Ebola on the march!
UNITED NATIONS — Schools have shut down, elections have been postponed, mining and logging companies have withdrawn, farmers have abandoned their fields. The Ebola virus ravaging West Africa has renewed the risk of political instability in a region barely recovering from civil war, United Nations officials said Tuesday, hours after the World Health Organization reported that new cases could reach 10,000 a week by December — 10 times the current rate. New York Times, Oct. 14, 2014
Ebola has spread to a second Texas health care worker, and the World Health Organization has predicted a frightening climb in new infections. Health authorities are scrambling to contain a highly infectious disease that kills through massive bleeding.
In the absence of a prompt and effective response, the director of the UN’s Ebola Emergency Response Mission, Anthony Banbury warned that the world faces “an entirely unprecedented situation.”
As the global response lumbers onward and thousands die, we started wondering about the “classic dogma” of infectious disease: Pathogens become less virulent — less deadly — over time since live hosts spread infections better than dead ones. The rapid and mysterious disappearance of the Black Death (bubonic plague) from Europe in the middle ages helped raise the question: After killing as many as 200 million in Europe between 1346 and 1353, did the Yersinia pestis bacterium lose its “will to kill,” in the interests of its own survival?
The comforting dogma is backed by some evidence — and rebutted by plenty of counter-examples, as we’ll see.
Evolution is a numbers game, and this comforting dogma could allow us to think that deadly Ebola will lose its grip over time, as evolutionary pressures “persuade” the virus to sheath its claws. As many as 70 percent of West African Ebola patients are dying, far more than previously reported. The original source of infection is likely a virus-infected bat butchered and eaten by some unlucky African.
It’s a nice notion that pathogens “always evolve towards less virulence,” Lone Simonsen, a research professor in global health at George Washington University wrote to us. “But this is in fact not necessarily what will happen, as it depends on how the changes affect its transmissibility in the human host.”
Transmissibility is the gauge of evolutionary “fitness,” but the discussion of pathogen evolution can get “pretty muddy,” says Caitlin Pepperell, an assistant professor of medical microbiology at the University of Wisconsin-Madison. “People tend to conflate two concepts: fitness and virulence. Virulence has to do with whether it kills you or makes you extremely sick.” Fitness concerns the ability to infect others and expand its own population.
Some things have been around for a long time, and are adapted to the host,” either through the host’s immunity, or the development of a symbiotic relationship, says Ann Palmenberg, a common-cold expert and professor of biochemistry at UW-Madison. “Cytomegalovirus infects virtually everybody on earth, 99 percent, but it does not cause a lot of damage.”
Cytomegalovirus infections are usually unnoticed, except in people with weak immune systems. Pregnant women can pass an active infection to their newborns.
Following the dogma- more evidence
A second virus with minimal symptoms is herpes simplex. “Herpes simplex causes a genital infection that will not hurt you much, but will be transmissible,” says Palmenberg. “I assume it was much more virulent and killed people initially and then the virus thought, ‘Hey, it’s much better if I stay alive longer.'”
There are many ways that viruses can adapt to be transmissible, Palmenberg says. “You don’t have to spread by lysing [dissolving] the cell; shedding a low amount over a long period [as with HIV] is a much better evolutionary strategy.”
The host-microbe relationship can be unstable, Palmenberg says. Most of the countless bacteria in your gut are benign or beneficial, “but you get the occasional outbreak” of disease if they acquire disease-causing genes.
During the infection and replication process, “RNA viruses,” including Ebola and HIV, insert DNA into host cells that force those cells to make new virus particles. Each human cell carries proof of an ancient stalemate between mammals and ancient RNA viruses, or retroviruses, Palmenberg says: “One-third of your genome is retrovirus,” Palmenberg says. These RNA viruses infected our ancestors but instead of killing them, merged into their genome and became part of their descendants — of us.
Counterexamples — flouting the dogma
Pathogen virulence does not always abate over time. For example, a 2013 study found that the West Nile Virus strain that reached New York in 1999 and a recently discovered “lineage 2” version have both evolved toward greater virulence over the past 300 or 400 years. 1
West Nile, transmitted by mosquitoes, can cause fatal brain infections.
