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coccidiosis

coccidiosis

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01/06/2013

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Immuno-epidemiology of coccidiosis

Don Klinkenberg Maite Severins Hans Heesterbeek

Coccidiosis
• Caused by Eimeria spp • Protozoan • Intestinal infection
– sometimes lesions – main problem: production loss

• Seven species in chickens
– location in the intestine – no cross-immunity

Parasite classification
• After lecture notes by Kretschmar (micro/macro):

Microparasite Parasite lifespan Reproduction within host Transmission Infection events Immunity Model type Short Rapid Direct One Complete SIR type

Macroparasite Long None Indirect Multiple Partial, slowly acquired Parasite load

Eimeria Short Rapid (but dose effect) Indirect Multiple Accumulative, slowly acquired ???

Essential characteristics
• Transmission through environment • Dose-dependent infectivity • Slowly acquired immune response
– stronger upon re-infection – reduces parasite excretion

• Within-host dynamics!

This presentation
• Model of within-host dynamics
– relation between uptake and excretion of infectious material (oocysts) – interaction with immune system

• Model of between-host dynamics (I)
– coupling excretion and uptake of oocysts – interaction chickens and environment

• Model of between-host dynamics (II)

Within-host model
• Eimeria characteristics:
– transmission through oocysts – Eimeria parasitises gut epithelial cells – limited number of asexual generations

Eimeria cycle
Oocyst uptake (W)
Sporozoites

Oocyst excretion (Z)

Schizont I (X(1) )
Gamont Merozoites II (u(2) ) Merozoites I (u(1) )

Schizont II (X(2) )

Eimeria cycle
Oocyst uptake (W)

Oocyst excretion (Z) Schizont I (X(1) )

Schizont II (X(2) )

Eimeria cycle
Oocyst uptake (W)

Schizont I (X(1) )

X X

( 1)

t +1 t +1

= a1Wt = λ1 X
( 2) ( 1)
t t

( 2)

Schizont II (X(2) )

Z t + 2 = λ2 X

Oocyst excretion (Z)

Adding immunity
• • • • Primarily T cell immunity Immunity evoked by schizonts Immunity inhibits schizont development Keeping the model simple: one immunity variable Y

Eimeria cycle with immunity
Oocyst uptake (W)

Oocyst excretion (Z)

Immunity (Y)

+ –

Schizont I (X(1) )

– +
Schizont II (X(2) )

Eimeria cycle with immunity
Oocyst uptake (W)

X X
+ +

( 1)

t +1 t +1

= a1Wt = λ1 X
( 2) ( 1)
t t

( 2)

Schizont I (X(1) )


Schizont II (X(2) )

Z t + 2 = λ2 X

Immunity (Y)


Oocyst excretion (Z)

Eimeria cycle with immunity
Oocyst uptake (W)

X X
+ +

( 1)

t +1 t +1

= a1Wt = λ1 X
( 2) ( 1)
t t

( 2)

Schizont I (X(1) )


Schizont II (X(2) )

Z t + 2 = λ2 X

f ( Yt )
t

f ( Yt )

Immunity (Y)


Oocyst excretion (Z)

Yt +1 = g Yt , X

(

( 1)

+X

( 2)

t

)

Eimeria cycle with immunity
X ( 1) t +1 = a1Wt X ( 2 ) t +1 = λ1 X ( 1) t f ( Yt )

Z t + 2 = λ2 X ( 2 ) t f ( Yt )

Yt +1 = g Yt , X ( 1) t + X ( 2 ) t

(

)

1 f (Y ) = m 1+ Y ( 1) ( 2) ( 1) ( 2) g Y , X + X = αY + ( β + γY ) X + X

(

)

(

)

Model summary
• Discrete time • Two asexual schizont generations • T cell immunity against schizont development

Model analysis
• Compare model experiments to data
– relation single dose and excretion
• saturation followed by decrease

– excretion during trickle infections
• excretion terminates after some time

– immunising effect of trickle and single immunisation
• trickle immunisation gives better protection

Single dose and excretion
Log(oocyst excretion)
8 7.5 7 6.5 6 5.5 5 0 2 4 6
E. tenella

Log(oocyst uptake)

Model analysis
• Model experiments
– single dose and excretion
• relation between W0 and Z4

– trickle infections – trickle vs single immunisation

Analysis: single dose
7.5
logz 4
l1 l2

6.5

5.5

a1λ1λ2W0 Z4 = ( 1 a1W m 1 +=pβ+logw00) l 1: logz 4
l 2: logz 4=p 1+(1-m )logw 0-mp 2

4.5 0 2 4 6 logw 0

Analysis: single dose
8 6 4 2 4 6 8
E. tenella

Analysis: single dose
8 6 4 2 4 6 8
E. acervulina

Analysis: single dose
8 6 4 2 4 6 8
E. maxima

Model analysis
• Model experiments
– single dose and excretion
• relation between W0 and Z4 • β > 0 (naïve immunity growth) • m ≠ 1 (non-linear immune effectiveness)

