Mystery Rays from Outer Space

“Episode de la fièvre jaune”

By analyzing hepatitis C virus genome sequences, you can trace the virus’s history through its spread by the slave trade, and linked 19th-century health models in different countries to viral spread and transmission. Similarly, by looking at leprosy DNA, you can track its spread along the Silk Road and along slave routes.

Yellow Fever was one of the most dreaded plagues of the 18th and 19th centuries, waning only after it was understood to be mosquito-borne, so that mosquito control pushed the virus back. It’s still prevalent in Africa and in some parts of South America, though. Yellow Fever virus, too, originated in Africa and was spread to the New World through the slave trade:

The most commonly cited hypothesis of the origin of YFV in the Americas is that the virus was introduced from Africa, along with A. aegypti,¹ in the bilges of sailing vessels during the slave trade. … We estimate that the currently circulating strains of YFV arose in Africa within the last 1,500 years and emerged in the Americas following the slave trade approximately 300–400 years ago. These viruses then spread westwards across the continent and persist there to this day in the jungles of South America.²

Mosquitoes aren’t merely passive carriers of the Yellow Fever virus. The virus actively infects the mosquitoes as well as their mammalian host, entering the insect gut, replicating and multiplying in various organs until it reaches the saliva, from which it can re-infect mammals³ when the mosquito bites and injects its anticoagulant saliva.

“Latest from the front — our friends the mosquitoes preparing and off for the summer campaign” (Harper’s Weekly, 1873)

Another pattern is possible: The virus could also be spread vertically, from the mosquito to its egg, infecting the newborn mosquito before it hatches. However, although this was shown to happen as long ago as 1905,⁴ just after mosquitoes were proven to be carriers, it hasn’t been very clear if this is a significant part of the natural viral cycle or if it’s more of a lab curiosity:

Although transovarial transmission of YFV has been demonstrated, the relative importance of this in maintaining the transmission cycle is unknown. ⁵

Now, genome sequence analysis suggests that in fact transovarial spread of Yellow Fever virus may well be common and important in the viral life cycle.⁶

This was based on comparisons of Yellow Fever virus genome sequences over time, with those of a close relative, Dengue virus. Dengue and YFV probably arose about the same time, in the same area, and were both spread along the slave trade. But Dengue seems to have diversified much more than YFV:

… it is intriguing that the overall age of YFV (emergence within the last 2,500 years) is broadly similar to the time of origin of the four DEN viruses. Hence, YFV and DENV seem to have radiated at approximately the same time. However, since this time, DENV has differentiated into four antigenically distinct viruses while YFV is still classified as a single serotype.⁶

(This is actually clinically very significant, because the most severe form of Dengue disease is caused by sequential infection with two different Dengue serotypes.) In fact, in general YFV shows a much slower rate of evolution over time than Dengue — about 5-fold slower per year. The authors consider a reject a number of explanations for this — it’s not that they have different mutation rates, because their raw mutation rates are probably quite similar; it’s not that they infect different hosts, because they have very similar insect and mammalian hosts; and so on — and finally suggest that the difference may be because YFV spends a significant part of each year lying more or less dormant in mosquito eggs:

In particular, it is possible that a mechanism of vertical transmission, such as transovarial transmission where the virus may remain quiescent in mosquito eggs for many months, plays a more important role in YFV than in DENV⁶

As a result of this quiescent period, YFV would simply have fewer replication cycles per year than does Dengue, and so it appears to evolve more slowly. For this to be detectable at this level, transovarian transmission would have to be a fairly common event, not just a once-in-a-while half-accidental option.

1. A. aegypti is the mosquito that is most involved in spreading the virus[↩]
2. Bryant, J., Holmes, E., & Barrett, A. (2007). Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas PLoS Pathogens, 3 (5) DOI: 10.1371/journal.ppat.0030075[↩]
3. Mainly primates, for functional transmission[↩]
4. Marchous E, Simond PL. 1905. La transmission hereditaire du virus de la fievre jaune chez la Stegomyia fasciata. C. R. Soc. Biol. 59:259[↩]
5. Barrett, A., & Higgs, S. (2007). Yellow Fever: A Disease that Has Yet to be Conquered Annual Review of Entomology, 52 (1), 209-229 DOI: 10.1146/annurev.ento.52.110405.091454[↩]
6. Sall, A., Faye, O., Diallo, M., Firth, C., Kitchen, A., & Holmes, E. (2009). Yellow Fever Virus Exhibits Slower Evolutionary Dynamics than Dengue Virus Journal of Virology, 84 (2), 765-772 DOI: 10.1128/JVI.01738-09[↩][↩][↩]

