That light at the end of the sequencing tunnel is a freight train, heading toward us with a mile-long load of data.
That light at the end of the sequencing tunnel is a freight train, heading toward us with a mile-long load of data.
I’m not finding time to give these papers a full post each, so let me pool together several in the same theme: MHC alleles and protection against pathogens.
It’s generally accepted that the reason there are so many MHC alleles is related to their ability to protect against pathogens.1 The version is probably the frequency-dependent selection model. According to this, pathogens are selected to be resistant to common MHC alleles, so individuals with rare alleles have a selective advantage and those alleles become more common, until pathogens are selected for resistance to them in turn. (Described in more detail here.).
The particular steps in this concept are each fairly straightforward and reasonably well supported. We know that different MHC alleles can be more or less effective against pathogens; we see some instances of pathogens developing resistance to particular MHC alleles, and so on. But it’s been quite difficult to put all the pieces together. The best examples of pathogens evolving resistance to MHC alleles, for instance, are within a single host, in the case of HIV. When we look at even this virus over a population instead, it’s much harder to detect any particular adaptation to MHC (though there may be some).
The problem is (probably) that we’re looking at a single frame of a movie. This is a dynamic process, as the pathogens and the individuals within a population co-evolve. It’s hard to see fossil MHC alleles and just as hard to see fossil viral epitopes. The snapshot we see today may be at any point along the process – the pathogen may have the upper hand, the hosts may, or they may be perfectly balanced. (Also, of course, the host need to deal with thousands of pathogens, while each pathogen may focus on one or a handful of hosts. It would take a fairly assertive pathogen to single-handedly push a host population toward differential allele usage. The host’s version of the movie frame would actually be a blur of a thousand frames from a thousand movies, each of which is shown at different speeds and with a different starting point, all overlapping and interacting with each other.)
So observations supporting the frequency-dependent model have been rather scarce; in fact, instances where MHC alleles differentially affect pathogens are themselves relatively scarce, and those are the starting points from which frequency-dependent selection arises. So I’m always intrigued when we learn of cases where there are specific resistance and susceptibility alleles of MHC for particular pathogens, in the wild, and in a population rather than an individual.
Here are some I’ve noticed in the past few weeks.
Koehler, R., Walsh, A., Saathoff, E., Tovanabutra, S., Arroyo, M., Currier, J., Maboko, L., Hoelsher, M., Robb, M., Michael, N., McCutchan, F., Kim, J., & Kijak, G. (2010). Class I HLA-A*7401 Is Associated with Protection from HIV-1 Acquisition and Disease Progression in Mbeya, Tanzania The Journal of Infectious Diseases DOI: 10.1086/656913
Other MHC class I alleles have been shown to be protective against HIV, so this is mainly adding to the list; but it;s a shortish list, so any additions are interesting.
MacNamara, A., Rowan, A., Hilburn, S., Kadolsky, U., Fujiwara, H., Suemori, K., Yasukawa, M., Taylor, G., Bangham, C., & Asquith, B. (2010). HLA Class I Binding of HBZ Determines Outcome in HTLV-1 Infection PLoS Pathogens, 6 (9) DOI: 10.1371/journal.ppat.1001117
An attempt to link observed protective MHC alleles, with the mechanism of protection, concluding that being able to induce T cell recognition of a specific HTLV-1 protein is associated with protection. This is conceptually similar to the proposed mechanism by which [some] MHC alleles protect against HIV,2 where a specific peptide target can’t mutate away from T cell recognition.
Appanna, R., Ponnampalavanar, S., Lum Chai See, L., & Sekaran, S. (2010). Susceptible and Protective HLA Class 1 Alleles against Dengue Fever and Dengue Hemorrhagic Fever Patients in a Malaysian Population PLoS ONE, 5 (9) DOI: 10.1371/journal.pone.0013029
They identify MHC alleles that may be associated with protection against disease, and protection against severe disease. I’m a little uncomfortable with the relatively small number of patients involved here (less than 100), and would like to see it confirmed in a larger study.
