breeding livestock for resilience: the high immune ...€¦ · disease resistance. hir can be used...
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Professor Bonnie MallardOntario Veterinary College
Centre of Genetic Improvement of Livestock
FarmSmart ConferenceJan 18 2020Guelph, ON
Breeding Livestock for Resilience:The High Immune Response Technology
FarmSmart Learner Outcomes
A farm to fork perspective on how state-of-the-art genetic & genomics technologies play a important role in managing disease in livestock.
How these methods contribute to economically and environmentally sustainable food production.
How breeding livestock for resilience can be used by industry to improve livestock health and increase farm profit.
Outline
1. Immuno-genetic approaches to health
2. The High Immune Response (HIR™) technology
3. Heritability of immune response traits
4. Economic benefits of selecting for improved immunity
5. Commercial tests for immune responsiveness – Immunity+
6. First genomics test for immunity
7. Other genomics tests for disease resistance (e.g. Zoetis Clarifide
and UK bTB Advantage)
What is the High Immune Response (HIR™) Technology?
Overview of HIR™
HIR IS A PATENTED TEST METHOD THAT PROVIDES A WAY TO IDENTIFY ANIMALS WITH INHERENTLY SUPERIOR IMMUNITY AND ENHANCED DISEASE RESISTANCE.
HIR CAN BE USED BY LIVESTOCK PRODUCERS AS A MANAGEMENT AND BREEDING TOOL TO NATURALLY IMPROVE THE HEALTH OF THEIR HERD.
HIR PROVIDES BENEFITS TO THE PRODUCER, THE CONSUMER AND THE ANIMAL THROUGH REDUCED USE OF ANTIBIOTICS AND OTHER THERAPEUTICS RESULTING IN A HEALTHY SUSTAINABLE FOOD CHAIN.
MARKETED BY SEMEX ALLIANCE INC AS, Immunity+™
Mallard et al. 1998. Proc. WCGALP 27:257
Immune
Response
Traits
Antibody to Test
Antigen
(HEWL)
Delayed-type
hypersensitivity
(PPD)
Lymphocyte
Proliferation
(ConA)
Serum
Immunoglobulin
(IgG)
Yorkshire Pigs Selected for
High & Low Immune
Responses based on EBVs
CONTROL
-1.5
-1
-0.5
0
0.5
1
1.5
0 1 2 3 4 5 6 7 8
GENERATION
EB
Vs
HIGH
LOW
1980’s – 1990’s
Estimated Breeding Values of Pigs Ranked
Within High, Control & Low Immune Response Lines
Wilkie and Mallard. 1999. Selection for High Immune Response. Vet Immunol Immunopath 72(1-2):231
ANTIBODY RESPONSE toA. pleuropneumoniae Bacterin Vaccine
G4 Pigs Selected for High and Low IR
NON RESPONDERS
High = 4%
Low = 19%
Control = 22%0
0.1
0.2
0.3
0.4
0.5
0.6
day 0 day 14 day 21
HighControlLow
Log o
f O
D @
1/8
00d
il’n
of
sera a
b ba
b
c
Wilkie and Mallard. 1999. Adv. Vet. Med. 41:39
0 1 2 3 4 5 6 7
HIGH
CONTROL
LOW
140
145
150
155
160
165
170
175
180
DAYS
GENERATION
HIGH
CONTROL
LOW
Average Days to 100 Kg of Pigs Selected
For High & Low Immune Responses
Wilkie and Mallard. 1999. Vet Immunol Immunopath 72(1-2):231
Lo
w A
MI R
Av
er a
ge
AM
I R
Hi g
h A
MI R
0
2 0
4 0
6 0
7 0
7 2
7 4
7 6
7 8
8 0
S u r v i v a l R a t e o f ~ 1 9 0 0 I m m u n e R e s p o n s e P h e n o t y p e d
F 1 B a r r o w s : A n t i b o d y - m e d i a t e d I m m u n e R e s p o n s e
% M
or
ta
lity
L o w A M I R
A v e r a g e A M I R
H i g h A M I R
p = 0 . 0 4 ( C h i - s q u a r e T e s t f o r T r e n d )
Pigs with High Immune Response Survive Better in the Face of Natural Disease Challenge
PigGen Canada Project 2017
% S
urv
ival
Could Immuno-Genetic Approaches be used to Improve
Immunity in Dairy Cattle
We focussed on selecting for broad-based
disease resistance (rather than on single diseases)
based on Estimated Breeding Values (EBVs) of immune response traits used in a Selection Index
0
10
20
30
40
50
60
1996 2001 2007 2014
Repro (Metritis)
Retained Placenta
Respiratory
Lameness
Mastitis
NAHMS Dairy 2007 Part II: Changes in the Dairy Cattle Industry 1991-2007 & NAHMS 2014 Health and Management Practices on US Dairy Operations
Understanding the Problem in DairyDisease Trends 1996-2014
Why are health traits so difficult to improve?