“Batrachia”, by Ernst Haeckel (Kunstformen der Natur, 1904)

There’s a constant viral assault on us humans, as there is on just about all other species. We as a species have to contend not only with the vast pool of human pathogens, those viruses that constantly circulate among humanity; but also with the continual probes on our defenses from other viruses, viruses that normally infect other species.  All of us are exposed to these on a regular basis: Dog and cat viruses, mouse viruses, crow and pigeon viruses, bat viruses, not to mention the ocean of insect and fungus and amoeba and plant viruses.

Almost all of these assaults don’t even scratch our defenses.  The viruses can’t even enter our bodies, and if they do then they can’t enter our cells, and if they do they can’t replicate in our cells, and if they do then they can’t  …

Most viruses, in other words, can’t effectively jump species.  Even when they do, they’re usually not well adapted to the new species, and they can’t establish a productive chain of infections. Even if they cause a disease, they burn themselves out, infecting fewer and fewer individuals each round of infection, until they disappear.

But every so often, in a tiny minority of cases, the virus does get a foothold.  This is one of the ways that “emerging infections” get started.  It covers things like HIV, SARS, parvovirus of dogs, Ebola, and of course the new H1N1 swine-origin influenza virus (SOIV), among many others.

Why did these guys take off, when so many other viruses failed? Why did SOIV infect people last year, while decades of exposure to pigs and swine H1N1 influenza viruses didn’t lead to earlier pandemics?  Basically, we don’t know, and we’d really, really like to know, so we have a chance of predicting the next SOIV or HIV before it’s a pandemic.

OK, so that explains why I’ve written a fair number of posts here on species-jumping in viruses (here, here, here, here, and here), and partly explains why I want to mention a new paper from Bertram Jacobs‘ lab¹.  (The rest of the reason is, as always, that I just think it’s  cool.)  I’m not sure why Jacobs has done this particular project, because he’s more of an interferon guy, but he’s looked at the origins of ranaviruses and finds evidence for lots of species shifts in their history.

“The Smooth Terrapin (Emys terrapin)”, by James Dekay (Zoology of New York; or, The New York fauna, 1843)

Ranaviruses are probably best known as frog viruses, but they infect a bunch of cold-blooded animals — fish, frogs, salamanders, turtles, and so on — and several of them are causes of emerging infectious disease (as I discussed last time I talked about ranaviruses, here).  Jacobs’ group looked at about a dozen of them whose genomes are completely sequenced², and tried to put together their evolutionary history, which turns out to involve all kinds of cross-species jumps:

…we hypothesize that the most recent common ancestor of the ALRVs was an ancestral fish virus …  Both of these hypotheses suggest that for the majority of evolutionary time vertebrate iridoviruses were confined to fish, and much more recently, there appear to have been at least three species jumps, from fish to frogs, from fish to salamanders, and from frogs to reptiles, and perhaps as many as four species jumps, including a jump from tetrapod amphibians back to fish. It is tempting to speculate that activities associated with human harvesting of aquatic organisms during the past 40,000 years led to the more common recent jumping of ranaviruses among aquatic organisms.¹

(My emphasis) They don’t offer any specific reasons why the ranaviruses should be able to leap from species to species like the chamois of the Alps, but they do make the general point that these viruses tend to be rather promiscuous to start with.  Not only are closely-related viruses able to infect different hosts, but even the same viruses often are able to infect a wide range of species; the fish virus they sequenced in this paper, epizootic hematopoietic necrosis virus, can infect a half-dozen different species of fish.  They raise an interesting comparison:

In addition, the ability of this group of viruses to infect such a wide variety of host species suggests that more host shifts are likely. Therefore, it is important that we understand more of the evolutionary traits of this unique group of viruses, as there is no other closely related group of viruses that infect such a broad group of hosts, with the possible exception of the orthomyxoviruses.¹

Orthomyxoviruses, of course, include influenza viruses, which notoriously infect humans, pigs, ducks, chickens, wild waterfowl, horses, and dogs; and you’ll recall all the reports during the epidemic phase of SOIV of the virus infecting all kinds of other pets and domestic animals.  Influenza viruses are apparently evolving at an even faster pace than the ranaviruses, and experimenting with even more species; but there may be lessons for us (as influenza hosts) in the ranaviruses.

