Can virulence management work?
Using evolutionary principles to lower the
virulence of pathogens
Bruno A. Walther
Master Program in Global Health and Development
College of Public Health and Nutrition
Taipei Medical University
Charles Darwin
(1809-1882)
Evolution is the
foundation for biology
“Nothing in biology makes sense except in
the light of evolution.”
Theodosius Dobzhansky, geneticist and evolutionary biologist
Antibiotic resistance is a classic example of
natural selection in action.
Two
possible
outcomes
depending
on
whether
the cost of
resistance
is high or
low.
high
low
Paul Ewald’s books about the evolution of infectious
diseases, including virulence evolution & management
Paul Ewald also has two chapters in this edited book
devoted to virulence evolution & management
Excellent introduction to the idea that we may be
able to influence the evolution of pathogen
virulence
Paul Ewald’s TED talk: “Can we domesticate germs?”
Ewald’s argument about virulence evolution rests on a
simple benefit cost analysis:
Benefit of high virulence to the pathogen: increasing
virulence means more copies leaving the host to be
transmitted to new hosts
Costs of high virulence to the pathogen: increasing
virulence means the host infects less new hosts
because of (1) decreased host mobility, (2) increased
host avoidance and (3) increased hygienic efforts.
Another cost may be increased immune reaction, but I
will not deal with that effect here.
Cost 1: decreased host mobility
Smallpox victim
Cost 2: increased avoidance
because of disgust and fear
Cost 3: increased hygienic efforts
These three costs are also
widespread among other species
Resting
Avoiding contamination
Grooming
Benefit cost tradeoff
B&C
Virulence
Optimal virulence
Virulence = increased reproduction of pathogens within host cells
= increased use of host resources = increased morbidity/mortality
Benefit: increasing virulence means more offspring leaving the
host to be transmitted to new hosts
Cost: increasing virulence means the host infects less new hosts
because of decreased host mobility and increased host avoidance
Benefit cost tradeoff
B&C
Virulence
Optimal virulence
If the pathogen can
decrease the costs
of host immobility,
avoidance and
hygiene by using
other means of
getting to new
hosts, e.g. a vector,
then the cost curve
becomes flatter,
leading to an
increased optimal
virulence
Different benefit and cost curves lead to the evolution of a
different level of optimal virulence
Example 1: water-borne pathogens
Water instead of hosts
moving pathogens to
new hosts
Ewald PW. 1987. Transmission modes and evolution of the parasitism-mutualism
continuum. Annals of the New York Academy of Sciences 503: 295-306.
Example 2: vector-borne pathogens
diseases
diseases
Insect vector moving
pathogens to new hosts
?
harmless <== ==> harmful
harmless <== ==> harmful
Ewald PW. 1983. Host-parasite relations, vectors, and the evolution of disease
severity. Annual Review of Ecology and Systematics 14: 465-485.
Example 3: sit & wait pathogens
Walther BA, Ewald
PW. 2004. Pathogen
survival in the
external
environment and
the evolution of
virulence.
Biological Reviews
79: 849-869.
Paul Ewald’s TED talk: “Can we domesticate germs?”
Instead of fighting fire with fire (as pathogens
become resistant to drugs, we use more drugs, so
resistance increases further, …), we can use
virulence management to create a win-win-win
situation
Through intelligent virulence management,
we
- Decrease the number of infected people
- Decrease virulence (so even people who get
sick do not get as badly sick as before)
- Reduce the use antimicrobial drugs, thereby
decreasing the evolution of antimicrobial
resistance
What’s not to like?