Guivier, E., Galan, M., Male, P., Kallio, E., Voutilainen, L., Henttonen, H., Olsson, G., Lundkvist, A., Tersago, K., Augot, D., Cosson, J., & Charbonnel, N. (2010). Associations between MHC genes and Puumala virus infection in Myodes glareolus are detected in wild populations, but not from experimental infection data Journal of General Virology, 91 (10), 2507-2512 DOI: 10.1099/vir.0.021600-0
We revealed significant genetic differentiation between PUUV-seronegative and -seropositive bank voles sampled in wild populations … Also, we found no significant associations between infection success and MHC alleles among laboratory-colonized bank voles, which is explained by a loss of genetic variability that occurred during the captivity of these voles.
The difference between wild and captive voles is reminiscent of the difficulty and confusion involved in MHC function in lab mice. In at least one set of experiments, it was necessary to have semi-feral mice before mechanisms could be teased apart.
Vaccination against smallpox ended some 40 years ago. As the vaccinated population gets smaller and the susceptible population gets larger, at least one poxvirus is re-exploring the human population. Not smallpox, of course, but monkeypox, which is becoming dramatically more common in humans than it used to be.2
Monkeypox (which is actually primarily a rodent disease — the monkeys it’s named after were also hapless aberrant hosts, like humans) is closely related to smallpox, and causes a very similar disease in humans — clinically virtually identical, they say (I haven’t seen either myself, and hope I never will), though with a somwhat lower mortality rate. Of course, having a lower mortality rate than smallpox is not exactly high praise: Monkeypox is quite bad enough, with mortality rates of up to 10%.3
Vaccination against smallpox used (and still uses — I just got re-vaccinated a couple weeks ago) live vaccinia virus, which is yet another poxvirus that is similar enough to both smallpox and to monkeypox that it provides excellent protection against infection with either. People who were vaccinated against smallpox are still resistant to infection with monkeypox; but a large and growing population are too young to have received vaccinia, and those people are at least five times more likely to be infected with monkeypox.4 As a result, there’s been a 20-fold increase in monkeypox infections in the Democratic Republic of Congo, and there has been at least one well-publicized case where the disease was shipped into the US in pet rodents.5
|Smallpox in California, 1919 (click for larger version)6|
A recent paper, looking for animal models of monkeypox that accurately reflect the human situation (so that different vaccines and treatments can be tested) finds that cynomologous macaques [a species of monkey] are susceptible and have similar symptoms as humans:
Animals started to show clinical signs of disease, including decreased appetite and activity, by day 3. … By 6–8 days post-exposure, macules began to form in all animals and macaques were also inactive, somnolent, and exhibited depressed posture. … Lesions progressed to papules by day 10 and evolved to vesicular and pustular stages by 12–14 days post-exposure. … Two non-survivors had too many lesions to count (>2000).3
The lesions they talk about here (macules, papules, vesicles and pustules) are, of course, the titular small pox. Not many people today still remember the pox, so I’ve included some pictures from the good old days. You’re welcome!
|“Hei, siudy, divchata, zhyvo!” (Poster advising vaccination against smallpox, ca. 1920)|
|Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)|
|Needleman et al, 1 Fig 1: Section of rat vidual cortext stained for MHC class I (green) and nuclei (red)|
I said the other day that not all MHC class I molecules are involved in immunity, and used HFE as an illustration of one that’s not directly involved in immunity. It’s worth mentioning, though, that even those MHC class I molecules that are involved in immunity, aren’t necessarily always involved in immunity.
That may need a little clarification. “MHC class I” molecules include a wide range of members. The ones most people think about2 are the classical members of the family, reasonably enough called “classical MHC class I“, or perhaps MHC class Ia molecules. These are very clearly immune molecules. They’re receptors for cytotoxic T cells and for natural killer cells, they select cells in the thymus, they do everything you’d expect an immune molecule to do.
There are many other family members, though, that are “non-classical” MHC class I, or MHC class Ib molecules. They’re clearly members of the same family, based on their structure: Many of them look, at first and even second glance, almost exactly like a class Ia molecule (see here for some structures). Some of these have clear immune functions (some CD1 molecules seem to be involved in the immune control of certain bacteria, for example).