– trickle infections & immunisation
• conclusions on γ and α

Conclusions within-host model
• Simple model of parasite input-output behaviour • Single immunity variable can explain experimental data • Solid basis for studying re-infection and between-host transmission

Between-host model
• Relate excretion to uptake with oocyst level in environment V • Simplifying assumption: average chicken

Eimeria cycle
Oocyst uptake (W)

Oocyst excretion (Z)

Immunity (Y)

+ –

Schizont I (X(1) )

– +
Schizont II (X(2) )

Eimeria cycle
outside the chickens Environmental oocysts (V)
×1 × a0

Oocyst excretion (Z)
×1

Oocyst uptake (W)
× a1

Immunity (Y) Gamont (G)
× λ

+ –
× λ

Schizont I (X(1) )


2

+
Schizont II (X )
(2 )

1

inside the chickens

Two new parameters
• Per time step of ca. 2 days • Uptake rate a0
– estimate from a single experiment: 0.01

• Oocyst degradation rate
– estimate from couple of articles: 0.5

Interesting variables
• Oocyst level in environment
– decrease due to degradation (+ uptake) – increase due to excretion

• Immunity level in average chicken
– increase due to presence of schizonts – decrease by fixed rate

• Number of infected cells as measure of damage
– numbers of schizonts and gamonts

Basic dynamics

outside the chickens

Environmental oocysts (V)
×1

5
× a0

Oocyst excretion (Z)

4

5
× a1

0 1

Oocyst uptake (W)

Gamont (G)
× λ

3

×1

Immunity (Y)

2
+ –
× λ


2

+

3 2
(2 )

Schizont I (X(1) )

Schizont II (X )

1

inside the chickens

Dynamics in single chicken cohort
• First dose of each infection generation most important
– major change compared to previous dose – fast decay of oocysts in environment

• Dynamics can be described in terms of infection generations

Damage in single chicken cohort
• Cumulative damage ≈ maximum damage
11 10 9 8 7 6 5 4  7.5  5  2.5
logdmax

logv0

2.5

5

7.5

10

Conclusion on damage
• Production damage is reflected by the maximum number of infected cells • Damage may take local minimum with intermediate oocyst level V0 • Mechanism
– maximum damage if a single infection generation dominates – minimum when generation dominance switches

Damage in single chicken cohort
• Cumulative damage ≈ maximum damage
11 10 9 8 37 6 5 4  2.5
logdmax

4

2

1
schizonts II gamonts 0 logv

 7.5

 5

2.5

5

7.5

10

Cleaning after each chicken cohort
• Minimizing damage requires optimal cleaning of the shed. • What happens if a proportion ρ of all oocysts are removed after each cohort? • Study relation between logv0 and logvend

Final oocyst level
8 6 4 2

logvend

logv0
 7.5  5  2.5  2 2.5 5 7.5 10

Removal of proportion 1 − ρ
0 -2

-3

logρ

Minimum damage Maximum damage

3 2 1

log ρ 8

 6

 4

 2

 1  2

logv0

 3  4

Conclusion on cleaning
• Removal of a proportion 1 − ρ of oocysts after each chicken cohort cannot minimize damage • Minimizing damage may be done by maximal removal + adding oocysts

Discussion of the model
• Single ‘average’ chicken • Deterministic model • No spatial effects

Different approach
• Individual chickens • Stochastic model • Spatial model • Cost:
– No continuous infection/immune level

Individual based model
• Patches interact with walking chickens • Patches
– oocyst level empty, low, medium, high (0; 103; 105; 107) – level rises if chicken excretes higher level – level falls after 14 days without excretion

Individual based model
• Chickens
– walk or ‘shuffle’ each hour – pick up maximum daily exposure (0, 101; 3; 5) – excrete once per day depending on
• uptake -4 days • level of immunity (no, partial, full) • regulated by excretion templates

– immunity level may increase depending on
• time since first dose • number and level of doses

Example: fit to data (Galmes)
1,000,000 100,000

1000x20 20000 control model 1000x20 model 100000 model control

10,000

1,000

oocysts x10^3

100

10

1

0 0 5 10 15 20 25 30 35 40

“damage” related to initial level
High oocyst excretion
6
mean # excretions/chick

walk shuffle

5 4 3 2 1 0 0.01 0.1 1 10 100

% initial contam ination

Local minimum
• Mechanism?
– High excretion due to serial medium doses
• medium doses require serial low doses

– If initial level is
• high: early excretion of many medium, so serial medium doses before immunity • intermediate: early exposure for start-up immunity, but less serial medium exposure • low: many chicks are not immune while others already shed medium doses

More generalized mechanism for local minimum damage
• Low initial level: exposure of naive chickens to large oocyst quantities excreted by first infection generation • Intermediate initial level: immunity builds up before large oocyst quantities are available • High initial level: large oocyst quantities available before immunity is reached • However: relation to level of mixing yet unclear

Our coccidiosis modellers
• Deterministic continuous model
– Don Klinkenberg, Hans Heesterbeek

• Stochastic discrete model
– Maite Severins, DK, HH

• Stochastic continuous model (not shown)
– Andriy Rychahivskyy, DK, HH

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