Field of Science

What can flies tell us about #virusevolution?

Some of the fly species used in this study (thanks to Ben Longdon).
 What influences whether a parasite - for example a virus - will infect a new host and jump species? Is it more to do with the virus, or the host? Maybe something entirely different, like whether the two hosts will ever meet. Investigating these factors may allow us to predict how viruses will behave in their natural environment and aid us in determining the likelihood of transmission and spread into - and throughout - a new species, like us, humans. Imagine if we had had this knowledge earlier, we may have been able to prevent such epidemics HIV, SARS or the recurring ebola outbreaks. 

 Well, this is exactly what one group - joint between Edinburgh and Cambridge Universities in the UK - are doing. Get the PLoS Pathogens paper here. Using perhaps the only experimentally amenable model system for animals - which consisted of flies and their viruses - they recently provide evidence that the likelihood of a virus replicating within a new host has a lot to do with how genetically related it is to the original host species. And, surprisingly, in some cases it has not much at all to with it - further compounding the complexities of virus emergence. But how did they do it?

Pathogens switching to new hosts can result in the emergence of new infectious diseases, and determining which species are likely to be sources of such host shifts is essential to understanding disease threats to both humans and wildlife. However, the factors that determine whether a pathogen can infect a novel host are poorly understood. We have examined the ability of three host-specific RNA-viruses (Drosophila sigma viruses from the family Rhabdoviridae) to persist and replicate in 51 different species of Drosophilidae. Using a novel analytical approach we found that the host phylogeny could explain most of the variation in viral replication and persistence between different host species. This effect is partly driven by viruses reaching a higher titre in those novel hosts most closely related to the original host. However, there is also a strong effect of host phylogeny that is independent of the distance from the original host, with viral titres being similar in groups of related hosts. Most of this effect could be explained by variation in general susceptibility to all three sigma viruses, as there is a strong phylogenetic correlation in the titres of the three viruses. These results suggest that the source of new emerging diseases may often be predictable from the host phylogeny, but that the effect may be more complex than simply causing most host shifts to occur between closely related hosts.

 This work largely follows on from studies where they originally discovered a number of new fly viruses (RNA viruses related to the mammalian rabies virus to be specific) that interestingly, weren't horizontally transmitted but were passed on from infected to non-infected vertically, that is via sperm or eggs. Horizontal transmission is what we see with influenza for example. But, when they examined how these viruses evolved when compared to their host species, they found something rather unexpected: despite being passed on from parent to offspring, these viruses were found to have changed host's rather often - something you'd expect more from viruses like avian influenza, SARS or HIV. The reasons why - and how - they did so is what this paper is about.

How can we test it?

 What the group did was inject three of these newly uncovered RNA viruses directly into a wide range of different Drosophila flies taken from the wild and measured how well each virus grew and persisted - something I can assure you is no easy job. The extent of virus growth was then compared to how distantly related the new host species was in relation to the original one and they tried to determine whether the genetic relatedness could explain observed differences in replication. Simple enough, so see the data below:

Their data - host fly phylogeny on the left and viral growth titres on the right in blue for each of the 3 viruses - red indicates the original host species of the virus. How does growth change in more genetically related hosts?

 When they employed their rather complex statistical analyses they discovered that two factors were explaining how well each virus grew in a new host, one's they termed: phylogenetic and distance effects. On one hand, the more closely related the new species was to the natural host, the better the virus grew (which you may think is pretty much expected) yet what was surprising was that this 'distance' effect didn't explain everything. After accounting for this 'distance effect' the relationships between species explained almost all the remaining variation in viral growth.  This effect was independent of genetic relatedness and resulted from a more general level of susceptibility to all viruses examined. This resulted in some species that were more distantly related (in fact, even the most distantly related) having the higher levels of growth.

They explain it a bit better here:
We call this first effect – where the change does not have a predictable sign – a phylogenetic effect, and the second effect - where change does have a predictable sign – a distance effect.

What explains these effects?

 So why do we see these effects at all, and can we use them to predict virus species jumps - even given the inherently unpredictable nature of the 'phylogenetic' effect? Well the distance effect is pretty intuitive with a large amount of virology literature detailing the intimate virus/host relationship: being obligate intracellular parasites, these microbes require host machinery for nearly all of their replication, think ribosomes, nucleotide synthesis, receptor entry, virus release. This is especially true for viruses with limited coding capacity and high rates of evolution like these RNA ones. So you could imagine there exists a very nice fit between a virus and it's host, you mess with this by taking a highly adapted virus and sticking it into a host it hasn't adapted to, you'll impact growth.

 But what about the phylogenetic effect? How come some groups of hosts allow the virus to grow to a similar extent independent of genetic distance? This, they state, could have much to do with the particular receptor being expressed or whether those hosts have a generally better immune system but the nature of this makes it near-impossible to predict the actual cause without further characterization of the viruses and the hosts, something that should be addressed in the future.

Rhabdovirus particles
Does this happen in the 'real world'?

 How applicable is this to the 'real world'? The paper makes a lot of assertions about its relevance for some of the more infamously species jumping viruses, like: influenza, SARS and HIV, but how closely should we apply this insect virus data to vertebrate/mammalian systems in the wild? The caveats that should be considered are that these guys didn't take into consideration the whole picture of viral emergence (something they didn't aim to do - or assert that they did). As for a virus to jump species, it must first be released from one, encounter another and infect/replicate there; this paper injected the viruses individually into the flies, thus circumventing transmission and not addressing ecological factors. Ultimately looking ta how these viruses evolve in the wild should give us some data on this.

  They also didn't look at the amount of infectious virus being released - their growth results were based on PCR of parts of viral genomes and not mature particles - maybe some of these flies allow for replication and gene expression but for some reason fail to form proper infectious virus, we don't know, and it would have been too difficult to look at it in this system but it's more than likely that the two are correlated: more infectious particles = more viral genome.

But this is only me purposely picking holes in some very good research, research that may explain how some viruses are so successful in jumping species while others are not: dengue/HIV versus SARS and ebola; those viruses that we acquired from a more closely related source (primates in the case of dengue and HIV) have been shown to infect us more efficiently, while SARS and ebola, caught from bats ultimately do not.

Ben Longdon, the PhD student behind much of this work said when I asked him about these viruses,

...some of these viruses have come from distantly related species .... However, a number of viruses (and other pathogens) have been recently acquired from closely related species (eg HIV and dengue from primates). ... [these viruses] have most failed to maintain sustained transmission in the novel host and so were not successful long term host shifts. So distance may be important in determining a successful host switch, but long distance host switches may occur and will sometimes be successful (this is some speculative).

Ben Longdon - the PhD student doing much of this work

With all these caveats taken into consideration, this work provides some much needed experimental evidence examining the role that genetic relatedness has on RNA virus species transitions. Although it did show us that in some cases genetic distance can't tell us a whole lot about it. This model system still has much more work to show us, exploring the role of transmission, ecological factors and especially, looking at why the phylogenetic effect exits. What would be very nice would be to see some of this work being carried out in wild populations of drosophila and maybe the incorporation of other viruses (DNA, positive sense RNA, double stranded RNA etc) into the model to determine whether this alters their behaviour. 
Longdon, B., Hadfield, J., Webster, C., Obbard, D., & Jiggins, F. (2011). Host Phylogeny Determines Viral Persistence and Replication in Novel Hosts PLoS Pathogens, 7 (9) DOI: 10.1371/journal.ppat.1002260

Rhabdovirus image -

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