Concerning lineage 2, now found in Greece, Italy and Russia, the researchers reported, “As the virus has spread and continued to evolve, it appears to have become more virulent leading to increased numbers of cases of avian, equine and human disease.”
In some pathogens, disease is almost an afterthought — harmful to the host and neutral to the virus. For example, the bacteria Streptococcus pneumoniae (the most common cause of meningitis acquired outside the hospital) is carried in the throat in healthy people. The bacterium may sit idly by as it competes with other bacteria for a niche in the throat, Pepperell says. But if its invasive genes activate, the bacteria can enter the blood stream and cause significant disease which does not, however, help it infect new hosts, which it easily achieves from its position in the throat or nose. “We probably don’t really understand the driver of virulence in those organisms,” Pepperell concludes. “This is not a case where it has evolved to reduced virulence.”
In many cases, however, causing disease can boost fitness — measured by the number of new infections. Cholera and other diarrheal diseases, for example, are spread by infected stools that are a by-product of infection.
Similarly, the bacterium that causes tuberculosis needs to be transmitted via coughing, Pepperell says. In this case, as with cholera and Ebola, high virulence translates into high fitness.
Ebola is largely spread by contact with infected blood, and evolving toward lower virulence would reduce its frightening and frighteningly dangerous bleeding. “This is a theoretical example of lower virulence linked to lower transmissibility, and therefore not a likely evolutionary path for the virus to take,” Simonsen says.
Lessons from HIV
More than 30 years ago, another fearsome virus emerged from the African bush. HIV, which causes the immune disease AIDS, descended from SIV, a monkey virus. Since 1981, AIDS has killed about 36 million people.
Has the heavily-studied HIV undergone significant evolution, and if so, in what direction?
There is some evidence that some HIV strains cause varying levels of disease, says Thomas Friedrich, an associate professor of pathobiological sciences at UW-Madison, and head of virology services at the Wisconsin National Primate Research Center. “In evolutionary terms, HIV has not had a long time to evolve toward a peaceful coexistence with humans, if it is ever going to do that. If we let nature take its course, over one-half million years, the virus could or could not co-evolve with the host to make it less pathological.”
HIV evolves in every patient, Friedrich said, as it struggles to survive attacks from the host immune system. “During the natural history of the infection of one person, we see evidence of adaptation to evade immune detection.” This evolutionary ability also enables HIV to evade drugs.
The AIDS crisis gave a shot in the arm to all aspects of virology, and one in particular seems applicable to the Ebola crisis, says David O’Connor, a professor in the UW-Madison School of Medicine and Public Health. The drug used with some success on a few Ebola patients, ZMapp, contains three antibodies. Antibodies, delivered by the immune system or as medicine, can block the attachment points that a virus needs to infect a cell. With HIV, and likely with Ebola as well, a single antibody will quickly fail due to genetic changes in the virus — evolution. However, a “triple cocktail” of drugs, which is the standard treatment for HIV, has a better chance of success. “The three antibodies are going to synergize, and reduce the viral replication, without causing resistance to emerge,” O’Connor says.
That’s the case with AIDS, and the hope with Ebola. We won’t know for sure until more of the difficult-to-manufacture ZMapp becomes available.
How variable is Ebola?
As we discuss viral evolution, we wonder: Is Ebola evolving now, and if so, in what direction? The only genetic study of the current outbreak documented variations among 300 base pairs in a genome containing 18,000 base pairs.
Whether that’s a lot or a little, “is a bit like a Rorschach test for scientists,” said O’Connor. “The real question is how many of these genetic changes are meaningful and are likely to rise up to dominate an individual’s virus population,” O’Connor says. “For example, how many of these could alter the shape of the virus to protect it from the immune system? Of the 300 base pairs [“letters” in the alphabet of RNA] with variation, there are only about 20 that could both change the shape of the virus and are found in more than 5 percent of viruses in an infected person. To me, that’s not a lot of changes given how much Ebola replicates.”
Pathogen evolution, in this case, is pretty straightforward: What doesn’t kill them makes them stronger. The pathogens that escape the immune attack are those that have some trick to evade attack. When these viruses or bacteria multiply, their offspring are likewise resistant.
