Transcript Oct 12 Lecture 12 Evolution of Virulence

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:
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SEIR Epidemiological Modeling
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R0: the “basic reproductive number” of a pathogen
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The trade-off hypothesis and Paul Ewald’s view:
route and timing of transmission determines
virulence
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Transmission and virulence de-coupled:
coincidental evolution
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Transmission and virulence de-coupled: shortsighted evolution
Evolution of virulence
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Virulence is the harm done by a pathogen to the
host following an infection; parasite-mediated
morbidity and mortality in infected hosts
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“Harm” here can mean specific signs and
symptoms (clinician’s definition) or a reduction in
host fitness (evolutionary biologist’s definition)
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Virulence varies dramatically among pathogens
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Some, like cholera and smallpox, are often lethal
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Others, like herpes viruses and cold viruses, may
produce no symptoms at all
Evolution of virulence
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Virulence is a relative term describing the severity
of disease (mortality rate 1 - 100%)
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Pathogenicity refers whether or not a pathogen
causes disease; it’s binary (yes / no)
Evolution of virulence
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Why are some microbes commensal and others
pathogenic?
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What causes qualitative and quantitative variation
in disease symptoms?
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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
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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
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Biologists traditionally believed that all pathogen
populations would evolve toward ever-lower
virulence
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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 conventional wisdom
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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
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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
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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
The conventional wisdom
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Other observations don’t fit so well, however.
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For some virulent pathogens like Neisseria
gonorrhoeae humans are the unique or dominant
host and vector
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For other, like the agents of malaria and
tuberculosis, there is evidence of a long
association with humans
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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
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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
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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
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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
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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
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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
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The trade-off hypothesis: Natural selection should
strike an optimal balance between the costs and
benefits of harming hosts
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There is a (virulence-related) trade-off between rate of
transmission and duration of infection
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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
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Natural selection would favor highly transmissible,
incurable commensals or even mutualists
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On the other hand, if transmission and virulence
were positively coupled, some level of virulence
will be favored
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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
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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 virusinduced mortality
Myxoma virus
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Trade-off between virulence and transmission: highly
virulent forms killed too quickly, reducing chance of
being picked up by vector
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Viruses that were too attenuated (mild) had fewer
lesions and lower viral load, again translating into
less chance of being picked up by vector
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Happy medium selected for, rather than ever-more
benign forms
Paul Ewald’s view
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Changes in rates of infectious transmission will
select for parasite strains or species with different
levels of virulence
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Assumes parasite virulence is constrained solely
by the need to keep the host alive long enough to
facilitate transmission to the next host
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How should this perspective apply to pathogens
with different modes of transmission (e.g. direct
versus indirect transmission)?
Paul Ewald’s view
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All else being equal, vectored diseases ought to
have a higher optimal virulence than directlytransmitted ones since immobilizing the host does
not prevent (and may even enhance) transmission
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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
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Diseases that spread by “cultural vectors” should
also tend to high virulence.
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Cultural vectors are simply amalgams of
behavior and environmental conditions that allow
immobilized hosts to transmit infections
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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
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So transmission by water may lead to a shift in
optimal virulence analagous to insect-vectored
transmission
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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.
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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
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“Sit-and-wait” pathogens, like M. tuberculosis can
survive in the external environment for a long, long
time.
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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?
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Even when transmission and virulence have no
relationship, or a negative relationship, high
virulence can be maintained
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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
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Did botulism toxin really evolve by selection
favoring Clostridium botulinum bacteria that kill
people who eat improperly canned food?
What if increased virulence is not
coupled to increased transmission?
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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?
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Many symptom-inducing toxins and other
virulence determinants may provide no within- or
between-hosts advantage
Other examples of coincidental
evolution?
What if increased virulence is not
coupled to increased transmission?
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Short-sighted evolution is the other way natural
selection can favor high virulence, without the
virulence being optimized to increase transmission
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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
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Whether those temporally/locally favored
characters will reduce the fitness of that organism
in other times or places is irrelevant
What if increased virulence is not
coupled to increased transmission?
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Myopia is a fundamental premise of the theory of
evolution by natural selection
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It is also the basis of the short-sighted evolution
hypothesis for parasite virulence
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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
What if increased virulence is not
coupled to increased transmission?
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Various agents of meningitis (Haemopihlus
influenzae, Neisseria meningitidus, S.
pneumoniae cause inflammation when they enter
the cerebral spinal fluid around the brain
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The invaders have a local, but dead end
advantage
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Same with poliovirus
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Same with HIV?
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Others?
What about virulence in SIV/HIV?
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Both HIV-1 and HIV-2 make humans sick
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Neither SIVcpz (cause of HIV-1) and SIVsm
(cause of HIV-2) leads to illness in chimps or
sooty-mangabeys
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AIDS-like symptoms very rare among African
primates (although seen in laboratory infected
Asian macaques)
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Is SIV millions of years old and therefore evolved
avirulence, like simian foamy virus?
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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
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R0: the “basic reproductive number” of a
pathogen (>1 yields a productive transmission
chain)
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The trade-off hypothesis: selection may
result in intermediate virulence
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Virulence may be the accidental result of
coincidental evolution
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Evolution is greedy and virulence may be from
short-sighted evolution and have no effect
on fitness