As headlines continue to warn of a looming H1N1 influenza pandemic, biologists at the Yale University School of Medicine are applying evolutionary theory to fundamental questions in epidemiology.
In a paper published Monday in the journal PLoS ONE, researchers Eunha Shim and Alison Galvani applied population genetics to the issue of containment of H5N1 influenza A virus - aka bird flu. Since the first confirmed case of H5N1 transmission to humans in 1997, epidemiologists have been watching the virus with growing concern.
H5N1 is common, and usually harmless, in wild birds. However, it is virulent in poultry (domestic chickens, ducks, and turkeys). Transmission to humans – via contact with infected birds – is rare, but when it occurs the virus is highly virulent, with mortality estimated between 50 and 70 percent. Virulence, broadly defined, refers to the harmfulness of a virus or other microbe to its host. Virulence and transmission rate are generally correlated with the rate of viral replication.
Human H5N1 infections remain rare, because the virus does not easily spread to humans, nor does it easily spread from one person to another.
Epidemiologists worry, however, that additional mutations in the virus’s rapidly evolving RNA genome could facilitate human-to-human transmission. As humans possess no natural immunity to H5N1, such an evolutionary step could spark a devastating pandemic. Shim and Galvani dramatically underscore this point by noting that the mortality rate for bird flu in humans is more than twenty-five times greater than the rate estimated for the 1918 Spanish flu pandemic that killed 20 million people.
So far, attempts to control H5N1 have focused on mass culling – usually the destruction of localized sub-populations of poultry within which bird flu has been detected. Shim and Galvani argue that such policies may only be making matters worse. Utilizing the principles of population genetics, they modeled the evolutionary dynamics of H5N1 in domestic chicken populations.
To make the model realistic, they built in parameters including population size, reproductive rate, life span, mortality rate, incubation period, and recovery rate – and substituted values drawn from observations in domestic chicken populations.
Their model predicts, perhaps counter-intuitively, that the standard response to bird flu outbreaks – high rates of culling – may exacerbate influenza infection. Shim’s and Galvani’s data suggest this could occur by a pair of complementary effects: by hampering development of immunity in the birds and by driving the virus toward increased virulence.
Setting aside the mathematical formalism applied by Shim and Galvani, the logic goes something like this:
An infected wild bird transmits the virus to a chicken on a farm. As the domestic host lacks an adequate immune response to the virus, it quickly spreads through the population. Shim’s and Galvani’s model assumes that some small proportion of the chicken population harbors an allele (a gene variant) which confers resistance to H5N1 infection. In their model, this is posited as a dominant allele – that is, an individual only needs a single copy of the allele in order to express its effect. (A recessive allele requires a double dose.) Because the virus is virulent in chickens, it exerts a selective pressure in favor of the resistance allele. That is, most individuals that possess this allele will survive exposure to the virus, while most of those without it will die. Consequently, the proportion of individuals possessing the allele – and exhibiting H5N1 resistance – will increase in subsequent generations.
This process is referred to as natural selection and is the mechanism of adaptive evolution. (Natural selection, of course, can work in the same way on a recessive allele, but it requires more time.)
If infected individuals are swiftly removed by culling, however, the resistance allele provides little or no survival advantage and is, therefore, unlikely to spread through the population. The upshot is that mass culling may be very effective in the short term, but it leaves the population vulnerable to re-infection. In addition, mass culling may contribute to evolution of a more virulent pathogen. The level of virulence exhibited by a virus is the result of an evolutionary trade-off.
A virus will tend to evolve toward maximizing its reproductive number – the average number of secondary infections arising when the virus is introduced into a susceptible population. However, there’s such a thing as being over-optimized. If a virus is exceedingly virulent it may kill its host faster than it can transmit its progeny to a new host. So, as it turns out, a virus tends to have the greatest reproductive success when it evolves a moderate level of virulence.
If, however, the average lifespan of the host is significantly reduced by some external factor – such as mass culling – this shifts the evolutionary balance. Under this scenario, more virulent sub-strains will have a better chance of being transmitted before their hosts are killed, thereby increasing their proportion in subsequent generations. In this way, the authors explain, mass culling may lead natural selection to favor the evolution of increased virulence. This observation poses a thorny dilemma. Shim’s and Galvani’s work reveals the long-term strategic problems presented by mass culling. However, mass culling has proven very effective as a short-term tactic for containment of H5N1 outbreaks when they occur.
Fortunately, the data suggest a solution that may nimbly avoid both horns of the dilemma. Shim and Galvani show that a less dramatic rate of culling, approximately equal to the background mortality rate, allows natural selection sufficient time to act on their hypothetical resistance allele. What’s more, the time required for the population to evolve an adequate level of resistance is actually shorter under this scenario than the time required given a complete absence of culling.
These results lead the authors to suggest that a more moderate application of culling than has typified previous responses to H5N1 outbreaks might be better suited to optimizing epidemiological and evolutionary, as well as agricultural and economic considerations. The authors further suggest evolutionary considerations may prove very helpful in formulating long-term strategies to control a variety of infectious diseases.
REFERENCE:
Shim E, Galvani AP (2009) Evolutionary Repercussions of Avian Culling on Host Resistance and Influenza Virulence. PLoS ONE 4(5): e5503. doi:10.1371/journal.pone.0005503
