pathogen virulence: evolutionary ecology outline: 29 jan 15 functionally dependent life-history...

Pathogen Virulence: Evolutionary ecology

Outline: 29 Jan 15

• Functionally Dependent Life-History Traits:

Virulence Important Example

• Pathogen Traits Evolve via Strain Competition

• Spatially Structured Transmission

Dispersal Limitation Reduces Virulence

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Virulence

Property of Host-Parasite Interaction

Parasite Generation Time Much Shorter

Virulence: Parasite’s “Strategy” for Exploiting Host

Virulence Evolution Affects Correlated Demographic Traits

Functional Dependence = Pleiotropic Interaction

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Increased Parasite Virulence

Faster Consumption of Host Resources

(1) Pathogen Reproductive Rate Increases

(2a) Host’s Mortality Rate Increases

or

(2b) Rate of Clearance by Immune System Increases

or

(2c) Host Reproduction Decreases

3

Virulence Trade-Off

Antagonistic Pleiotropy

Pathogen Increases Propagule Production (Hence, Infection Transmission) Rate

Duration of Infectious Period Decreases

Evidence Reviewed

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How Does Virulence Evolve?

Pathogen-Stain Competition

2 Phenotypes Differ in Virulence (Resident, Mutant)

Compete Between (and) Within Hosts

3 Modes of Strain Competition

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Pathogen-Strain Competition

1. Cross-Reactive Immunity

Competition Strictly Between-Host Scale

Flu strains

2. Coinfection: Two Strains Exploit Same Host Individual

Compete Both Within & Between-Host

3. Superinfection: More Virulent Strain Excludes Other

Compete Both Within & Between-Host

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Strain Competition

Important Ecological Generality

Cross-Reactive Immunity

Example of

Pre-emptive Competition

Two Species (Strains),

Same Niche

(Allstadt et al. 2009)

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Strain Competition

Important Ecological Generality

Coinfection: Example of

Scramble Competition =

Exploitative Competition

Two Species Interact Indirectly Through Exploitation of Same Limiting Resource

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From quizlet.com

Strain Competition

Important Ecological Generality

Superinfection: Example of

Interference Competition

Two Species Interact Directly Aggressive Exploitation ofSame Limiting Resource

9

quizlet.com

Strain Competition:Adaptive Dynamics

Host-Pathogen Dynamics

Exert Selection Pressure on Competing Strains

Mutant-Resident Competition

Competitive Exclusion; Alter Parameters of Dynamics

Evolutionarily Stable Strategy (ESS) Resists Invasion

Adaptive Dynamics: Interplay of Ecology, Evolution

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Strain Competition:Adaptive Dynamics

“Solve” Strain Competition for a Preemptive Case

General: ESS Virulence Graphically

Virulence Evolution in a Second Preemptive Case

Pathogen with Free-Living Stage

e.g., Bacteriophage

Superinfection, Vary Pathogen Dispersal Distance

Impact on ESS Virulence

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Cross-reactive Immunity

One Strain per Infected Host Individual

Strain Competition: Between-Host Scale Only

Ecology: Preemptive Competition

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Host Preemption

Assume Homogeneous Mixing Host Population

“Optimally Virulent” Strain, Max R0

Equivalently

Minimizes Equilibrium Density Susceptible Hosts

No Strain Coexistence (Pure ESS)

Recall: Same Niche13

Host Preemption

Homogeneous Mixing, No Recovery

Transmission-Infectious Period Trade-off

() Transmission Efficiency, Direct Contact

() Virulence, Extra Infected-Host Mortality

Host Exploitation Strategy: d/d > 014

Natural Selection: Optimize

Invasion Dynamics (Conceptual Core)

Can Rare Mutant Invade Resident * at ecological (dynamic) equilibrium?

This case: ESS does Max R0( )

: Background Host Mortality

S: Susceptible Density15

Natural Selection: Optimize

SI Transmission

Plus Host Birth, Death

Resident Pathogen’s Dynamics Sets Resource Availability (Susceptible Density) for Mutant Strain of Pathogen

Can Mutant find enough hosts to grow when rare?

