Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

March 10th, 2010

Vaccinia virus in Brazil: What a long, strange trip

Krishna milking a cow
Krishna, milking a cow

Vaccinia virus is a widespread virus whose natural host remains unknown.  It turns out to be pretty good at jumping across species.

Vaccinia, of course, is the vaccine against smallpox.  Even though smallpox is eliminated in the wild,1 vaccinia is still very widely used in research and even, to some extent, in the clinic, because the broad and deep experience with the virus gained from its importance in vaccination has carried over into other fields.

When Jenner developed his vaccine against smallpox, he used the cowpox virus.  But — in spite of a widespread misconception — vaccinia is not cowpox.  They’re quite distinct viruses, though they are related.  At some point along the centuries of vaccine use cowpox was replaced by vaccinia. (It’s also worth pointing out that the disease Jenner called cowpox, may not have been cowpox as we know it today. 2  It may have been a distinct strain of virus, or it may have been a different virus altogether.)

Remember that for a couple of hundred years, there was no tissue culture to grow the virus in, and it was basically propagated by continually re-infecting animals and collecting virus from their scabs.  At some point, presumably a cow that was being used as a vaccine incubator was infected with vaccinia instead of cowpox, and the vaccinia proved more effective, or perhaps safer or more convenient, as a vaccine, crowding out the vaccine cowpox.

Cowpox innoculation - Zhu Chunxia
“Cowpox inoculation sites”
Douzhen dinglun (Definitive Treatise on Pox Diseases)
by Zhu Chunxia, 1888

(By the way, it’s interesting to note that cowpox has an MHC class I immune evasion function,3 whereas vaccinia virus does not.  Obviously this immune evasion doesn’t prevent cowpox from acting as a strong immunogen, because it was an effective  vaccine for decades if not centuries, but perhaps it’s one reason vaccinia was a more popular vaccine.)

Where vaccinia virus came from — what animal it was infecting before it jumped into cattle  — no one knows.  Although vaccinia must have (or have had) a natural host at one point, the true host for the virus is now cultured cells in the lab incubator.

Does that mean vaccinia isn’t found in the wild? Not at all.  Vaccinia virus does infect a bunch of animals, in many parts of the world.  But what’s happened is that the virus has gone feral: It’s jumped from vaccinated humans into other species — usually cattle — and then spread among that population.  In Brazil, this feral vaccinia virus has become a significant emerging disease in cattle, from which it jumps back again into humans:

Starting in 1999 several VACV strains were shown to be responsible for zoonotic disease affecting more than 1100 dairy cattle and up to 80% of their handlers in rural tropical rainforest and woodland savanna areas in southeast Brazil 4

The origin of this Brazilian bovine vaccinia is unknown.  Almost certainly it’s derived from the vaccine — the alternative explanation, that it’s derived from the original, natural host of vaccinia, seems really unlikely, especially since the disease has only been detected in the past ten to twenty years. But genetically, it doesn’t look much like any of the known vaccine strains.5  (However, I remember reading a paper that I can’t turn up right now, that talked about vaccinia-based vaccines in the early 20th century. It made the point that there wasn’t particularly careful oversight or recording of precise strains or provenance of smallpox vaccines, and emphasized that there were several different strains of vaccinia used in South America, not all of which were well characterized.)   Grant McFaddden’s interpretation of the feral virus’s relationships is that there were probably recombinations between different strains of the virus, which makes it hard to reconstruct the genetic history of the virus; complicated by a long period of adaptation to its new host(s):

On the other hand, the Brazilian isolates appear to have escaped in a single event or in multiple events and probably adapted to a new host, until they re-emerged in man or cattle at least 25 years later. 2

Cowpox (Wellcome Images)
Cowpox on a cow’s udder
Trattato di vaccinazione con osservazioni sul giavardo e vajuolo pecorino
by Luigi Sacco, 1809

There’s another puzzling aspect to the Brazilian vaccinia epidemics: How are they spreading? Although most of the epidemics can be traced back to infected humans, there are some exceptions:

… some VACV outbreaks are temporally and spatially distant from previously notified BV areas. … Rats, mice, opossums, foxes, wild dogs and small felids are frequently observed around farming properties. In theory, some of these species, especially rodents, could be VACV reservoirs. 6

Indeed, the virus was recently isolated from a wild mouse,6 suggesting that rodents might be spreading the virus between farms.