Low heritability
1. Complexity of the genetic regulation of disease resistance
2. Difficulty in measuring the relevant trait
3. Poor data quality & inconsistency in disease diagnosis and recording
Selection to fight one disease may be counter-productive to other diseases
Complexity of the Immune System
24%
77%
BOVINE GENOME
Immune Response Others
Approximately 5500 genes out of ~23,000 total genes with linear and non-linear
effects on immunity
Determining Disease Prone Animals
67%
33%
Producers and Vets identify that some animals are more
prone to disease than others?
Yes No
1%
44%
38%
25%
90%
0% 50% 100%
Genetic Tests
Herd Records
DHI Reports
Vet Reports
VisualInspection
Determining which animals are more prone to disease problems
% of Respondents
Survey 2010
ANTIBODY- MEDIATED IMMUNE RESPONSE
CELL-MEDIATED IMMUNE RESPONSE
Capturing the Performance of Immune System:
14 Days 1 Day
i. Blood Collectionii. IM Immunization
i. Blood Collectionii. ID Immunization
i. Skin Thickness measurement
STEP 1: The Phenotypic Test
HIR Ranks Cattle asHigh, Average or Low Immune Responders
Selection for Immune Response is Based on
Estimated Breeding Values
Studies in number of species show IR is highly heritabletherefore will respond to selection
Immune Response
~
Significance of being a High Immune Responder
Less likely to be seropositivefor paratuberculosis
Improved milk & colostrum quality
Improved response to vaccine
Beneficial associations with herd life and some
reproductive traits
Better hoof health – digital dermatitis
Decreased occurrence of mastitis, pneumonia, metritis,
ketosis, retained placenta
Altered miRNA profiles in colostrum/milk
(Epigenetics)
Unique genomic IR profiles
Increased heifer growth rate
Disease data from: Wagter, et al. 2000 J. Dairy Sci. 83:488-498; Thompson-Crispi, et al. 2012. J. Dairy Sci. 95:3888-3893; Thompson-Crispi, et al. 2013. Clin Vacc Immuno. 20:106-112.
Benefit - Lower Disease Incidence
IR vs Disease Incidence (Combined Diseases)
HIGH
16%
14%
12%
10%
8%
6%
4%
2%
0% AVERAGE LOW
7.5%
11.3%
14.4%
Recorded Diseases Include:
Mastitis, Metritis, Ketosis, Retained Placenta, Respiratory, Lameness
> than 100 herds tested in our research
PATHOGEN
E. coli,
S. aureus
+ others
LOW AMIR
n=86
AVE AMIR
n=289
HIGH AMIR
n=83
ALL
COWS
Incidence Rate
High Severity
30.7a
6.15c
27.9a
1.98d
17.1b
2.13
26.3
2.72
Reduction in Mastitis by High AMIR = (26.3 - 17.1)/ 26.3 = 35%
Reference: Thompson-Crispi et al Clin Vaccine Immunol 2013 vol 1 106-112
Incidence of clinical mastitis per 100 cow-yearsby EBV Low, Average and High AMIR
Mastitis Incidence on Canadian Farms
58 Herds
Benefit – Improvement in Lameness
High AMIR cows had less
Infectious Digital Dermatitis,
but more Non-Infectious
Hoof Lesions
High CMIR cows tended to
have less Interdigital
hyperplasia
2014-2016 Data from Mallard Group
Cartwright & Mallard et al., JDS 2017
Infectious Digital Dermatitis
H-AMIR
A-AMIR
L-AMIR
High23%
Low 50%
Ave 60%
N=190
Leading Cause of Culling
Discovery Questions
How might you use this information to improve your on-farm practises?
Who could help you to implement information about immune response into your herd?
What resources might you need to put these changes into practise?