But others don’t have any apparent immune function. As I say, HFE is one such molecule. It’s a class Ib molecule that looks very much like a class Ia, but it seem to be strictly involved in regulation of iron metabolism. There are quite a few others, as well.
This isn’t surprising. The ancestors of the first MHC class I molecules were probably some kind of cell-interaction molecules, evolved to interface with other cell-surface molecules. The MHC module retains that capability, and it’s a useful tool to include in your generic molecule-binding toolkit. It’s not surprising that variants of MHC class I bind iron, or pheromone receptors, or antibodies, or what have you; because that capability was part of their initial and underlying function.
Which brings me back to my original comment. Not only do variants of MHC class I have various interface capabilities, so do the classical class I molecules themselves. And there’s at least one context where it seems that classical MHC class I molecules act purely in this ancient cell/cell interaction process, without any hint of an immune function: Classical MHC class I molecules are involved in brain development and, perhaps, function. 3
I’m not going to go into a lot of details on the mechanism or the role. For one thing, I don’t know much about brain development; for another, it’s still pretty mysterious as to what exactly MHC class I molecules are doing. But there they are, in the brain during development, and if you get rid of MHC there are at least some subtle defects in brain development.
What I mainly get out of these papers is that brain researchers get much prettier pictures than do immunologists. Admire the ones here1 while we wait for them to figure out what’s going on.
Zohar O, Reiter Y, Bennink JR, Lev A, Cavallaro S, Paratore S, Pick CG, Brooker G, & Yewdell JW (2008). Cutting edge: MHC class I-Ly49 interaction regulates neuronal function. Journal of immunology (Baltimore, Md. : 1950), 180 (10), 6447-51 PMID: 18453559
Goddard CA, Butts DA, & Shatz CJ (2007). Regulation of CNS synapses by neuronal MHC class I. Proceedings of the National Academy of Sciences of the United States of America, 104 (16), 6828-33 PMID: 17420446
I have as much respect for viruses’ ability to manipulate their host as the next guy, and I’m probably more of a fan of viral immune evasion than that next guy. But I still do think that coincidences do happen.
A paper from John Trowsdale and colleagues1 shows that Kaposi’s Sarcoma Herpesvirus (KSHV) destroys HFE, and they suggest that this is “a molecular mechanism targeted by KSHV to achieve a positive iron balance.” Without dissing their observations (which are perfectly convincing) I’m not entirely convinced by their conclusion. Still, it’s an interesting suggestion, and I’m keen to see some kind of followup to it.
The reason I’m not convinced is that this has the look of a spillover effect to me. We already know that KSHV attacks MHC class I molecules via its K3 and K5 molecules, and that it does so by targeting the cell-surface pool to lysosomes. This is a very familiar pattern; most, if not all, herpesviruses block MHC class I molecules. Although it’s been hard to formally prove “why” herpesviruses do this,2 the general assumption is that this allows the virus to at least partially avoid recognition by T cells, and this lets the virus survive better — perhaps because it builds a larger population very early, or perhaps because it is able to last longer late, or whatever.
At any rate, there’s a fairly simple and logical reason why it would make sense for KSHV to block MHC class I molecules, and as I say they do, in fact, do this. Now, why would they attack HFE? HFE is an iron-binding protein that’s involved in the regulation of iron metabolism. Why would KSHV be interested in iron metabolism?
Quite a few pathogens are actually very concerned about iron metabolism, of course. Bacteria generally need iron for their metabolism,3 and pathogenic bacteria have evolved ways of grabbing iron away from their hosts (while their hosts have evolved way of holding on tighter and tighter to that iron). But in general viruses, as opposed to bacteria, don’t have specific needs for iron. Trowsdale’s group makes the argument — and offers some experimental evidence — that KSHV does in fact want iron. “KSHV presumably down-regulates HFE to affect iron homeostasis,” they say, and “These results indicated an iron requirement for lytic KSHV and with the virus targeting HFE to satisfy this demand.” However, I don’t think they really show this directly; they show that there are changes in iron receptors in the presence of KSHV, but as far as I can see they don’t show that the presence or absence of iron actually affects the virus in any way.