As mentioned, Ebola is composed of RNA rather than DNA, and “While we have evidence from other RNA viruses that a single base pair change can change the the structure or function of the virus,” O’Connor says, “the vast majority of single base-pair changes will only modestly affect the ability of the virus to replicate, in one way or another, positive or negative.”
Viruses that are unstable and frequently change shape are difficult to vaccinate against, but Ebola seems fairly stable, says O’Connor. “The issue of enormous diversity, over time, and in different populations, is probably the biggest single obstacle to a universal HIV or influenza vaccine. With Ebola, that does not seem as formidable an obstacle.”
A preliminary test of a candidate Ebola vaccine on 20 human volunteers began Oct. 13 at the Walter Reed Army Institute of Research in Silver Spring, Md.
Making sense yet?
We started with the fantasy that Ebola would quickly abate, following its predecessors in its effort to stay alive, but we’ve learned that many factors affect whether a pathogen benefits by becoming more or less virulent, or staying pretty much as it is.
One more wrinkle: Not all changes in deadliness reflect a change in pathogen genetics; changes in medicine, the environment, host immune systems and human behavior and economics can all play a role. The recent Ebola outbreaks in Africa occurred in villages with few connections to the outside world, and they burned themselves out, says Pepperell, the tuberculosis researcher. “If you have a small, poorly connected population, the virus is going to disappear with a high mortality rate.”
Once Ebola appeared in Monrovia, Liberia, and other cities in West Africa, the picture changed, she adds. “If you have a huge, well connected population, you will not run out of hosts quickly, and the selection pressure to soften the virulence is not very strong, and there is no advantage to evolving toward less virulence.”
Pepperell adds that, “People who are not strong on evolutionary biology tend to think that everything that evolves is driven by advantageous mutations that increase in frequency, but many modes of evolution are neutral. Some aspects of bacterial physiology are really driven by chance.”
The classic dogma is, “A vast oversimplification,” Pepperell concludes. “The evolutionary strategies employed by different pathogens are different from each other, and I don’t think you can make one simple rule to apply to all of them.”
Edward Holmes of the University of Sydney, who has studied the evolution of viruses used to attack the hordes of rabbits that over-ran Australia in the last century, wrote us to say that the path of pathogen change, “All depends on the relationship between virulence and transmission, and which is (a) very poorly understood and (b) differs between each pathogen. In short, predicting how virulence will evolve in the long-term (or even the short-term) is very difficult and often little more than speculation.”
Having heard all these criticisms of the dogma, there still is a grain of truth, says Palmenberg, a researcher into the common cold virus. “I think this is true of any host parasite relationship. If the parasite is so effective that it kill all its hosts, it will have killed itself. That has probably occurred millions and millions of times in evolution, but it’s an end game.”
In a sense, she adds, the pathogen will recognize, “‘Oh *$&^^#%#(, we have killed ourselves!’ The only examples we have in nature are those that were successful [in reducing virulence].”
None of which tells us how Ebola will end up if control efforts fail. It could simmer down, or it could run rampant. “There are Ebola-related viruses that are not as pathogenic, in the same family,” Palmenberg says, “but there is no way of saying who is right and who is wrong. Ebola will be what it will be; we can’t predict the endpoint. Even if Ebola kills all humans on earth, it will still have rats and bats that may count as hosts.”
Moral of the story: Don’t wait for evolution to save us. Unless a vaccine makes a dramatic appearance, we’ll need to do the hard work of controlling this deadly virus.
– David J. Tenenbaum
Kevin Barrett, project assistant; Terry Devitt, editor; S.V. Medaris, designer/illustrator; David J. Tenenbaum, feature writer
- Molecular evolution of lineage 2 West Nile virus, Allison R. McMullen et al, Journal of General Virology (2013), 94, 318–325 ↩
- RNA Virus Evolution: A Guide for the Perplexed, Eddie Holmes, University of Sydney (Australia). ↩
- Black death in Europe ↩
- Q & A on NPR with the co-discoverer of ebola. ↩
- New ebola cases may soon reach 10,000 a week, officials predict. ↩
- Ebola: The longer the outbreak, the greater the risk of mutation. ↩