Whither Disease EcologyMulti-host, Multi Parasite in Wildlife3 Points to think about Ecology & Disease

R0 oR Not ?

HUD DOB

Grouse

MaasaiWolf

RatsTenrec

SheepMouse

Peter Hudson, Kezia Manlove, Emily Almberg, Paul Cross, Francis Cassirer, …..and of course: Andy Dobson

Discussion: Isabella Cattadori & Jamie Lloyd Smith Deep Thanks to: RAPIDD, NIH, NSF, MAF,

Key Point 1: Vaccinating with Lemons:Save America Eat More Citrus Fruit ………

3

1: Spurious Correlations : The Need for a Killer Experiment

“If we Import 4,500 Tons of Lemons per annum we could eradicate all Highway Fatalities!”

Only 24.8 million Lemons = 0.1 lemons per person!Spurious correlations do not prove cause & effect why should models?

4

Parasite

Free LivingStages

Host Deaths

Births

19871988198919901991199219931994199519961997

1

10

100

1000

10000

19871988198919901991199219931994199519961997

1

10

100

1000

10000

1. Killer Experiments : Needs an Experimental test

200 500 800 3000 6000 10000

Worms

0

2

4

6

8

10

Brood

siz

e

E

C

E

E E

E

EE

C

CC C

CC

C

E

Hudson et al. 1992 J.Anim Ecol

0 5 10 15 2010

100

1000

10000

Years

Nu

mb

ers

2

Step 1

Step 3

0

2

4

6

8

10

1000 10000

Worms

Broo

d si

ze

Do parasites reduce fecundity?

5

Underlying RockRainfall

Peat Depth

Predation

Viral Pathogens

Social Behavior

Ticks

Hares

Deer & Sheep

Aggression Relatedness

Host Density

Raptors

Corvids

Foxes

Grazing

Unstable Dynamics

Stable Dynamics

Sunshine

Cover

Survival

Fecundity

Dispersal

Food Quality

Parasite

Hudson et al. 2002 Phil Trans Roy Soc

Community Impact

1. Parasites embedded in the Community System

12

Biodiversity reduces risk of exposure to zoonotic infections~ Non competent hosts are a sink to infection (wasted bites)

Generalized: The Competent Hosts are The Resilient hostsSo depauperate communities more likely to transmit

1. The Dilution Hypothesis: In desperate need of Experimental tests

Borrelia

Ixodes vectors

Density of Competent Host Den

sity

of N

on C

ompe

tent

Hos

t

Norman et al 1999

C

NC

NC

NC NC

NC

6

Biodiversity reduces risk of exposure to zoonotic infections

Generalized: The Competent Hosts are The Resilient hostsSo depauperate communities more likely to transmit

1. The Dilution Hypothesis: In desperate need of Experimental tests

Borrelia

Ixodes vectors

Experimental manipulation?

1. Predictions: Norman model 2. Experimentally Remove competent3. Negative Control: Remove non

competent – Chipmunk

7

Key Point 1: Neither correlations or models provide proof …. We need perturbation experiments to reveal mechanisms……

8

2. Multiscale Issues: Coinfection, heterogeneity and transmission

Protein

Indirect-Comp:Immuno

Modulated

Transmission

Dynamics

Pandemic

CommunityInteraction

Julius Jauregg 1857-1940

Hypothesis: Coinfections generate transmission heterogeneities

Within HostModels

Between HostModels

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0 50 100 150 200 250

010

00

020

00

030

00

040

00

0

1977 2013

T. retortaeformis

Bordetella bronchiseptica

Myxoma Virus

RHD Virus

Graphidium strigosum

Trichostrongylus retortaeformis

Passalurus ambiguous

Mosgovoyla pectinata

Cittotaenia denticulata

Month

inte

nsity

2 4 6 8 10 12 14 16 18

01

23

45

67

89

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M2M3M4M5M6M7M8M9M10

M3

2. Multiscale Issues: Coinfection, heterogeneity and transmission

Rabbits

10

Single Parasite Immune Pathway Models(Note: Chronic Infections)