|HFE heavy chain (red) complexed with beta-2 microblogulin (blue)||HLA-A2 (classical MHC class I) heavy chain (red) complexed with beta-2 microblogulin (blue) and a peptide (green)|
So let’s say KSHV doesn’t really care about iron per se. Why is the virus attacking this iron receptor, then? To me, the simpler solution is that it’s just a side effect of the virus attack on MHC class I, because HFE is in fact an MHC class I molecule.4 Not all MHC class I molecules are involved in immunity, and HFE is the classic counterexample, an MHC class I molecule that has a clear non-immune role. 5
Even though HFE has a different role, it has a very similar structure to the classical MHC class I molecules — see the images to the right (click for larger versions), and for more comparisons see my post from a couple of years ago, “MHC Molecules: The Sitcom“. It doesn’t have the peptide bound in the top groove (green in the HLA-A2 complex here) that classical MHC class I molecules use to provide specific signals to T cells, but it’s very similar. It’s plausible — at least to me — that the virus doesn’t care in the least about iron metabolism, but is just attacking everything on the cell surface that looks like an MHC class I molecule, and HFE is getting caught in the covering fire.
Interestingly, though, this isn’t the first time this has been proposed. A few years ago a paper from Drakesmith et al proposed pretty much the same model for HIV, via the HIV immune evasion molecule nef. Nef downregulates a large number of immune-related molecules, and also downregulates HFE. Drakesmith et al, like Trowsdale’s group, argue that this is “deliberate”, and that the modified iron metabolism directly benefits HIV;6 but I don’t know if that’s been followed up (Trowsdale’s paper, surprisingly, doesn’t cite Drakesmith et al).
I’m open to the idea that viruses do “want” to tweak iron metabolism, because that would be pretty cool, but so far I’m leaning to notion that HFE is just an accidental victim of the viral war on immunity.
HapMap 3, officially announced in today’s issue of Nature,1 is an “integrated data set of common and rare alleles” in human populations, built from “1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations“.
As well as being a resource for genome-wide studies, there are a number of things that can be done with the data directly. One of those is to help identify regions that are under positive natural selection. The authors found a number of them, including several immune-related genes in the Kenyan population.
A little sadly for me, none of these genes are ones I’m particularly familiar with. The three that are listed are:
CD226. This is an activating NK cell receptor. An allelic variant in CD226 has been linked to a number of autoimmune diseases,2 so it wouldn’t be surprising to learn that it’s under some form of selection. I didn’t check the actual SNP that was shown to be selected, to see if it’s the same one that’s linked to autoimmunity.
I’m sure that any more immune-related genes are under strong selection — we know that MHC genes are very strongly and rapidly selected, for example — but they don’t necessarily send up flags in this sort of analysis.
Maiti AK, Kim-Howard X, Viswanathan P, Guillén L, Qian X, Rojas-Villarraga A, Sun C, Cañas C, Tobón GJ, Matsuda K, Shen N, Cherñavsky AC, Anaya JM, & Nath SK (2010). Non-synonymous variant (Gly307Ser) in CD226 is associated with susceptibility to multiple autoimmune diseases. Rheumatology (Oxford, England), 49 (7), 1239-44 PMID: 20338887[↩]
In 1920 there was an outbreak of smallpox in Detroit (see the map below). Of the 133 cases with known history, only two had been vaccinated in the previous 10 years — three others had been vaccinated 12, 60, and 80 (!) years previously; the remainder were unvaccinated. The Detroit Department of Health had this commentary (my emphasis):
How quickly we forget the ravages of disease! In the autumn of 1918 the world was visited by the worst plague of recent times — influenza. Probably 1 per cent of the population of the globe was swept away by this scourge. People raved and bewailed at their helplessness. There was no known preventative. We know that crowding aided this disease, but as a reliable preventive against influenza, telling a person to avoid crowds in a congested city has about as much effect as telling a fly to keep out of baby’s cup of milk.