1. Jancovich, J., Bremont, M., Touchman, J., & Jacobs, B. (2009). Evidence for Multiple Recent Host Species Shifts among the Ranaviruses (Family Iridoviridae) Journal of Virology, 84 (6), 2636-2647 DOI: 10.1128/JVI.01991-09[↩][↩][↩]
2. Including epizootic hematopoietic necrosis virus, whose genome they sequenced themselves[↩]

Man chasing rabbit (From “Fliegende Blätter”, Munich, 1889)

Everyone knows about rabbits in Australia. Introduced in the mid-1800s, they multiplied ridiculously and ate their way across the country, leaving barren devastation behind them.

Myxomavirus, a poxvirus that originated in South America, was introduced in the early 1950s and temporarily controlled the rabbit population, cutting their numbers by 85% (to a mere hundred million rabbits); but the rabbits evolved some resistance, and the virus evolved somewhat reduced virulence, and after about 15 years the rabbit population started to build up again. (I’ve talked about myxomatosis and rabbit control here and here.)

Myxomavirus isn’t a natural pathogen of European rabbits; its natural hosts are American rabbits, in which it causes a much more mild disease. It’s a virus that jumped into a new species, was very virulent in that new species, and then became less so over 15 years or so of transmission in the new species.

Myxomavirus is often used as an example of a virus that evolves toward avirulence, with the message usually being that this is the usual path of evolution. For example, you’ll see comments like, “Typically, viruses that rapidly kill their host have a very short history, as they rapidly run out of places to reproduce.” As I’ve tried to point out several times (see the myxomavirus links above), this isn’t true; pathogens in general evolve toward improved transmission, not reduced virulence. In many cases, reducing virulence does enhance transmission, but it’s not the only path. And myxomavirus doesn’t even support the claim all that well, given that even the “low-virulence” strain that’s out there now still has a mortality rate about the same as Ebolavirus, or smallpox.

OK, hold that thought.

Extermination of rabbits in California (From “The Picture Magazine,” 1894)

Myxomavirus worked well to control rabbits for a while, then became less effective. In 1995, a new virus was introduced into Australia and New Zealand,¹ a calicivirus that causes Rabbit Hemorrhagic Disease, called (with stunning originality) Rabbit Hemorrhagic Disease Virus (RHDV). Where did RHDV come from?

Basically RHDV is the opposite of myxomavirus. The parent of RHDV is a natural virus of European rabbits, but it causes little or no disease. RHDV is a natural mutation of this virus, and it has very high virulence – the opposite of the viruses-evolve-to-low-virulence claim. Even with the help of Australian farmers, RHDV is highly successful. It spread around the world in the mid-1980s after first appearing in Chinese rabbits in 1984.

One of the most intriguing aspects of RHDV evolution is that this virus appears to have maintained its very high virulence during the 25 years since it emerged. At face value this suggests that virulence is adaptive for transmission. ²

Rabbit’s eye (Max Brödel, 1932)

In fact, it’s been believed that the virulent RHDV is such a successful mutation that it arose several times, independently, from the mild parent virus. (Compare to the feline infectious peritonitis story, where the prevalent explanation for the appearance of a virulent FIP infection is that innocuous gastrointestinal coronaviruses, that are widespread in cats, mutates to form the virulent form; and this mutation is independent for each cat, rather than arising once and then spreading.)

At least, that’s been the established explanation, but a recent paper² shows that a couple aspects of that aren’t correct. The authors looked at genome sequences of many rabbit caliciviruses (the mild parent calicivirus as well as the virulent RHDV) to track its origins and spread. RHDV is indeed a recent mutation from a mild parent virus; that much is correct. But RHDV probably only arose once, not multiple times, and the origin of RHDV was well before 1984) when it was identified as a disease.

The independent-mutation hypothesis was based mainly on finding RHDV-related viruses circulating in Europe in the 1950s:

Prior phylogenetic work led to suggestions that RHDV with sequences closely related to those that emerged from China in 1984 were circulating harmlessly in the United Kingdom and other European localities during the 1950s; hence, it was suggested that virulence emerged at least twice during the late 20th century: once in Europe and once in China. ²

But Kerr et al looked more closely at these early isolates, and don’t think they’re real:

… we show here that the sequences from the 1950s and 1970s from the United Kingdom appear to be modern contaminants: given the rate of RHDV evolution documented here and that of RNA viruses more generally, these early RHDV sequences are expected to be far more divergent from their modern counterparts. ²

(Compare to the influenza database, where there also seems to be a significant level of mis-identified virus.)

