Oct 12 Lecture 12 Evolution of Virulence

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Evolution of VirulenceGuest lecture Joel
Wertheim11/6/08
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Today

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

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Todays Lecture

• SEIR Epidemiological Modeling
• R0 the basic reproductive number of a pathogen
• The trade-off hypothesis and Paul Ewalds view
  route and timing of transmission determines
  virulence
• Transmission and virulence de-coupled
  coincidental evolution
• Transmission and virulence de-coupled
  short-sighted evolution

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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
  (clinicians definition) or a reduction in host
  fitness (evolutionary biologists 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

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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 its binary (yes / no)

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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

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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
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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.

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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
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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 evolveIs this view correct?

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The conventional wisdom

• Many observations are consistent with the
  conventional wisdom Legionnaires disease, Lyme
  disease, Ebola fever, and SARS are consequences
  of human infection with symbionts of other
  species that have recently jumped into humans

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The conventional wisdom

• Other observations dont 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?

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Does the conventional wisdom hold for HIV/SIV?
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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

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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

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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
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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?

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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
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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

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• 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.

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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

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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

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Paul Ewalds 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)?

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Paul Ewalds 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

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

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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
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Paul Ewalds 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

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Paul Ewalds 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?

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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)
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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?

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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

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Other examples of coincidental evolution?
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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

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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

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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?

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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?

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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)
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SIVsm gag MRCA 1809 CE
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SIVcpz env MRCA 1492 CE
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Review

• R0 the basic reproductive number of a pathogen
  (gt1 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