I was at the International Conference on Emerging Infectious Diseases (ICEID) in Atlanta a couple of weeks ago. There were some fantastic presentations that really made me think. One speaker, Arturo Casadevall, discussed his thoughts on the role of fungal pathogens in the natural history of life on Earth. I won’t recap his whole argument, but I will say that it’s captivating and you can read more about it here. In the pursuit of his fungus story, Dr. Casadevall dropped in this little bombshell. He said that virulence is an emergent property of the host-pathogen interaction (1). Something that had been fuzzy for me suddenly came into focus. An emergent property is exactly the right way to look at it!
Virulence, for those who aren’t infectious disease people, is generally taken to mean the degree of pathology (damage) caused to the host by an organism. We tend to think of it as a property of the microbe, but it’s not. Virulence is a product of the interaction between the host and the microbe. It’s a characteristic of my relationship to the pathogen that infects me. Without me, the pathogen causes no damage. It’s non-virulent. That’s pretty cool by itself, but it’s not really big news. Even though we sometimes let ourselves slip, we really know that virulence cannot be separated from host factors, such as immune function.
But there’s more to Dr. Casadevall assertion than just that. He’s saying that the host-pathogen interaction is a chaotic system. For those of you don’t know much about chaotic systems (I would generally include myself in that category), they are dynamic systems that are highly sensitive to initial conditions (also known as the butterfly effect).
An emergent property is pattern that arises from the underlying chaotic processes. So you have a system. It’s chaotic (it’s all kinds of crazy), but suddenly emerges something that has structure (the crazy makes sense). One big example of this is life! Take me. I am a highly complex organism that is the product of chaotic evolutionary interactions at various scales (organismal, cellular, intracellular, molecular). I am an emergent property of the evolutionary process. (So are you!) It’s difficult to explain why these structures exist by looking at the inputs individually. You have to look at the system as a whole.
A few months ago, I was doing some research for an assignment evaluating the impact of HIV on the virulence of syphilis. Given that the immune response against syphilis infection is mediated by exactly the factors that AIDS depletes (CD4+ T-cells), I wondered how T. pallidum spp. Pallidum (which causes syphilis) might be evolving in AIDS patients with syphilis. In other words, if T. pallidum is under less immune pressure in those patients, could the pathogen evolve toward causing worse infection without penalty? One way to consider this question is to use math to model the interaction of the immune system and the pathogen. Researchers have begun to do just that, though not yet for the case of syphilis. Using predator-prey theory (the immune cells are the predator, the microbe is the prey), Andy Fenton at the University of Liverpool and his colleagues used modeling to predict the effect of the immune response on pathogen competition within the host (and therefore virulence). They found that the evolution of virulence can be highly non-linear and dependent on specific immune features (2, 3).
Does this meet the technical criteria of a chaotic system? I couldn’t tell you. But it certainly seems that Dr. Casadevall and Dr. Fenton are on to something. It’s time to think beyond simple, reductionist relationships to get at what’s really going with virulence.
(1) Casadevall A, Fang FC, Pirofski L-a (2011) Microbial Virulence as an Emergent Property: Consequences and Opportunities. PLoS Pathog 7(7): e1002136. doi:10.1371/journal.ppat.1002136
(2) Fenton, A. and S.E. Perkins (2010) Applying predator-prey theory to modelling immune-mediated, within-host interspecific parasite interactions. Parasitology 137(6): p. 1027-1038.
(3) Fenton, A., J. Lello, and M.B. Bonsall (2006) Pathogen responses to host immunity: the impact of time delays and memory on the evolution of virulence. Proceedings of the Royal Society B-Biological Sciences 273(1597): p. 2083-2090.