So RHDV probably only originated once, which is a little more reassuring than the notion that this high virulence is so easy to achieve that it can appear many times over a short period. Did the original mutation appear around 1984, when the disease was noted? The authors identified 4 distinct strains of RHDV and noted:

A common feature of all of these groups is that many lineages likely originated during the 1970s, suggesting that there was a period of viral radiation at this time…. Crucially, this also means that there were already multiple separate lineages of RHDV before the documented emergence of RHD in China in 1984.  … This implies either that high virulence evolved multiple times in multiple viral lineages close to 1984 or (more plausibly) that virulence emerged earlier in the 20th century but the disease was not documented until 1984 when the trade in rabbits provided the opportunity for RHDV to spread from an established, but apparently cryptic, transmission cycle. … Therefore, we propose that the most likely scenario is that virulent RHDV strains evolved once, early in the 20th century, but were not detected until 1984. ²

(My emphasis) This seems, at first glance, surprising. RHDV kills almost all of the rabbits it infects. Wouldn’t you notice it if all your rabbits suddenly fell over dead? How could RHDV circulate for years or decades without being detected? Kerr et al make some points about the nature of the disease (it can infect very young kits without killing them, for example), but also comment:

Given the difficult sociopolitical conditions in China and neighboring countries in the first half of the 20th century, it is plausible that a virulent disease in rabbits was able to evolve in this region without leaving a clear record. ²

The pandemic swine-origin H1N1 probably has been circulating in swine for quite a while (years? decades?) without being picked up, and probably circulated in humans in Mexico for months before it was detected there. It’s pretty easy to believe that rabbits in China during the Cultural Revolution didn’t get as much attention as pigs in the US in the 2000s.

So, an interesting story in its own right, especially thinking about evolution of virulence in pathogens; and also, a story that probably reflects some important lessons for human health.

1. It wasn’t supposed to be introduced then; it was penciled in for few years later, after more study, but somehow it jumped from the island where it was being studied to the mainland. The usual explanation is “via insects”, but of course one has to wonder if some Australian farmers didn’t help the insects along some. As I recall from the news reports at the time, the “accidentally introduced” virus spread throughout Australia very fast, almost as if dead rabbits were being carted around by car or something.[↩]
2. Kerr, P., Kitchen, A., & Holmes, E. (2009). Origin and Phylodynamics of Rabbit Hemorrhagic Disease Virus Journal of Virology, 83 (23), 12129-12138 DOI: 10.1128/JVI.01523-09 [↩][↩][↩][↩][↩][↩]

Leprosy is a fascinating disease for many reasons.  Historical, because, well, it’s leprosy.  Genetic, because the bacterium is apparently derived from a single clone that infected humans some 4000 years ago,¹ and that has undergone “massive gene decay” in the process of becoming an obligate pathogen:

Thus, since diverging from the last common mycobacterial ancestor, the leprosy bacillus may have lost more than 2,000 genes. ²

Immunological, because as mycobacteria, leprosy and tuberculosis may have an entire branch of the immune system dedicated to their control and destruction.  Epidemiological, because leprosy is one of the very few diseases that has the potential for elimination without vaccines.  And now let’s add phylogeography and anthropology to the list, with a paper that offers a detailed analysis of leprosy’s migration through humanity. ³

This was done by genetic analysis, tracking through sub-types of leprosy in various areas, both modern and ancient — the latter being “obtained from leprosy graveyards in Croatia, Denmark, Egypt, England, Hungary and Turkey“, and allowing the authors to determine the strains of leprosy that circulated as much as 1500 years ago.  Their conclusions (building on and extending earlier work):

• The progenitor of leprosy arose in East Africa
• New strains then spread into Asia, through two different routes: One northern route, and one southern
• The Southern route into Asia was probably the Silk Road: “the trade route between Europe and Asia known as the Silk Road appears likely to have been a means of transport and disease transmission“.  They point out that this is the opposite path of the Black Plague, which likely spread from Asia to Europe along the Silk Road.
• Another strain of leprosy moved from East Africa westward into the Middle East and Europe
• This strain in turn spawned strains that are found in West Africa and countries linked to West Africa by the slave trade.  (Compare to the phylogeography of hepatitis C, among other diseases spread by slavery)
• Leprosy in North America came from relatively recent European immigrants, rather than coming along with the original Bering Strait peoples.

