Evolution of Pathogen Virulence

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 1

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 4

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 6

Strain Competition

Important Ecological Generality

Cross-Reactive Immunity Example of Pre-emptive Competition

Two Species (Strains), Same Niche (Allstadt et al. 2009) 7

Strain Competition

Important Ecological Generality

Coinfection: Example of Scramble Competition = Exploitative Competition Two Species Interact Indirectly Through Exploitation of Same Limiting Resource From quizlet.com 8

Strain Competition

Important Ecological Generality

Superinfection: Example of Interference Competition Two Species Interact Directly Aggressive Exploitation of Same Limiting Resource

quizlet.com 9

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 10

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 11

Cross-reactive Immunity

One Strain per Infected Host Individual Strain Competition: Between-Host Scale Only

Ecology: Preemptive Competition 12

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 Niche

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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 > 0 14

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 Density 15

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? 16

Natural Selection: Optimize  b Per-capitum Birth  Transmission Rate (Mass Action)

 Non-Disease Mortality (All) ( + ) Infective Mortality

: Virulence > 0 No Recovery from Infection 17

Dynamics of Epidemic 𝑑𝑆𝑡

𝑑𝑡

𝑑𝐼𝑡

= 𝑏 𝑆𝑡 + 𝐼𝑡 − 𝛽 𝑆𝑡 𝐼𝑡 − 𝜇 𝑆𝑡 = 𝛽 𝑆 𝐼 − 𝜇 + 𝛼 𝐼 𝑡 𝑡 𝑡 𝑑𝑡

Birth, Infection Transmission, Death 18

Analysis

𝑅0 : 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 = 𝛽 𝑆𝑟𝑒𝑠 Transmission Duration: Time = 𝜇 + 𝛼 −1 Transmission Ends at Host Death 𝑅0 =

𝛽 𝑆𝑟𝑒𝑠

𝜇+ 𝛼

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𝑅0 (𝑀𝑢𝑡𝑎𝑛𝑡, 𝑅𝑒𝑠𝑖𝑑𝑒𝑛𝑡) =

Mutant Invades: 𝑆𝑟𝑒𝑠 >

𝛽𝑚 𝑆𝑟𝑒𝑠

𝜇+ 𝛼𝑚

𝜇 + 𝛼𝑚

𝛽𝑚

Recall: 𝜕𝛼 𝜕𝛽 > 0 among strains Note:

𝜕𝑅0 𝜕𝜇

< 0; Background Mortality & Virulence

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Natural Selection: Optimize     R0    S      Endem icEquilibrium, R  *   1 Rare Invader ;

Advances if R0  ,  *   1

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Natural Selection: Optimize 

   R0  ,    S  *       *

 Sets Susceptible Density for Invader *

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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 27

Host-Pathogen Dynamics S(t) Susceptible Density I(t) Infectious Density P(t) Free-living Stage (Virions, Spores) r Host Reproduction c Host Self-Regulation  Transmission (Adsorption)  Mortality; Includes Virulence 𝜃= 𝜇+ 𝜈  FLP Shed Rate  FLP Burst Size  FLP Decay Rate: Focus 28

Host-Pathogen Dynamics Equilibria Endemic Equilibrium (Extinction Unstable) Disease Free: (𝑟 𝑐 , 0, 0)

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Local Stability: FLP Persistence = 1

𝜉

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ESS Virulence: Pathogen Strain Competition

Preemptive Competition: ESS Minimizes S* Positive Equilibrium Density of Susceptibles

Traits: Functionally Dependent Altering 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: 𝜕𝜈 𝜕𝜉 < 0 Functional Constraint: 𝜈 𝜉 = 𝑏𝜈 𝜉 − 𝜎 ; 𝑏𝜈 , 𝜎 > 0

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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 𝑆 ∗ =

𝜉

𝛼𝛽

= 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 𝑆 ∗ = 𝜉 𝜇 + 𝜈 𝜉

𝛼𝛾

For 𝜎 < 1: Strain Competition Reduces Decay Rate Virulent and Persistent For 𝜎 > 1: Competition Favors Intermediate Virulence 𝜈 ^ = 𝜇 𝑏𝜈 𝜎 − 1 −1 ; Curse Broken 35

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 37

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 40

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 43

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 44

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 45

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 46

Mean-Field Results

Pairwise Invasion Homogeneous Mixing

Evolution to Criticality Coexistence: Niche Difference

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Mean-Field Results

Pairwise Invasion Homogeneous Mixing

Coexistence: Niche Difference CompetitionColonization Trade-Off 48

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 50

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 53

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 54

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 55

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? 56

Contemporary Questions Within-Host Dynamics Parasite, Specific Immune Cell Densities Affects Between-Host Transmission Population Dynamics Host-Pathogen Coevolution Transmission Resistance, Tolerance Virulence, Optimal Immune Response

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