In 1920 influenza returned and exacted further toll of lives. The previous epidemic had not produced an antidote nor a preventative of influenza. The bacteriologists have not been idle. They have worked industriously trying to discover the true cause of the disease and a means of immunizing against it. It is not to their discredit that their efforts have not met with success.
Smallpox is another matter. Jenner, an English physician, proved beyond a shadow of a doubt that material from a pox pustule in a cow when added to the scarified skin of human beings gave them immunity against smallpox. This was in 1796. Vaccination soon became universal.
Boston’s experience is interesting. In 1721 out of a population of 11,000 there were 5,989 cases of smallpox and 850 deaths. In 1730 in a population of 15,000 there were 4,000 cases and 509 deaths. After vaccination had been introduced the disease practically disappeared. From 1811 to 1830 there were but 14 cases. Smallpox has disappeared where compulsory vaccination is in effect.
We do not know how to immunize against influenza.
We do know how to immunize against smallpox.
Shall we utilize this knowledge or not? If not why continue to search for an influenza panacea? If it is not to be used, once discovered, why waste time and effort to discover it? 1
See also earlier posts:
|“Adenovirus” (by Mapposity)|
There are two aspects about virology that constantly amaze me: How much we know about viruses, and how little we know about viruses.
Adenovirus research offers examples of both. Adenoviruses are probably among the best-studied virus groups.1 We really do know an amazing amount about them. But it was only last year that Linda Gooding’s group offered the most convincing demonstration yet that adenoviruses actually establish a truly latent infection — a really basic aspect of their lifestyle, 2 and a new paper from her group3 is looking at some equally-basic implications of that finding. (I talked about Gooding’s earlier latency finding here.)
It’s been known pretty much since day 1 that adenoviruses persistently infect tonsils;4 that was why they were first isolated, when the virus grew out of apparently-normal tonsil tissue in culture. The critical distinction is between mere “persistence” and true “latency”. In a latent infection, the virus shuts down production of new viruses, and is maintained basically as DNA within the host cell. Persistence is cruder — the virus continues to replicate, but at a low level that balances its destruction. Simplistically, latency is a destruction-free process, while persistence can include viral and cellular destruction.
Adenoviruses establish their latency in tonsils, which of course have lots of lymphocytes, but we usually think of adenoviruses as infecting epithelial-type cells, or hepatocytes, or whatever. Clinically, these guys typically cause cold-type symptoms, which you tend to get from fairly superficial infections of the respiratory tract lining. We don’t tend to think of adenoviruses as effective infectors of lymphocytes, but it turned out that their latent infection was, in fact, in T lymphocytes. It looks like adenoviruses have one cell type (epithelial-type cells) for a lytic infection that leads to shedding of infectious virus, and another cell type for latent infection, allowing the virus to remain in the host and potentially re-infect an epithelial type later on.
Accordingly, Gooding and her team set up infections of cultured T lymphocytes in vitro, to see what would happen. In particular, they wanted to know whether, and how, the viral replication cycle would be controlled; and whether and how the host cell would be affected by the infection. I will skip over most of their findings and and highlight a couple that surprised me:
(1) The “Occupied!” sign. To get into a cell, adenoviruses usually need to bind to their cellular receptor, the CAR receptor.5 But latently-infected cells almost permanently shut off this receptor. For hundreds of days after the initial infection, cells express little or no CAR. The latent virus doesn’t want any competition; it has found a congenial long-term environment, and it doesn’t want some interloper infecting its cozy cell and perhaps destroying it.
There seem to be several mechanisms for the shutdown, but at least part of it is that the virus apparently permanently modifies the host DNA:
CAR synthesis and expression remained repressed even after the viral genome was lost (Fig. 8 and data not shown), suggesting a virus-induced epigenetic change to the cells that does not require the continued presence of the virus.3
And in fact the CAR isn’t the only thing to be modified for this purpose:
Even when CAR levels were restored by transduction with a CAR-containing retrovirus, the previously infected cells could not be reinfected3
We don’t know how the latent viruses were blocking superinfection, but it’s clear that the latent viruses really don’t want company.