Immune system: a strong chain of protection for cow and calf
PASSIVE IMMUNITY
MATERNAL ANTIBODY
AMIR – Extracellular
ex. E. coli, Staph MastitisScours
CMIR – Intracellular
ex. Johne’sTB
Viruses
0
0.5
1
1.5
2
2.5
3
wk 0 wk 2 wk 3 wk 4 wk 6
Optical D
ensity V
alu
e (
DO
)
Specific Antibody in Colostrum and Milk
High
Ave
Low
Wagter LC. 2000 J. Dairy Sci. 83(3):488
*
*
* **
Benefit – Improved Colostrum and Milk
Correlations Between Specific Antibodyin Cow Colostrum vs Calf Sera Post-suckling
Correlation between Ab in Colostrum and Calf Blood = 0.74, p<0.04*N = 8 Cow/Calf pairs Wagter-Lesperance PhD thesis - 2016
Calves getting the colostrum from High Responders have more antibody in their blood.
Estimated cost savings for High vs Average Responder
for a common set of diseases –
(mastitis, metritis, ketosis,retained placenta, Johnes),
plus improved vaccine and colostrum responses is:
$247.91/cow/lactation.
Economic Benefit for Common Diseases per Standard Deviation of HIR
Cost:Benefit Analysis
Cost of HIR Test $20-$80/cow
HIR Benefit $247.91/cow/lacation
Cost:Benefit Year 1 3:1 or $248/cow
Cost:Benefit Year 2 6:1 or $496/cow
Cost:Benefit Year 3 9:1 or $992/cow
Agri-Studies Inc
Discovery Questions
How might you use this information on colostrum to improve your calf management?
Does information on HIR open up different disease treatment strategies?
How might your veterinarian help you put these changes into practise?
How can HIR be used as both a breeding and management tool?
Semex Exclusive Patented Technology
From the University of Guelph
December 2012
2012 –Semex Licences the HIR Technology from UoG
Bulls Designated as Immunity+
Approximately 10% of sires
PROVEN ON FARMS AROUND THE GLOBE:35 commercial herds totaling 30,000 Immunity+ daughters
Building a Stronger Herd
Dr Chesnais, Senior Geneticist, Semex
~12% Less
Disease on Farm
>
GWAS of Immune Response
Is a Genomics Test based on HIR™ Test System Possible?
Thompson-Crispi et al 2014, BMC Genomics
Reference Population (n ~ 6000)
HIR™ Phenotyped Genotyped (50K SNPs)
Step 1 – The Reference Population
+
Figure2:
The genomic analysis for AMIR detected four significant
SNPs on chromosomes 2, 11, and 14 (5% FDR),
and associations on chromosomes 21 and 23 (1% FDR)
GWAS: 2500 cows (60 herds) + 1000 bulls (4 Semex herds)50K imputed to 777K using another 3000 Reference Animals
Ref: Mallard et al 2018 Proc WCGALP
ELEVATE WITH SEMEX
Only Semex Can Leverage Immunity+ Rankings & Testing
June 2018Semex Launches First Genomics Test for Females
ELEVATE WITH SEMEX
Immune Genomics Validation• Gathered genotypes and health records
from 15 large US dairies
• Calculated disease incidence after adjusting for age and lactation effects of all genotyped animals (N=6,500)
• Used this information to determine how to display Immune Genomics values
• Significant differences (p<0.05) found for lameness, mastitis, persistent mastitis and overall disease frequency
Validation in the Field
Using genomically tested cows, instead of simply the sire
status, we can see that those cows with a stronger immune
system resist disease even better.
These High Immune Response cows have on average
30% less disease than their herdmates with either
average or low immune response genetics.
DISEASE DATA ON ~10,000 GENOMICALLY-TESTED COWS
High Immune Response (HIR) for DairyMore than 7 Awards since 2013
U of G Innovation of the Year 2018
Governor General Innovation Award 2017
Other Genomic Indices
1 – Based on Clinical Disease Recorded Data(e.g. Zoetis, CDN, Other)
2 - Based on Diagnostic Tests(e.g. bovine TB skin test)
Low Heritability
Canadian Compass will be similar
TB Advantage launched 2016 –
a genetic index aimed to help UK dairy farmers improve resistance against bovine tuberculosis (bTB).
Now available for Holsteins following research at Roslin Inst., with Genus ABS and UK Dairy Genetics Advisory Forum showing genetic variation between animals in response to TB skin test.
