R 0 o R N o t ? HUD DOB Grouse Maasai Wolf Rats Tenrec Rats Tenrec Sheep Mouse 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! “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! 4

Parasite Free Living Stages Host DeathsBirths   1. Killer Experiments : Needs an Experimental test E C E EE E E E C C C C C C C E Hudson et al J.Anim Ecol 2 Step 1 Step 3 Do parasites reduce fecundity? 5

Underlying Rock Rainfall Peat Depth Predation Viral Pathogens Social Behavior Ticks Hares Deer & Sheep AggressionRelatedness Host Density Raptors Corvids Foxes Grazing Unstable Dynamics Stable Dynamics Sunshine Cover Survival Fecundity Dispersal Food Quality Parasite Hudson et al 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) 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 hosts So depauperate communities more likely to transmit 1. The Dilution Hypothesis: In desperate need of Experimental tests Borrelia Ixodes vectors Density of Competent Host Density of Non Competent Hos t Norman et al 1999 C NC 6

Biodiversity reduces risk of exposure to zoonotic infections Generalized: The Competent Hosts are The Resilient hosts So depauperate communities more likely to transmit 1. The Dilution Hypothesis: In desperate need of Experimental tests Borrelia Ixodes vectors 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:ImmunoModulated Transmission Dynamics Pandemic CommunityInteraction Julius Jauregg Within Host Models Between Host Models 9

T. retortaeformis Bordetella bronchiseptica Myxoma Virus RHD Virus Graphidium strigosum Trichostrongylus retortaeformis Passalurus ambiguous Mosgovoyla pectinata Cittotaenia denticulata Month intensity M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M2 M3 M4 M5 M6 M7 M8 M9 M10 M3 2. Multiscale Issues: Coinfection, heterogeneity and transmission Rabbits 10

Single Parasite Immune Pathway Models (Note: Chronic Infections) Thakar et al 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 PLOS Comp Biol Co-infection Immune Pathway Model – No Direct The Co-infection Hypothesis: Prevalence changes with coinfection Common Cytokines LungSmall Intestine 12

[][] Knock out node experiments ~ Parasite activity from simulations -= Key nodes for persistence Bordetella Worm + Bordetella Bordetella+ 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, Ticks 2.Toxic to some genotypes 3.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: R 0: Whence the Alternative Hypotheses: Persistence R 0 ~ initial spread, likelihood of epidemic, vaccination proportion BUT Selection does not always maximize R 0 : e.g. Superinfection NEED to test other hypotheses & Models – Persistence R 0 ~ initial spread, likelihood of epidemic, vaccination proportion BUT Selection does not always maximize R 0 : e.g. Superinfection NEED to test other hypotheses & Models – Persistence R 0 = Transmission* Infectious Period (1/mortality) R 0 with High transmission * Low infectious period = Low Transmission * High infectious period But Different dynamics & Persistence likelihood R 0 = Transmission* Infectious Period (1/mortality) R 0 with High transmission * Low infectious period = Low Transmission * High infectious period But Different dynamics & Persistence likelihood Grenfell 2002 Epidemic Fadeout 16

Trichostrongylus life cycle M1M1 b Parasite Free Living Stages Host DeathsBirths   Dobson & Hudson Model M2M2 T a γ μ Threshold Host Density ~ Persistence H T = M 1 γ β(λ-M 1 ) Critical Community Size Host Replenishment Threshold Host Density ~ Persistence H T = M 1 γ β(λ-M 1 ) Critical Community Size Host Replenishment Simple, Direct, Monoxenic Life Cylce 3: R 0, Dynamics & Persistence: The Alternative Hypotheses Epidemic Fadeout 17

R0R0 Free living larvae life expectancy No Arrested Development Arrested Development 3. Persistence Mechanisms: Arrested Development = Hypobiosis b Parasite Free Living Stages Host DeathsBirths   Dobson & Hudson Model M2M2 T a γ μ AD 18

1. Macroparasite Complex Life Cycles: Heteroxenic Opisthorcis life cycle M1M1 M2M2 M3M3 T1T1 T2T2 T3T3 Dobson, Hudson & Lyles 1992 Geoff Parker : Complex life cycle evolved to increase R 0. Reduced larval mortality & increased adult body size leads to high fecundity ~ Complex Life Cycles ~ Indirect ~ Heteroxenic 19

Key Point 3: Maximizing R 0 is but one Hypothesis.. Alternative: Persistence Persistence Mechanisms in Neuro infections 20

Point 1: Need for Experiments Point 2: Coinfections generate heterogeneities Point 3: R 0 is but one hypothesis ~ Persistence

4. What happens After Disease Invasion? … Bighorn Sheep Mycoplasma ovipneumoniae [= M.ovi] Wild LambExperimental Infection 21

Cassirer et al What happens After Disease Invasion? Host or Pathogen? 22

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