One interesting conclusion is that the genome decay of M. leprae is much older than humans (occurring over a million years ago, whereas humans are only a few hundred thousand years old), even though the genetic evidence says the present bacteria were clonal just a few thousand years ago.  They suggest that

Alternatively, the genome decay could well be ancient, but M. leprae may only recently have become a human pathogen. For instance, it is conceivable that an ancestral form of M. leprae infected an invertebrate host such as an insect, which later acted as a vector for transmitting the bacillus to humans.  ³

1. Monot, M. (2005). On the Origin of Leprosy Science, 308 (5724), 1040-1042 DOI: 10.1126/science/1109759[↩]
2. Cole, S., Eiglmeier, K., Parkhill, J., James, K., Thomson, N., Wheeler, P., Honoré, N., Garnier, T., Churcher, C., Harris, D., Mungall, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Duthoy, S., Feltwell, T., Fraser, A., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Lacroix, C., Maclean, J., Moule, S., Murphy, L., Oliver, K., Quail, M., Rajandream, M., Rutherford, K., Rutter, S., Seeger, K., Simon, S., Simmonds, M., Skelton, J., Squares, R., Squares, S., Stevens, K., Taylor, K., Whitehead, S., Woodward, J., & Barrell, B. (2001). Massive gene decay in the leprosy bacillus Nature, 409 (6823), 1007-1011 DOI: 10.1038/35059006[↩]
3. Monot, M., Honoré, N., Garnier, T., Zidane, N., Sherafi, D., Paniz-Mondolfi, A., Matsuoka, M., Taylor, G., Donoghue, H., Bouwman, A., Mays, S., Watson, C., Lockwood, D., Khamispour, A., Dowlati, Y., Jianping, S., Rea, T., Vera-Cabrera, L., Stefani, M., Banu, S., Macdonald, M., Sapkota, B., Spencer, J., Thomas, J., Harshman, K., Singh, P., Busso, P., Gattiker, A., Rougemont, J., Brennan, P., & Cole, S. (2009). Comparative genomic and phylogeographic analysis of Mycobacterium leprae Nature Genetics, 41 (12), 1282-1289 DOI: 10.1038/ng.477 [↩][↩][↩]

There’s been recent excitement over the discovery of bornaviruses fixed in the human genome^{1, 2}.  Exciting and unexpected as that is, as usual, the insects are way ahead of us.  The genome of a parasitoid wasp has poxvirus sequences in it!

Detecting ancient lateral transfers is more problematic. By examining protein domain arrangements in Nasonia relative to other organisms, we uncovered an ancient lateral gene transfer involving Pox viruses, Wolbachia, and Nasonia. Thirteen ANK repeat–bearing proteins encoded in the N. vitripennis genome also contain C-terminal PRANC (Pox proteins repeats of ankyrin–C terminal) domains. This domain was previously only described in Pox viruses, where it is associated with ANK repeats and inhibits the nuclear factor ΚB (NF- ΚB) pathway in mammalian hosts …³

These parasitic wasps are not the same family as the magnificent braconid parasitic wasps that have developed a symbiotic relationship with polydnaviruses (see my posts here and here), and braconids’ incorporation of nudivirus genomes already trumps the bornavirus findings.  But still.  Poxviruses!

I don’t think we have any functional information on what the Nasiona are doing with the poxvirus genes here, and I know very little about wasp biology, but given that:

• in mammals these genes are  inhibitors of the innate immune response,
• the innate immune response is relatively  conserved from insects to humans, and
• Braconid wasps use their symbiotic viruses to inhibit their prey’s immune responses,

I wonder if the Nasonia have independently come up with the same idea as Braconids, and incorporated a viral immune evasion molecule to use in their venom to suppress their prey’s immune response to the wasp’s eggs and larvae.

1. Original paper in Nature[↩]
2. See commentary in the New York Times;  the Virology Blog; and Not Exactly Rocket Science[↩]
3. The Nasonia Genome Working Group (2010). Functional and Evolutionary Insights from the Genomes of Three Parasitoid Nasonia Species Science, 327 (5963), 343-348 DOI: 10.1126/science.1178028[↩]

Geographic distribution of H5N1 highly pathogenic avian influenza viruses (HPAIVs) used in this study. Darkened provinces indicate locations of virus isolation.