The implication is that over the past hundred years or so, vaccinia virus has sequentially jumped from its original, unknown host, into cattle, into humans, then back into cattle, into rodents, back into cattle, and then back into humans, not counting its long side-trip into the laboratory incubator.  It’s the Michael Jordan of jumping viruses.

  1. Hopefully! But see this post for more[]
  2. Moussatché N, Damaso CR, & McFadden G (2008). When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond. Journal of infection in developing countries, 2 (3), 156-73 PMID: 19738346[][]
  3. Alzhanova, D., Edwards, D., Hammarlund, E., Scholz, I., Horst, D., Wagner, M., Upton, C., Wiertz, E., Slifka, M., & Früh, K. (2009). Cowpox Virus Inhibits the Transporter Associated with Antigen Processing to Evade T Cell Recognition Cell Host & Microbe, 6 (5), 433-445 DOI: 10.1016/j.chom.2009.09.013[]
  4. Essbauer, S., Pfeffer, M., & Meyer, H. (2010). Zoonotic poxviruses? Veterinary Microbiology, 140 (3-4), 229-236 DOI: 10.1016/j.vetmic.2009.08.026[]
  5. DRUMOND, B., LEITE, J., DAFONSECA, F., BONJARDIM, C., FERREIRA, P., & KROON, E. (2008). Brazilian Vaccinia virus strains are genetically divergent and differ from the Lister vaccine strain Microbes and Infection, 10 (2), 185-197 DOI: 10.1016/j.micinf.2007.11.005[]
  6. Abrahão, J., Guedes, M., Trindade, G., Fonseca, F., Campos, R., Mota, B., Lobato, Z., Silva-Fernandes, A., Rodrigues, G., Lima, L., Ferreira, P., Bonjardim, C., & Kroon, E. (2009). One More Piece in the VACV Ecological Puzzle: Could Peridomestic Rodents Be the Link between Wildlife and Bovine Vaccinia Outbreaks in Brazil? PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007428[][]
March 4th, 2010

Blowing out the candles

Our cells die all the time, in vast numbers.  Cells are programmed to die when all kinds of things happen: They may have reached the end of their productive life (as with cells of the gut or skin); they may detect damage to their DNA (as in cancer); or they may have detected viral infection. (See here, where I posted a movie of cells undergoing programmed death.)

In principle, dying is fine,  because most cells can be easily replaced. 1 Unexpected cell death isn’t fine, mind you — it means there’s something abnormal going on, and the immune system detects uncoordinated cell death as danger and responds with inflammation — but the usual form of cell death is highly coordinated, with the cell carefully tidying up before blowing out the candles.

This video2 helps show just how organized programmed cell death is.  Here we’re seeing a cell whose mitochondria are double-stained.  Cytochrome c is green (it’s part of the mitochondrial energy-generating system); red is a dye that indicates functioning, respiring mitochondria. The cell is forced into programmed cell death.3 At the start the mitochondria are both green and red, making yellow.  Watch the dual waves sweep over the cell: First the cytochrome leaks out, leaving only the red behind, and then — this 15-second movie shows about 10 minutes of activity — the mitochondria wink out altogether as they stop breathing, leaving behind a peaceful corpse.

A time-lapse movie of a HeLa cell expressing cytochrome c-GFP (green), stained with TMRE (red), and treated with TRAIL to induce programmed cell death

  1. Obviously there are exceptions, like neurons, that aren’t as easily replaced.[]
  2. This is one of the supplementary videos from
    Bhola, P., Mattheyses, A., & Simon, S. (2009). Spatial and Temporal Dynamics of Mitochondrial Membrane Permeability Waves during Apoptosis Biophysical Journal, 97 (8), 2222-2231 DOI: 10.1016/j.bpj.2009.07.056[]
  3. By treatment with TRAIL[]
March 2nd, 2010

Frogs and jumping viruses

Frogs (by Haeckel)
“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.

Dekay - Salamanders & turtle
“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[]