slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Evolution of Virulence Guest lecture: Joel Wertheim 11/6/08 PowerPoint Presentation
Download Presentation
Evolution of Virulence Guest lecture: Joel Wertheim 11/6/08

Loading in 2 Seconds...

play fullscreen
1 / 45

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


  • 216 Views
  • Uploaded on

Evolution of Virulence Guest lecture: Joel Wertheim 11/6/08. Today. The “conventional wisdom” on virulence Modern theories for how virulence evolves and is maintained. Today’s Lecture:. SEIR Epidemiological Modeling R 0 : the “basic reproductive number” of a pathogen

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Evolution of Virulence Guest lecture: Joel Wertheim 11/6/08' - lisle


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide2

Today

  • The “conventional wisdom” on virulence
  • Modern theories for how virulence evolves and is maintained
slide3

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
slide4

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
slide5

Evolution of virulence

  • 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)
slide6

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…
slide7

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

slide8

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.

slide9

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

slide10

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?
slide11

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
slide12

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?
slide14

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
slide15

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
slide16

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

slide18

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?
slide19

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

slide20

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
slide21

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.
slide23

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
slide24

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
slide25

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)?
slide26

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
slide27

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

slide28

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
slide29

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

slide31

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
slide32

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?
slide33

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)

slide34

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?
slide35

What if increased virulence is not coupled to increased transmission?

  • 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
slide37

What if increased virulence is not coupled to increased transmission?

  • 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
slide38

What if increased virulence is not coupled to increased transmission?

  • 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
slide39

What if increased virulence is not coupled to increased transmission?

  • 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?
slide40

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?
slide41

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)

slide45

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