“We found several patterns that suggest one general model of evolution in this viral system: 1) within regions, viral mixing in poultry moves toward heterogeneity and the emergence of local types; 2) differentiation was centered around regional viral hubs located at centers of human and bird population density; and 3) evolution occurs because of relative isolation of the hubs, most likely fed by the abundant supply of domesticated poultry (and people) at the hubs. The analysis thus suggests that at the scale of neighboring city hubs and the intervening hinterland, evolution of H5N1 follows the pattern described by classical theory of genetic differentiation due to isolation by distance.” ¹

Genetic versus geographic distance of HK821-like HPAIVs in Vietnam.

This is in Vietnam, and the basic finding was that H5N1 viruses isolated in Vietnam show signs of local evolution, in that the viruses cluster into local sub-strains in different areas of the country.  I’m not all that knowledgeable about H5N1 spread, but I had thought that infection of wild, especially migratory, birds would be an important factor in spreading H5N1 between chickens.  If I’m interpreting this paper right, it looks as if H5N1 is mostly circulating within local regions, within the chicken population, and distant spread isn’t a major factor. That has obvious implications for control of the virus.

1. Carrel, M., Emch, M., Jobe, R., Moody, A., & Wan, X. (2010). Spatiotemporal Structure of Molecular Evolution of H5N1 Highly Pathogenic Avian Influenza Viruses in Vietnam PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008631[↩]

As if understanding this complex evolutionary puzzle were not already sufficiently challenging, we have learned recently that two types of adaptive immune system have evolved in vertebrates: a recently recognized system in jawless vertebrates (hagfish and lamprey) and the more familiar adaptive immune system of jawed vertebrates. … This leads to the conjecture that two interactive lymphocyte arms are a fundamental feature of the adaptive immune system that was selected to provide balance and self-regulation.

Cooper, M., & Herrin, B. (2010). How did our complex immune system evolve? Nature Reviews Immunology, 10 (1), 2-3 DOI: 10.1038/nri2686

HA structure showing mutating amino acids1

Anyone who’s taken a virology class, and many who haven’t, know about “antigenic drift” and “antigenic shift”. These are usually used to explain influenza virus changes over time (although of course the same concepts apply to many other viruses). Antigenic shift refers to large, abrupt changes in the virus;² antigenic drift refers to smaller changes. Antigenic shifts are associated with pandemic influenza, as the pre-existing immune responses to influenza from previous years aren’t protective any more (because the virus has shifted away from them). Antigenic drift doesn’t let the virus escape immune control altogether, but does give the virus an advantage in infecting people — presumably, people with strong responses are still protected, but those whose exposure was maybe a few years ago, or who happened to make a weaker antibody response, to the previous virus, would be susceptible to the new virus but protected against the original. Antigenic drift happens all the time, and new drifted variants of influenza take over every year or two, which is why we need new seasonal flu vaccines on a regular basis.

What drives antigenic drift? The simple answer is that it’s driven purely by immunity. According to this notion, viruses that are resistant to being neutralized by antibody are most able to replicate and transmit to new hosts. Jon Yewdell’s group, however, has just revisited antigenic drift,¹ and propose a somewhat different model: Antigenic drift is the result of viruses cycling between immune and non-immune hosts, and it’s almost a side effect of the way the virus interacts with cells.  (Unusually for Jon, I don’t htink he coined any new and exciting acronyms for his new model.)

Model for antigenic drift selection (click for larger version)1

Normally, influenza virus doesn’t “want” to bind very strongly to its cellular target, ³ because then it’s harder for newly-formed viruses to escape from the cell (because it binds to the receptors on the way out, as well). But in the presence of neutralizing antibody, the virus needs to bind more strongly to the receptor to overcome the effects of antibody binding. Yewdell’s group argue that it’s this whip-saw effect that pushes long-term changes in antigenicity:

Thus, antigenic drift can be a by-product of Darwinian selection for mutations that optimize host cell receptor binding during influenza A virus transmission between immune (increased receptor binding) and naïve individuals (decreased receptor binding). ¹

One difference between Jon’s model and the standard concept is that with the latter, you’d expect that there would be more antigenic drift as immunity increases among the population. Yewdell’s model, though, predicts that sequential passage through immune and non-immune individuals drives antigenic drift. This actually leads to an important prediction:

In our model, antigenic drift is accelerated by sequential passage of influenza A virus between immune and nonimmune individuals, which in the human population are nearly all children. Therefore, decreasing the naïve population size by increasing pediatric influenza A virus vaccination rates will likely slow antigenic drift and temporally extend the effectiveness of influenza vaccines.¹

(My emphasis.)  They also point out that, because changes in antigenicity run in parallel with changes in receptor binding affinity, antigenic drift can itself could be pushing other changes in virus personality. That’s because the drift changes push changes in receptor binding, which in turn alters the cells to which the virus can interact; and changing the cells that the virus infects will inevitably change the nature of an infection as well. For example, does the virus best infect cells of the upper respiratory tract — leading to coughs and sniffles — or the lower respiratory tract — leading to pneumonia.

