Lecture 15 Evolution of virulence I

Today and next class: Midterm next Thursday. The “conventional wisdom” on virulence Modern theories for how virulence evolves and is maintained

Today and next class: R 0 : the “Basic reproductive number” of a pathogen The trade-off hypothesis and Paul Ewald’s view: route and timing of transmission determines virulence Transmission and virulence de-coupled: coincidental evolution Transmission and virulence de-coupled: Short-sighted evolution

evolution of virulence Virulence is the harm done by a pathogen to the host following an infection; parasite-mediated morbidity and mortality in infected hosts “Harm” here can mean specific symptoms and pathologies (clinician’s definition) or a reduction in host fitness (population biologist’s definition) Virulence varies dramatically among pathogens Some, like cholera and smallpox, are often lethal Others, like herpes viruses and cold viruses, may produce no symptoms at all

Evolution of virulence Why are some microbes commensal and others pathogenic? What causes qualitative and quantitative variation in disease symptoms? There are three (modern) general models to explain the evolution of virulence, the trade-off hypothesis, the coincidental evolution hypothesis, and the short-sighted evolution hypothesis Plus one old-fashioned idea that persists…

The conventional wisdom 1. Think globally, act locally. 2. Given enough time a state of peaceful coexistence eventually becomes established between any host and parasite. -Rene Dubos

The conventional wisdom Biologists traditionally believed that all pathogen populations would evolve toward ever-lower virulence Why? Damage to the host must ultimately be detrimental to the interests of the pathogens that live within it.

The conventional wisdom The logic behind this view is pleasing to human sensibilities: a fully-evolved parasite would not harm the host it needs for its survival, proliferation, and transmission The corollary is that pathogenesis is evidence of recent associations between parasites and their hosts. Virulence is an indication that not enough time has elapsed for a benign association to evolve…Is this view correct?

The conventional wisdom Many observations are consistent with the conventional wisdom: Legionnaire’s disease, Lyme disease, Ebola fever, and SARS are consequences of human infection with symbionts of other species that have recently jumped into humans In other older diseases, like rabies, humans play a negligible role in the transmission of the parasite

The conventional wisdom Other observations don’t fit so well, however. For some virulent pathogens like Neisseria gonorrhoeae humans are the unique or dominant host and vector For other, like the agents of malaria and tuberculosis, there is evidence of a long association with humans Is “long” not long enough, or could it be that some pathogens evolve to become increasingly virulent?

The conventional wisdom The conventional wisdom runs up against a big problem when it comes to articulating the mechanism responsible for the alleged evolutionary pressure toward benign associations For a parasite to evolve to become gentle and prudent in its treatment of its host requires some form of group selection since natural selection operating at the level of the individual parasite often favors virulence

The conventional wisdom In the 1980s, evolutionary biologists realized that if transmission and virulence were positively coupled, natural selection acting on individuals could favor the evolution and maintenance of some level of virulence It comes down to elucidating the relationship between the rate of parasite-mediated mortality and the rate of transmission. If the relationship is positive, some level of virulence may be favored In other words, if killing your host is correlated with higher transmission, natural selection may well favor virulence

Some basic epidemiological theory: The compartmental approach distinguishes various classes of hosts during an epidemic, and then tracks the movement of individual hosts from one class to another: Susceptible individuals S Exposed individuals E Infective individuals I Removed individuals R

R 0 : The basic reproductive rate The fundamental epidemiological quantity R 0 R 0 represents the average number of secondary infections generated by one primary case in a susceptible population Can be used to estimate the level of immunization or behavioural change required to control an epidemic What R 0 is required for an outbreak to persist? What R 0 must be brought about if an intervention is to be successful?

R 0 : The basic reproductive rate = rate constant of infectious transfer (transmissibility) = density of the susceptible host population = rate of parasite-induced mortality (virulence) = rate of parasite-independent mortality = rate of recovery

The post intervention R 0 values were < 1. What do you think happenned?

The trade-off hypothesis for the evolution of virulence The trade-off hypothesis: Natural selection should strike an optimal balance between the costs and benefits of harming hosts There is a (virulence-related) trade-off between rate of transmission and duration of infection A virulent strain of parasite may increase in frequency if, in the process of killing its hosts, it sufficiently increases its chance of being transmitted

If all parameters were independent, benign parasites would evolve Natural selection would favor highly transmissible, incurable commensals or even mutualists On the other hand, if transmission and virulence were positively coupled, some level of virulence will be favored In other words, if higher virulence were linked to increased rate of transmission, there would be a trade-off between this benefit versus the cost of reducing the time that an infected individual could transmit its pathogen.

= rate constant of infectious transfer (transmissibility) = density of the susceptible host population = rate of parasite-induced mortality (virulence) = rate of parasite-independent mortality = rate of recovery

The classis example: Myxoma virus Pox virus introduced into Australia to control European rabbit populations Vectored by mosquitos and fleas, skin lesions Initially the virus was extremely virulent (99%) mortality A sharp drop in virulence was initially observed However, the circulating virus remained much more virulent than lab strains Positive coupling between transmission and virus- induced mortality

Myxoma virus Trade-off between virulence and transmission: highly virulent forms killed too quickly, reducing chance of being picked up by vector Viruses that were too attenuated (mild) had fewer lesions and lower viral load, again translating into less chance of being picked up by vector Happy medium selected for, rather than ever-more benign forms

Paul Ewald’s view Changes in rates of infectious transmission will select for parasite strains or species with different levels of virulence Assumes parasite virulence is constrained solely by the need to keep the host alive long enough to facilitate transmission to the next host How should this perspective apply to pathogens with different modes of transmission (e.g. direct versus indirect transmission)?

Paul Ewald’s view All else being equal, vectored diseases ought to have a higher optimal virulence than directly- transmitted ones since immobilizing the host does not prevent (and may even enhance) transmission There does seem to be some support for the idea that insect-vectored diseases are more virulent