Evolution of Virulence Guest lecture: Joel Wertheim 11/6/08 - PowerPoint PPT Presentation

Presentation Transcript

Evolution of VirulenceGuest lecture: Joel Wertheim11/6/08

Today

The “conventional wisdom” on virulence
Modern theories for how virulence evolves and is maintained

Today’s Lecture:

SEIR Epidemiological Modeling
R0: 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 signs and symptoms (clinician’s definition) or a reduction in host fitness (evolutionary 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

Virulence is a relative term describing the severity of disease (mortality rate 1 - 100%)
Pathogenicity refers whether or not a pathogen causes disease; it’s binary (yes / no)

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

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.

Simian foamy virus (SFV) tree is very similar to host tree suggesting that the ancestral primate was infected with a retrovirus over 30 million years ago

No known associated disease in monkeys/apes

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?

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

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?

Does the conventional wisdom

hold for HIV/SIV?

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

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

R0: The basic reproductive rate

The fundamental epidemiological quantity
R0 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 R0 is required for an outbreak to persist?
What R0 must be brought about if an intervention is to be successful?

R0: 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 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.

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

Different transmission patterns lead to different optimal virulence levels of transmission and virulence are coupled

Paul Ewald’s view

Diseases that spread by “cultural vectors” should also tend to high virulence.
Cultural vectors are simply amalgams of behavior and environmental conditions that allow immobilized hosts to transmit infections
Diarrheal pathogens, for example, can be passed through drinking-water systems. An immobilized victim can still infect lots of people if contaminated materials get into drinking water

1854 Broad Street Cholera Epidemic

and the birth of epidemiology:

Cholera was thought to be caused by miasma (bad air)

In one week, 600 people near Broad Street died of Cholera

John Snow determined the source was a single water pump

When the pump was closed, the epidemic ceased

Paul Ewald’s view

So transmission by water may lead to a shift in optimal virulence analagous to insect-vectored transmission
Again, there is some evidence that is suggestive. For example as water supplies were cleaned up in India in the 1950s and 1960s, a milder form of cholera displaced the more virulent form.
The problem is that the evidence is almost anecdotal and Ewald advocates on behalf of his favorite theory without considering alternative explanations

Paul Ewald’s view

“Sit-and-wait” pathogens, like M. tuberculosis can survive in the external environment for a long, long time.
How is the cost/benefit calculation affected in such cases?

Experimental evolution: evolution of virulence

When researchers gave the viruses more opportunities for horizontal transmission (red dots), the viruses evolved higher virulence and higher reproductive rates than predominantly vertically transmitted viruses (blue dots)

What if increased virulence is not coupled to increased transmission?

Even when transmission and virulence have no relationship, or a negative relationship, high virulence can be maintained
According to the coincidental evolution hypothesis, the factors responsible for virulence may have evolved for some purpose other than providing a within-host or transmission advantage
Did botulism toxin really evolve by selection favoring Clostridium botulinum bacteria that kill people who eat improperly canned food?

How about C. tetanae, a soil bacterium that once in a while colonizes a human host? Are the symptoms of tetanus linked to successful chains of transmission?
Many symptom-inducing toxins and other virulence determinants may provide no within- or between-hosts advantage

Other examples of coincidental evolution?

Short-sighted evolution is the other way natural selection can favor high virulence, without the virulence being optimized to increase transmission
Natural selection is a local phenomenon: characters that confer a survival and/or replication advantage on the individual organisms that express them at a given time/environment will be favored
Whether those temporally/locally favored characters will reduce the fitness of that organism in other times or places is irrelevant

Myopia is a fundamental premise of the theory of evolution by natural selection
It is also the basis of the short-sighted evolution hypothesis for parasite virulence
Mutants that are better able to avoid host defenses, or proliferate in the host, or invade new cell/tissue types will have an advantage in the host even if they induce higher virulence that actually reduces the rate of transmission to other hosts

Various agents of meningitis (Haemopihlus influenzae, Neisseria meningitidus, S. pneumoniae cause inflammation when they enter the cerebral spinal fluid around the brain
The invaders have a local, but dead end advantage
Same with poliovirus
Same with HIV?
Others?

What about virulence in SIV/HIV?

Both HIV-1 and HIV-2 make humans sick
Neither SIVcpz (cause of HIV-1) and SIVsm (cause of HIV-2) leads to illness in chimps or sooty-mangabeys
AIDS-like symptoms very rare among African primates (although seen in laboratory infected Asian macaques)
Is SIV millions of years old and therefore evolved avirulence, like simian foamy virus?
Or is SIV much younger?

Phylogenetic analyses suggest SIV is a recent (not ancient) infection

Complete SIV/Host Trees

Charleston and Roberston, Syst. Biol. (2002)

SIVagm/AGM Trees

Wertheim and Worobey, PLoS Pathogens (2007)

SIVsm gag MRCA = 1809 CE

SIVcpz env MRCA = 1492 CE

Review

R0: the “basic reproductive number” of a pathogen (>1 yields a productive transmission chain)
The trade-off hypothesis: selection may result in intermediate virulence
Virulence may be the accidental result of coincidental evolution
Evolution is greedy and virulence may be from short-sighted evolution and have no effect on fitness