(2) Rearranging the furniture. The latent virus doesn’t stop at hanging an “occupied” sign; it modifies its host cell in other ways as well, apparently again by long-term or even permanent epigenetic modification of the DNA. That means that even after the virus itself is altogether gone, not even latently present, there are modified cells hanging about:
Remembering that adenoviruses infect just about everyone, that may mean that we’re all walking around carrying cells that are tagged and functionally altered by these viruses.
There’s been speculation for many years that adenovirus infection may underlie some forms of human tumors. One argument against this has been that there’s no evidence of adenovirus DNA in tumors, for the most part.6 (One rule of thumb in determining if a virus is actually causing a tumor is if it’s actually present in the tumor.) But of course, if adenoviruses leave a permanent scar on cellular DNA that lasts longer than the virus itself, this may not be relevant:
One compelling reason to gain an understanding of this nonlytic infection is the likelihood that adenovirus gene products cause damage to the host cell genome. … While these functions are irrelevant to the lytic infection of epithelial cells where all infected cells die, they are of serious concern when infected lymphocytes have carried the viral genome and survived. … Despite this normal appearance, the cells display altered gene expression long after the virus is lost.3
|Rosy Apple Aphid (Whalon lab, MSU)|
Normally I don’t talk about research that’s well covered elsewhere, but I like this one so much (and it links back to so many of my earlier posts; check the footnotes for those links) that I’ll make an exception here. I’d seen bits and pieces of this story, but I didn’t have the big picture until I listened to Carl Zimmer’s1 latest Meet The Scientist podcast2 where he interviewed Nancy Moran.3
So this is kind of about insect immunity. Insects have lots of innate immune responses, the short-term sorts of things that in vertebrates we call ‘inflammation’, but they don’t have the long-term adaptive responses 4 that incorporate antibodies and T cells — those systems arose in sharks and their progeny (and, apparently mostly independently, in lampreys and hagfish,5 but that’s a different story).
The hallmark of adaptive immunity, in contrast to innate immunity, is its flexibility: Different responses for different agents, and capable of changing as the target changes. So insects can’t do that, although of course their immune system has worked pretty well for a few hundred million years.
Except aphids have a sort of changable immune response. How does that work?
|Parasitic wasp laying eggs in an aphid
(from University of Wisconsin)
This is an immune response, not to bacteria or viruses, but to parasitic wasps. Aphids are popular targets for some of these wasps: The wasps lay eggs in the aphid, the eggs hatch into baby wasps, and the baby wasps eat the aphids from the inside out until they kill the aphid and then they fly away to predate some more. Except in some aphids, the baby wasps are killed as they hatch, and the aphids survives to make more aphids.
And this immunity to the wasps is — on a population basis, not an individual basis — rather flexible. Insects in general are good at evolving toxin resistance over years or decades, but aphids have apparently been doing this over millions of years. It turns out that different aphids kill the baby wasps in different ways, using different toxins to do so, and the toxins change over time as well. So the wasps can’t develop resistance to the toxins. It’s a little bit — a very little bit — like an adaptive immune system, at least in broad terms.
Not all aphids are immune at all (or there would be no wasps). You can take susceptible aphids and make them resistant, though. You just have to infect them with a particular bacterium. This is a symbiotic6 bacterium, that only lives in aphids — it’s dependent on the aphid host to provide it with essential nutrients — and these bacteria carry toxin genes. They help their host survive by providing toxin genes, that kill the wasps that parasitize the hosts the bacteria are symbiotic with.
But not so fast! The bacteria don’t naturally have toxins! The toxins come from parasites of the bacteria! There are bacteriophages, viruses that infect the bacteria, that carry the toxins. When the viruses parasitize the bacteria that are parasitizing the aphids, then the parasitic wasps can’t parasitize the aphids that are hosting the bacteria that are hosting the viruses!
And if you look at the bacteriophages as a population, they have a section of their genome that is highly diverse. That part is the region that carries the toxin. Different phages, different toxins, that can spread to new bacteria and then to new aphids, so the aphids can have a supply of new toxins to take care of newly-resistant wasps.