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Natural Selection: Optimize

b Per-capitum Birth

b Transmission Rate (Mass Action)

Non-Disease Mortality (All)

( + ) Infective Mortality

: Virulence > 0

No Recovery from Infection

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Dynamics of Epidemic

=

𝑑 𝐼 𝑡𝑑𝑡

=𝛽𝑆𝑡 𝐼 𝑡− (𝜇+𝛼 ) 𝐼 𝑡

Birth, Infection Transmission, Death

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Analysis

: New Cases/Case When Invading Pathogen Rare

Epidemiology: Invade All-Susceptible Population

Evolutionary Ecology: Invade Host-Resident Strain at Endemic Equilibrium

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Natural Selection: Optimize

Transmission Rate: Infections/Time =

Transmission Duration: Time =

Transmission Ends at Host Death

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𝑅0(𝑀𝑢𝑡𝑎𝑛𝑡 ,𝑅𝑒𝑠𝑖𝑑𝑒𝑛𝑡)=𝛽𝑚𝑆𝑟𝑒𝑠

(𝜇+𝛼𝑚)

Mutant Invades:

Recall: among strains

Note: ; Background Mortality & Virulence

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Natural Selection: Optimize

1,;

1,

*0

*

0

RifAdvancesInvaderRare

RmEquilibriuEndemic

SR

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Natural Selection: Optimize

InvaderforDensityeSusceptiblSets

SR

*

**0 ,

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Natural Selection: Optimize von Baalen & Sabelis (1995, Am Nat)

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Natural Selection: Optimize

1. ESS Virulence Maximizes R0 (for any Susceptible Density)

2. ESS Virulence Minimizes Susceptible Density

Too Few Susceptible Hosts for Mutant Invasion

3. Greater Background Mortality Greater Virulence

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Natural Selection: Optimize

4. ESS May Exhibit Intermediate Virulence

Under Host Preemption; Natural Diversity

5. No Strain-Coexistence Possible

Under Well-mixed, Preemptive Competition

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Preemptive Host Competition

Pathogen with Free-Living Stage

Life History:

Alternates Intra-Host Environment, External Environment

Bacteria/Viruses, Including Bacteriophage

“Curse of the pharaoh”

Persistent free-living stage costly; Requires conversion of large amount of host resources; Pathogens with persistent free-living stage likely virulent

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Host-Pathogen Dynamics

S(t) Susceptible Density

I(t) Infectious Density

P(t) Free-living Stage

(Virions, Spores)r Host Reproduction

c Host Self-Regulationa Transmission (Adsorption)q Mortality; Includes Virulence

g FLP Shed Rateb FLP Burst Size

FLP Decay Rate: Focus

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Host-Pathogen Dynamics

Equilibria

Endemic Equilibrium

(Extinction Unstable)

Disease Free: ()

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Local Stability: FLP Persistence =

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ESS Virulence: Pathogen Strain Competition

Preemptive Competition: ESS Minimizes S*

Positive Equilibrium Density of Susceptibles

Traits: Functionally DependentAltering Virulence: Antagonistic Pleiotropy

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ESS Virulence: Pathogen Strain Competition

Curse of the Pharaoh: Increased persistence of FLP

(reduced ) demands more host resources,

and virulence () increases.

Equivalently:

Functional Constraint: ;

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Functional Constraint: Virulence(Decay Rate)

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Minimize S*

Suppose Shed Rate = 0; Burst Size > 0

Lytic Virus, Bacteriophage

Then = Decay/(Adsorption x Burst size)

ESS Reduces and Increases Virulence

Virulent and Persistent

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Minimize S*

Suppose Shed Rate > 0; Burst Size = 0

Animal Virus; Bacterial, Fungal Infection

Then

For : Strain Competition Reduces Decay Rate

Virulent and Persistent

For : Competition Favors Intermediate Virulence

; Curse Broken

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Shed Rate > 0 and Burst Size > 0

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Preemptive Host Competition

Strain Minimizing Equilibrium Density of Susceptibles Should be ESS

No Coexistence of Different Levels of Virulence

(Not True for Coinfection and Superinfection)

Curse of the Pharaoh Oversimplifies

Strain Competition

Caraco annd Wang (2008) J Theor Biol 250:569-579

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Homogeneous Mixing Host Population