Thakar et al. 2012 Plos Comp Biol

Bordetella bronchiseptica Trichsotrongylus retortaeformis

2. Multiscale Issues: Coinfection, heterogeneity and transmission

Compartment I = Local Response Compartment II = Systemic Response 11

Thakar et al. 2012 PLOS Comp Biol

Co-infection Immune Pathway Model – No Direct

The Co-infection Hypothesis: Prevalence changes with coinfection

Common Cytokines

Lung Small Intestine

12

[ ]Knock out node experiments ~ Parasite activity from simulations -= Key nodes for persistence

Bordetella

Worm +Bordetella

Bordetella+Worm

Worm

IL12 II stimulates Th1 response is necessary for bacteria clearance IL10 ..stimulated subversely by bacteria as a regulatory cytokine

[ ]13

Broad Spectrum Systemic Anthlemintic:1. Kills Helminths, Mites, Bed bugs,

Lice, Ticks2. Toxic to some genotypes3. Stimulates immune response

Bordetella bronchiseptica

Myxoma Virus

RHD Virus

Graphidium strigosum

Trichostrongylus retortaeformis

Passalurus ambiguous

Mosgovoyla pectinata

Cittotaenia denticulata

14

Key Point 2: Coinfections introduce important transmission heterogeneities? How & When?

3: R0: Whence the Alternative Hypotheses: Persistence

R0 ~ initial spread, likelihood of epidemic, vaccination proportion BUT Selection does not always maximize R0: e.g. Superinfection NEED to test other hypotheses & Models – Persistence

R0 = Transmission* Infectious Period (1/mortality) R0 with High transmission * Low infectious period

= Low Transmission * High infectious period But Different dynamics & Persistence likelihood

Grenfell 2002

Epidemic Fadeout

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Trichostrongylus life cycle

M1

b

Parasite

Free LivingStages

HostDeaths

Births

Dobson & Hudson Model

M2

T

a

γ

μThreshold Host Density ~ Persistence

HT = M1 γ β(λ-M1)

Critical Community Size

Host Replenishment

R0= βλH . (α+b+μP) (γ+βH)

R0= T 1

M1M2

Simple, Direct, Monoxenic Life Cylce

3: R0 , Dynamics & Persistence: The Alternative Hypotheses

Epidemic Fadeout

17

R0

Free living larvae life expectancy

No Arrested Development

Arrested Development

3. Persistence Mechanisms: Arrested Development = Hypobiosis

b

Parasite

Free LivingStages

HostDeaths

Births

Dobson & Hudson Model

M2

T

a

γ

μ

AD

18

1. Macroparasite Complex Life Cycles: Heteroxenic

Opisthorcis life cycle

R0= T1 T2 T3 1

M1M2 M3

HT= lower

M1M2

M3

T1

T2

T3

Dobson, Hudson & Lyles 1992

Geoff Parker : Complex life cycle evolved to increase R0. Reduced larval mortality & increased adult body size leads to high fecundity

~ Complex Life Cycles ~ Indirect ~ Heteroxenic

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Chicken Pox ~ Shingles

Rabies ~ Multiple Host Species?

Key Point 3: Maximizing R0 is but one Hypothesis.. Alternative: Persistence

Persistence Mechanisms in Neuro infections

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Point 1: Need for Experiments Point 2: Coinfections generate heterogeneitiesPoint 3: R0 is but one hypothesis ~ Persistence

4. What happens After Disease Invasion? … Bighorn Sheep

Mycoplasma ovipneumoniae [= M.ovi]

Wild Lamb Experimental Infection

2121

Cassirer et al . 201337

4. What happens After Disease Invasion? Host or Pathogen?

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Keypoint 4: Alternative hypotheses: Pathogen evolution:Host selection ~ those with long infectious periods

~ but not humans

4. What happens After Invasion? … Pathogen or Host Selection ?

Phocine Distemper Virus Rabbit Hemorrhagic Virus Mycoplasma in Bighorns