Just to make this even more complex, you know how the wasps subdue their prey? They inject in a complex mix of toxins that shut down the insect immune system. Guess where those toxins come from?7 From the symbiotic viruses8 that the wasps have incorporated into their own genomes millions of years ago, that carry immune evasion genes that the wasps have adapted to use to subdue the aphids that carry the bacteria that carry the viruses that provide the toxins that protect the aphids against the wasps that carry their own viruses to attack the aphids.
PRRS is “porcine reproductive and respiratory syndrome”, which pretty much sums up the disease. It’s caused by — you’ll never guess — Porcine reproductive and respiratory syndrome virus (PRRSV), an arterivirus that emerged in 1987. That was the year I left large animal veterinary practice, so I never had a chance to deal with PRRS clinically.
Twenty-three years may not seem like all that long a time, but if you’re an RNA virus that’s a lot of generation times and a whole lot of time for mutations and evolution, and PRRS viruses are an evolutionarily mess. 1 There are North American type PRRSV viruses and European type viruses, there are mysterious clusters of related viruses, there are clusters of related diseases, there are thousands of sequences, and it’s just kind of baffling what’s gone on with the whole schtick.
A new paper2 has tried to sort out part of the mess by analyzing some 8624 North American-type PRRSV sequences, from nearly a dozen countries, and working out evolutionary relationships between them all. 3 (The focus on the North American series — the Type II PRRSV — is because this group seems to be a more common source of disease; although the European strains are far from rare themselves.)
There were a couple of interesting points that parallel some other viruses:
1. Feral vaccines. It’s already known, or at least strongly suspected, that some of the modified-live PRRSV vaccines have started to go feral on a small scale (not nearly as dramatically as the vaccinia virus I mentioned a while ago), and that’s supported by this genetic analysis:
In the vaccine-associated sublineage phylogenies (data not shown), there were a number of well-supported small clusters that might reflect the small-scale transmission of the vaccine viruses in the field … 2
As well as vaccinia, there are other live vaccines that are known to spread into the population. The sort of limited transmission that seems to be showing up here is more typical of this sort of thing than are the vaccinia instances I talked about before.
2. The amazing flying pigs. Even though this is just one of the two major sub-groups of PRRSV and it’s less than 25 years since it emerged, they came up with nine fairly distinct lineages of the virus (see the figure to the right). As you’d expect the lineages speak to the history of the virus — which is to a large extent the history of the pigs that carried the virus.4
This version of the virus probably started out in North America (though how it got there … ?) and then got introduced into other countries on several independent occasions. Two of these introductions were in the late 1980s, shortly after the North American emergence. Aside from that there’s evidence of a bunch of smaller introductions:
… lineage 1 had several Thai sequences clustered with early Canadian sequences … ; lineage 8 contained highly pathogenic Chinese strains and their relatives … ; and lineages 8 and 9 had several Italian isolates which were distributed separately along the phylogeny …, indicating independent introductions of PRRSV from the United States to Italy. 2
They were even able to identify smaller-scale travel patterns, between individual states in the USA:
Iowa plays a central role because its viruses were introduced recurrently to all nine other states (Fig. 5B). The remaining states were not just receiving sites. Their local strains also were transmitted to other states repeatedly, but within a narrower range. … Our phylogeographic analyses reveal, for the first time, an interstate PRRSV traffic network in the United States. … The result also indicates that long-distance spread is a frequent process for PRRSV … 2
This is a reminiscent of the history of the pandemic H1N1 influenza virus, when it was still in swine. (Remember that pandemic H1N1 is genetically a mixture of a North American swine influenza strain and a Eurasian strain.) There’s a large national and global traffic in pigs, and even though most countries are reasonably careful in the way they handle incoming pigs it’s not a guarantee against virus introduction. I’m not singling out pigs, either — other kinds of livestock also are global travellers, and obviously so are humans. But it’s a reminder that it isn’t just humans and their viruses that can quickly travel and spread around the globe.