaccinate or kill enough of that species. Both are extremely difficult and undesirable courses of action. With the virus persistent in bats, there is always the potential for human infection in the future.↩
In the last article, I wrote about a study which looked at the ability for the flu virus to package all 8 segments of its RNA genome. In short: they often don’t package all 8. And if the process of stuffing flu particles with RNA isn’t that picky (hey, important pieces are supposedly missing here), you could think that any one RNA segment is just as likely as another to be left out.
But work published in 2014 provided a neat example of how this process can be far from random, and can be directly influenced by the virus itself.
It all focuses on a mutant of the flu NP (or NucleoProtein). NP smothers flu RNA, keeping it organised for transcription and copying the viral genome, as well as allowing it to be packaged into the virus. Following previous experimental infections with the mouse-adapted influenza A strain ‘PR8’, a single mutation in NP (F346S) was found to increase virus replication in guinea pig noses. Whatever this change in NP was doing, as far as making new viruses goes, it was doing a good job. But when the same lab group looked at infection in cell culture, they found something wrong with the virus: it didn’t make very much NA protein.
NA (or NeurAminidase) is an enzyme that sits on the surface of the flu particle and allows the virus to cut itself free from infected cells (and may also have a role in cleaving through mucus on the way into the host1). By all measures, flu needs NA for infection. Yet, compared to the starting PR8 strain, the mutant virus produced less NA protein, less NA mRNA, and populations of purified virus particles contained fewer copies of the NA RNA segment. In other words, there appeared to be less of the protein because there was a shortage of instructions to make it – and all seemingly because of a single mutation in NP.
Furthermore, the authors show in this work that the mutant flu virus (F346S) produced a greater proportion of “semi-infectious” viruses during replication. Semi-infectious means a flu virus without all 8 RNA segments and incapable of completing an infection cycle all by itself. When equal amounts of fully infectious particles were added to cells, the authors saw that the mutant virus infected 8x as many cells.2This demonstrated that the vast majority of mutant virus particles were semi-infectious. See the following diagram for clarity:
A virus stock is made up of a) fully infectious particles (green circles) and b) semi- or non-infectious viruses (red crosses).Here, both mutant and normal flu samples total 10 particles each, but the proportion of circles and crosses is different for each virus. If you wanted to infect cells with 9 green circles from each stock, you would end up adding 90 total particles from the mutant and just 10 from the normal virus stock. This explains how so many more cells are infected during the mutant infection.
So how can a virus lacking such an important protein replicate better during guinea pig infection? Especially given that so many particles aren’t fully infectious on their own?
Firstly, why isn’t it just worse at replicating? Here, the authors suggest that the virus replicates well in guinea pigs because a large number of cells get infected with multiple viruses. If one virus lacks all 8 segments, then another can help out if they infect the same cell. Here’s this image again from my last article:
Lefty here only has 7 of the 8 pieces of RNA he needs, so this infection is doomed to fail. Righty and friend also only have 7 pieces, but between them they have the full set – they’ve all they need to make more virus.
I think the authors do a cool job of showing how co-infection occurs over time in the guinea pigs. When they took cells washed from infected noses at 9 hours after infection and flow sorted them, they saw that only a small proportion (25–44%) of cells produce both proteins HA and NA. But when they did the same thing at 48 hours after infection, 80–90% of cells contained both. These data suggest that early in infection, cells are generally infected with individual viruses, both fully or semi-infectious. But once more rounds of flu are produced in the guinea pig the majority of cells get infected with multiple viruses. Who cares about carrying all 8 RNA segments when you have a load of mates to help you out?
So while co-infection minimises the detrimental effect of semi-infectious particles, how exactly does this mutant virus replicate better in guinea pigs?
The authors suggest a number of possibilites in the discussion of this work, notably that some unknown beneficial effect of the NP mutation may outweigh the lack of NA, or that in combination with the NP mutation, reduced NA activity could be an advantage. It’s certainly not clear. To finish, I’ll posit a version of the second possibility.
Perhaps, in the absence of NA, the flu particles are simply aggregating together. This idea is supported by work from the Barclay lab at Imperial College London, in a 2013 paper.3 Specifically checking out figure 5, flu virus particles possessing a shorter form of NA aggregated together far more than those with the normal longer length NA. Why does this happen? Because sialic acid (the cell molecule to which the flu virus binds in order to infect cells) gets stuck on to newly formed virus particles and must be cleaved off by the NA protein. NA usually cuts flu free from cells, but it can also sever the tethers between viruses. The short NA is worse at this than the longer form, and you know what, I bet viruses lacking NA altogether are terrible at separating themselves.
On the topmost cell, influenza buds and escapes normally due to the presence of NA (long red lines) on the virus surface, which cleaves the sialic acid molecules on the cell (very long green lines). On the bottom cell, the flu particles are covered in far fewer copies of NA, impairing the break down of sialic acid. The flu HA protein (short black lines) binds sialic acid on both the cell and virus membranes, leading to aggregation of virus particles. If some NA is present, the aggregate could come away from the cell and infect as one mass.
And if you’re a flu particle looking for a friend to go co-infecting with, what better way than to hold hands as you both enter the cell at the same time?
Whilst this hypothesis isn’t complete, as I have no answer as to how NP affects NA or what else it may be doing, I figure less NA on viruses = better virus aggregation and thus more efficient co-infection. Greater co-infection could allow for greater reassortment of novel mutations, and could aid the virus in the battle against intracellular immunity by overwhelming the cell before immune signalling is fully established.
Big clumps of virus sounds ideal for infection, but viruses don’t just ‘worry’ about what to do inside a host. What about getting between hosts?
Note: a virus doesn’t have to be fully infectious to get into a cell. So long as it can enter a cell and produce some virus proteins, that’s enough. The differentiation between semi and fully infectious is just about whether the virus can get in, copy itself AND get out again to repeat it all.↩
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