To test this idea, we developed an individualbased, probabilistic, cellular automata model
to simulate the effects of host mobility, host
avoidance and hygienic behaviour on the
evolution of pathogen virulence
- Individual-based: no averages, but actual
people and pathogens are simulated
- Probabilistic: opposite of deterministic,
meaning things happen with a certain
likelihood
- Cellular automata: people and pathogens
move around a realistic 2-dimensional world
Dai & Walther (In review)
We built a computer model which can model the
evolution of virulence depending on
- Host immobility (e.g., people staying at home
when sick)
- Host avoidance (e.g., people moving away from
infected people, or wearing facemasks)
- Targeted hygiene (e.g., cleaning rooms with the
sickest people)
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2-dimensional world
Movement of 1 person
(peak shows their home)
These movements are a combination of stochastic
movements constrained by realistic assumptions (return to
home at night, attraction to hotspots where people mix)
The null model was then that
- Persons and pathogens move around this
simulated world unaffected by the sickness
level of each person
- Pathogens contaminate the environment
according to the sickness level of the person
- Pathogen die in the environmental according
to logarithmic decay
Model 1: Immobility
The sicker the person,
the more immobile
they became
Virulence increases
with pathogen
durability and
population density, but
decreases (up to a
point) with host
immobility
Model 2: Avoidance
The sicker the person,
the more other hosts
avoid a sick host
Virulence increases
with pathogen
durability and
population density, but
decreases with host
avoidance
Model 3: Hygiene
The sicker the person,
the more the cell is
cleaned in which the
person resides
Virulence increases
with pathogen
durability and
population density, but
decreases with hygienic
efforts
Model 1: Immobility
Model 2: Avoidance
Model 3: Hygiene
Summary
Virulence management seems
possible, but
- increasing host immobility (=
staying at home) has little effect
because healthy hosts still come in
contact with the sick hosts
Summary
Virulence management seems
possible, but
- increasing host avoidance
(staying away from sick people,
wearing protective clothing such
as face masks) works well for nondurable pathogens, but not for
durable pathogens
Summary
Virulence management seems
possible, especially when
- increasing targeted hygiene,
meaning those environments with
the most severe cases are also
cleaned the most often
Future research
If we can fight pathogens with vaccines or
antimicrobials (e.g., antibiotics, antihelminths), then
we are happy.
However, if these do not work, virulence
management as outlined in these three results could
be a third way to decrease sickness and death,
possibly saving millions of lives.
Therefore, we need to test this idea of virulence
management in further computer simulations, but
also in animal models and real-world settings (e.g.,
to fight hospital-borne pathogens).
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Future research
Study how management of virulence can be
achieved (e.g., increasing targeted disinfection
routines in hospitals).
These pathogens cause severe infections and death in Taipei Medical University hospital:
Carbapenem-resistant Acinetobacter baumanni (CRAB)
Candida albicans
Klebsiella pneumoniae
Pseudomonas aeruginosa
Escherichia coli
Methicillin-resistant Staphylococcus (MRSA)
Coagulase-negative staphylococci
Enterobacter cloacae
Stenotrophomonas maltophilia
Proteus mirabilis
Can we stop them?
And how can we stop them?
MRSA infection
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Future research
The commonly used search-and-destroy strategy
is rather similar to our targeted hygiene strategy.
Patients are screened for dangerous pathogens
(e.g., meticillin-resistant Staphylococcus aureus
= MRSA) and, if necessary, patients considered
at increased risk of MRSA carriage are
quarantined.
Quarantine is achieved through protective
equipment, strict hand hygiene, and antibiotic
treatment of carriers (both patients and carers).
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Future research
The search-and-destroy strategy has reduced the
prevalence of MRSA in hospitals from > 10% to
< 1%.
Since MRSA is a typical sit-and-wait pathogen,
combining the targeted hygiene strategy with the
search-and-destroy strategy could further
decrease both the incidence and the virulence of
MRSA.
Monitor prevalence and virulence factors during
the implementation of these strategies.
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Future research
Study how shark skin structure can be used to
repel bacteria in hospitals.
Janine Benyus
Biomimicry
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Future research
Study how silver coating can be used to repel
bacteria in hospitals.
Advances in coatings technology has enabled
medical equipment producers to introduce silvercoated instruments and hospital equipment for
use in treating patients — eliminating, on
contact, almost every bacterial or fungal
exposure.
A silver-coated antimicrobial dressing kills
antibiotic-resistant “superbugs.”
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