Assumed in Dynamics

Full Mixing: Hosts Highly Mobile over Timescale of Expected Lifespan

Might Preclude Terrestrial Plants, Territorial Animals, etc.: “Viscous Populations”

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Contact Structure, Van Baalen (2000)

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Pathogen: Dispersal Limitation

Contact Structures: Constrain Opportunities for Pathogen to Generate New Infections

Ecology: Dispersal Limitation, Neighborhood Interactions

Ecological Implications:

Epidemic Invasion, Endemic Infection Levels

Evolutionary Implications:

(Including) Virulence

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Pathogen: Dispersal Limitation

Contact Structure: (L x L) Lattice

Each Site: One of 4 Elementary States

Local Neighborhood: All Ecological Interactions

• Opportunities for Host Reproduction (Open Sites)• Sources of Infection

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SPATIAL SUPERINFECTION

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SPATIAL SUPERINFECTION

Virulent Can Displace “Avirulent” Strain

Interference Competition

Discrete-Time Dynamics

Transmission (Virulence); No Recovery

Key: Superinfection (Virulence Difference)

Within & Between-Host Competition

Neighborhood Size: 8, 48

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Develop Concepts

1. Mean-Field Analysis: Homogeneous Mixing

2. Pair Approximation: Local Correlation

3. Simulate Full Stochastic Spatial Model:

Large-Scale Correlated Fluctuations,

Strong Clustering Possible

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Develop Theory: Deduce Predictions

Pairwise Invasion Analyses: Adaptive Dynamics

Resident Strain at Ecological Equilibrium

Can Invading Strain (Mutant) Advance?

Assumed Time Scales

Convergence Stability; Evolutionary Stability

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SPATIAL SUPERINFECTION

Dynamics: Local Transition Probabilities

Stochastic Spatial Model

How do local interactions produce ensemble effects (population, community scales)?

Model/Theory: Caraco et al. (2006)

Theoretical Population Biology 69:367-384

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Mean-Field Results

Pairwise InvasionHomogeneous Mixing

Evolution to

Criticality

Coexistence:

Niche Difference

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Mean-Field Results

Pairwise InvasionHomogeneous Mixing

Coexistence:

Niche Difference

Competition-Colonization

Trade-Off

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Spatial Model Results

Increased Virulence

Decreased Infection

Increased Clustering

Pair Correlation Model OK

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Adaptive dynamics spatial process

Pair Approximation

Convergent Stable

Evolutionarily Stable

(Local ESS)

Virulence Constrained

By Contact Structure

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Adaptive dynamics spatial process

Simulation

Max Virulence Lower

Local ESS Reduced

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Adaptive dynamics spatial process

Weaker Competitive Asymmetry Via

Superinfection

Reduce ESS

Reduce Coexistence

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predict

1. Spatial Structure Constrains Maximal Virulence

Capable of Dynamic Persistence, Through

Extinction of Highly Virulent Strains

2. Spatial Structure Reduces Evolutionarily Stable

Level of Virulence

3. Larger Neighborhood Relaxes Constraint,

Dynamic Penalty of Clustering Attenuated

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predict

4. Spatial Structure Promotes Coexistence:

Extended Transmission/Low Virulence,

Poor Interference Competitor/Good Colonizer

and

Attenuated Transmission/High Virulence,

Advantage of Superinfection/Poor Colonizer

5. Coexistence Increases with Neighborhood Size

6. Comp. Asymmetry Increases Coexistence

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Contemporary Questions

Virulence in Pathogens with Both Contact and Environmental Transmission

Avian Flu: Contacts; Virus Persists In Drinking Water

Hyperparasites & Hypovirulence

Vertical Transmission

Sterilizing vs Killing Pathogens

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Contemporary Questions

Vector-Borne More Virulent Than Direct Contact (?)

FLP: “Curse of the Pharaoh”

Conditions for More Virulence

Infective Dose: Remarkable Variation

Ecological Consequences

Strain Competition?

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Contemporary Questions

Within-Host DynamicsParasite, Specific Immune Cell DensitiesAffects Between-Host TransmissionPopulation Dynamics

Host-Pathogen CoevolutionTransmission Resistance, ToleranceVirulence, Optimal Immune Response

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