Can virulence management work? Using evolutionary principles to lower the virulence of

pathogens

Bruno A. WaltherMaster Program in Global Health and Development

College of Public Health and NutritionTaipei 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

Grooming

Resting

Avoiding contamination

Virulence = increased reproduction of pathogens within host cells = increased use of host resources = increased morbidity/mortalityBenefit: increasing virulence means more offspring leaving the host to be transmitted to new hostsCost: increasing virulence means the host infects less new hosts because of decreased host mobility and increased host avoidance

B & C

Optimal virulence

Virulence

Benefit cost tradeoff

Different benefit and cost curves lead to the evolution of a different level of optimal virulence

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

Benefit cost tradeoffB & C

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

?

Ewald PW. 1983. Host-parasite relations, vectors, and the evolution of disease severity. Annual Review of Ecology and Systematics 14: 465-485.

Insect vector moving pathogens to new hosts

diseases diseases

harmless <== ==> harmful harmless <== ==> harmful

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 individual-based, 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

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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Dai & Walther (In review)

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 non-durable 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

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).

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These pathogens cause severe infections and death in Taipei Medical University hospital:

Carbapenem-resistant Acinetobacter baumanni (CRAB)Candida albicansKlebsiella pneumoniaePseudomonas aeruginosaEscherichia coliMethicillin-resistant Staphylococcus (MRSA) Coagulase-negative staphylococciEnterobacter cloacaeStenotrophomonas maltophiliaProteus mirabilis

Can we stop them? And how can we stop them?

MRSA infection

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.

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Future research

Janine BenyusBiomimicry

Study how silver coating can be used to repel bacteria in hospitals.

Advances in coatings technology has enabled medical equipment producers to introduce silver-coated 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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Future research