1. Hensley, S., Das, S., Bailey, A., Schmidt, L., Hickman, H., Jayaraman, A., Viswanathan, K., Raman, R., Sasisekharan, R., Bennink, J., & Yewdell, J. (2009). Hemagglutinin Receptor Binding Avidity Drives Influenza A Virus Antigenic Drift Science, 326 (5953), 734-736 DOI: 10.1126/science.1178258[↩][↩][↩][↩][↩]
2. “Changes” here mean changes in the ways the immune system responds to the virus — hence, “antigenic” changes. In practice, the changes are antibody-based changes, although in principle antigenic shift and drift could also refer to T cell-based recognition.[↩]
3. The influenza hemagglutinin, HA, protein binds to sialic acid on cells of the respiratory system.[↩]

[W]e have estimated that natural selection drives twice as much change in immune-related proteins as in proteins with no immune function. Interestingly, the rate of adaptation is also more variable among immunity genes than among other genes in the genome, with a small subset of immunity genes evolving under intense natural selection. We suggest that these genes may represent hotspots of host–parasite coevolution within the genome.

–Obbard, D., Welch, J., Kim, K., & Jiggins, F. (2009). Quantifying Adaptive Evolution in the Drosophila Immune System PLoS Genetics, 5 (10) DOI: 10.1371/journal.pgen.1000698

(This is particularly interesting to me because I’m trying to look at co-evolution between pathogens and immunity myself.  I’ve been tentatively suggesting that adaptive immune components (co)-evolve faster than innate immune components; of course, Drosophila only have innate immunity, so this paper suggests that the innate immune system also evolves rapidly.  That’s not unexpected, and doesn’t disprove my hypothesis, but it’s interesting anyway.  Also, there are some techniques in here I might be able to make use of.)

Tammer Wallaby

Everyone knows that the MHC is in the MHC, right? Well, it’s not necessarily so.

That’s not as tautological as it sounds. MHC (major histocompatibility complex) can refer to either the protein complex, or to the genomic region. In most species the genes encoding MHC proteins are clustered together into a distinct region of the genome that usually contains a bunch of genes that are functionally, and in some cases structurally, linked. For example, the human MHC genomic region contains not only many MHC class I genes, but also the TAP genes that are required for their function (outline of function here); MHC class II genes, and a number of genes required for their function; some proteasome subunits that are also involved in the antiviral MHC function; and so on. There’s a crude map here, and a somewhat more detailed one here; in humans and many other species the MHC genomic region is densely packed with genes, many of which are immunologically important.

Although the details are different the same concept applies to many vertebrates — chickens ¹, Xenopus (frogs),² and sharks,³ for example, have only one classical MHC class I gene, but it’s recognizably in the MHC genomic region, tightly linked to TAP and not quite as tightly linked to MHC class II genes.

Why are these functionally-related genes clustered together? There are probably a bunch of reasons, and the reasons may actually be different for different species. A recent paper,⁴ showing a partial exception to the rule, makes some interesting suggestions. Siddle et al⁵ have looked at wallaby MHC genes and find that their classical MHC class I genes are actually scattered throughout the genome, and are not in the MHC region.

First of all, what’s the advantage of having a single MHC class I gene tightly linked to TAP (probably the primordial organization)? TAP transports peptides to the MHC (again, cartoons of MHC class I function here), and the MHC then presents the peptides to T cells for antiviral surveillance. That means that TAP needs to handle the same kinds⁶ of peptides that the MHC class I does. By linking the genes for TAP and the MHC class I, the two can evolve in tandem — if a particular MHC class I gene likes to bind peptides ending with, say, arginine, then it can co-evolve along with a TAP that likes to transport peptides ending in arg. MHC class I genes are extremely variable, and in non-mammalian species, TAP genes are also relatively variable, ⁷ arguing for this kind of co-evolution.

The problem with this organization is that it only really allows one MHC class I specificity. If the TAP has a certain, strong, specificity (ending with Arg, say), and you had several different MHC class I proteins each with different peptide preferences (one that wants peptides ending with Arg, but another that wants peptides ending in tyrosine), then some of them wouldn’t match the TAP peptides and would go wanting.