Like other indexes the scale ranges from -3 to +3, with a positive number predicting daughters with greater resistance. For every +1 point, 1% fewer daughters are expected to become infected.
Heritability of this trait is low (9%)
UK – Bovine Tuberculosis IndexTB Advantage
Badger buries calf carcass
Discovery Questions
What are the practical advantages to a genomics test for immunity?
What role does heritability play in genomic selection for health?
Do genomic tests for health open up new opportunities for breeding within your herd?
Adapting the High Immune Response (HIR™) Technology to Improve
Beef Cattle Health
Bovine Respiratory Disease (BRD) is the Most Costly Disease in Canadian Beef Industry
The Problem –Disease Risk and Over Use of Antibiotics
BRD accounts for up to 80% of feedlot sickness and costs
the US industry $700M annually!
Could Selecting for High Immune Responders
Reduce BRD and Drug Use?
We believe so!
Incidence of BRD/Pneumonia in Dairy
Herd A – 265 head
Herd B – 1267 head
Herd C – 2724 head
Pneumonic Nonpneumonic Percent P valueHigh Responders
2 34 5.6%
Vs. p = 0.09Herdmates 35 194 15.3%
Pneumonic Nonpneumonic Percent P value
High Responders
11 149 6.9%
Vs p = 0.22
Herdmates 101 1006 9.1%
Pneumonic Nonpneumonic Percent P valueHigh Responders
45 186 19.5%
Vs. p = 0.005Herdmates 683 1810 27.4%
Stakeholder Opportunity & Value
In order to secure this opportunity we are:
1 - establishing an HIR test system for beef calves well-suited to feedlots settings
2 – obtaining data on whether HIR/Immunity+ can reduce BRD in Canadian and American Angus
MORE TO COME……..
HIR will provide the same valuefor the beef industry?
Resilient animals are defined as having better immunity and are better adapted to stress, such as climate change.
Objective: Evaluate the Effects of Heat Stress on the Resilience of HIR Classified Cattle.
Resilience to Climate Change Project
Rectal Temperatures of 36 Ontario Beef Cows of Mixed Breeds during Normal THI (< 74) and above Normal THI (≥ 74)
Effect of Temperature Humidity Index (THI) on Body Temperature of Cattle
1 columns with different letters differ significantly 1
Ref: Nasrin Husseini, MSc Thesis, 2020
62.5% of cows had rectal temperature ≥39.5 when THI was 74 or greater
High Antibody Responders Regulate Body TemperatureBetter than Herd-mates during Hot Days in Ontario
H-AMIR A-AMIR L-AMIR
TN
4 HR -H
S1
24 H
R- H
S1
4 HR- H
S2
24 H
R -
HS2
0
5
10
15
HSP70 Concentration by Immune Response Phenotype
Treatment
HS
P70
Co
nce
ntr
ati
on
(n
g/m
l) High (n=15)
Average (n=15)
Low (n=15)
p = 0.07
p = 0.02
p = 0.04 p = 0.06
p = 0.04
p = 0.05
Thermo-neutral = TN(in vitro 37 degrees)
Heat Treatment 1 = HS1(in vitro 42 degrees, 4hr)
Rest 18hr then,
Heat Treatment 2 = HS2(in vitro 42 degrees, 4hr)
Heat Shock Protein 70 (HSP70) Protects Cells during Heat Stress
Shannon Cartwright, PhD Thesis
Discovery Questions
Would it be helpful to identify resilient animals in your herd?
Would resilience apply equally whether you are a dairy or beef producer?
Some Answers to the Discovery Questions to Improve Animal Health
1) Selectively breed your High/High females to Immunity+ sires
2) Super-ovulate your High/High females and use average or low as recipients
3) Low responders dairy cows could be bred for beef or culled
4) Discuss with your vet how to group livestock by immune response for treatments (eg vaccinations and antibiotic use)
5) Consider using immuno-stimulants to boost immunity of average and low cows (eg Imrestor, Cr yeasts…)
6) Bank colostrum from high immune responders
7) Purchase powdered colostrum from HIR females
8) Provide additional cooling for low responder cows
Funding is gratefully acknowledged from:
NSERC
OMAFRA
DFO
CFREF – Food from Thought
Corporate Sponsor - Semex Alliance
Thanks to our High Immune Response Teamand to our Funding Agencies
QUESTIONS
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