(By the way, this makes a start at explaining a paper that puzzled me some time ago [post is here]. The chicken B21 MHC class I allele was said to have very weak peptide preferences — allowing “promiscuous peptide binding”. But if TAP has strong peptide preferences, then the MHC is only going to bind to a limited subset of peptides, no matter how promiscuous the MHC is itself. That doesn’t explain everything, but it makes a start. I should mention, though, that a different group looking at B21 did, in fact, identify peptide binding preferences,⁸ suggesting that binding isn’t actually promiscuous; but now I wonder if they were detecting TAP preferences rather than MHC.)

Although it’s not a hundred percent clear why MHC class I is so diverse,⁹ according to the most plausible explanations the advantages of diversity are going to be increased if you have several different MHC class I genes, with different peptide-binding properties. If you can hoick the MHC away from TAP, then, you’d allow the MHC to start diversifying independent of TAP. You’d probably need TAP to now be fairly peptide-promiscuous (which it is, in most mammals), and shift the peptide specificity over to the MHC class I molecules themselves.

Humans, mice, and most mammals that have been looked at do this (separate MHC class I from TAP, and have multiple MHC class I alleles) by sliding the MHC class I genes over to the side, remaining within the MHC genomic region but becoming far enough separated from TAP that the genes can evolve more or less independently. Wallabies apparently have done the same thing functionally, but instead of sliding over and keeping the genes in the MHC genomic region, they’re scattered throughout the rest of the genome, apparently via retrotranspon-mediated transposition.

The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens.⁴

Incidentally, it occurs to me that there is an extra cost to this increased diversity. By un-linking TAP specificity from MHC class I peptide preferences, mammals force TAP to be highly promiscuous, and to transport a wide range of peptides — unlike in chickens, TAP no longer “knows” what MHC allele it’s dealing with and has to offer every possible peptide sequence that any of the thousands of MHC class I alleles could bind. That means that there must be a vast amount of wasted peptides transported into the endoplasmic reticulum; in contrast, I would expect chickens, for example, to predominately only transport peptides that can bind to their MHC class I. If you suspect, as I do, that peptides are intrinsically toxic at high doses, then mammals must have developed (or enhanced) some mechanisms for destroying the extra peptides, that non-mammalian vertebrates don’t have to worry about. I have a guess as to what the mechanism might be, but I’m not sure exactly how to test it right now.

1. Kaufman J, Milne S, Gobel TW, Walker BA, Jacob JP, Auffray C, Zoorob R, Beck S: The chicken B locus is a minimal essential major histocompatibility complex.Nature 1999, 401:923-925. [↩]
2. Nonaka M, Namikawa C, Kato Y, Sasaki M, Salter-Cid L, Flajnik MF: Major histocompatibility complex gene mapping in the amphibian Xenopus implies a primordial organization.Proc Natl Acad Sci U S A 1997, 94:5789-5791. [↩]
3. Ohta, Y., McKinney, E.C., Criscitiello, M.F., and Flajnik, M.F. 2002. Proteasome, TAP, and class I genes in the nurse shark Ginglymostoma cirratum: Evidence for a stable class I region and MHC haplotype lineages. J. Immunol. 168:771-781.[↩]
4. Siddle, H., Deakin, J., Coggill, P., Hart, E., Cheng, Y., Wong, E., Harrow, J., Beck, S., & Belov, K. (2009). MHC-linked and un-linked class I genes in the wallaby BMC Genomics, 10 (1) DOI: 10.1186/1471-2164-10-310[↩][↩]
5. The same Siddle, I believe, who I recently cited for work on the Tasmanian Devil genome a couple of times[↩]
6. That is, the same general amino acid sequences[↩]
7. Ohta Y, Powis SJ, Lohr RL, Nonaka M, Pasquier LD, Flajnik MF. Two highly divergent ancient allelic lineages of the transporter associated with antigen processing (TAP) gene in Xenopus: further evidence for co-evolution among MHC class I region genes. Eur J Immunol. 2003 Nov;33(11):3017-27.[↩]
8. Sherman MA, Goto RM, Moore RE, Hunt HD, Lee TD, Miller MM (2008) Mass spectral data for 64 eluted peptides and structural modeling define peptide binding preferences for class I alleles in two chicken MHC-B haplotypes associated with opposite responses to Marek’s disease. Immunogenetics 60:527–541.[↩]
9. MHC diversity: see here and its linked articles, also here and here and linked articles therein[↩]