Resistance to experimental infections with Haemonchus contortus in Romanov sheep

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Resistance to experimental infections with Haemonchus

contortus in Romanov sheep

G Luffau, J Vu Tien Khang, J Bouix, Tc Nguyen, P Cullen, G Ricordeau, C

Carrat, F Eychenne

To cite this version:

Original

article

Resistance

to

_experimental

infections

with Haemonchus

contortus

in

Romanov

_sheep

G Luffau

1

J Vu

Tien

_Khang

₂

J Bouix

2

TC

_Nguyen

P

Cullen

4

G Ricordeau

C Carrat, F

_Eychenne

Institut National de la Recherche

_Agronomique;

1

Station

de _Virologie et _{d’Immunologie,} Centre de Recherches de

_{Jouy-en-Josas,}

78350

_{Jouy-en-Josas;}

2

Station

d’Amédioration _Génétique des _Animaux, Centre de Recherches de _Toulouse, BP _27, 3i326 Castanet-Tolosan _Cedex;

s

Laboratoire

des _Groupes

_Sanguins,

Centre de Recherches de _{Jouy-en-Josas,} 78350 _{Jouy-en-Josas;}

4

Laboratoire

de _{Génétique Biochimique,} Centre de Recherches de

_{Jouy-en-Josas,}

78350 _{Jouy-en-Josas,} France

(Received

22

_August

_{1989; accepted} 28 _February

₁₉₉₀₎

Summary

-Responses to immunization with

_aggregated

human serum albumin

(HSA)

and to _{repeated experimental} infections with H contortus were studied in 51 female lambs

of the Romanov _breed, born from 8 sires and 36 dams. The 8 sires were of

_haemoglobin

genotype Hb

_AB;

the 51 lambs were distributed into 3 groups of 17 _each,

_{corresponding}

to

the 3 _genotypes

_HbAA,

HbAB and HbBB. In addition the

_experimental

lambs were

_typed

for _antigens of the _major

_{histocompatibility}

_system

(OL./1).

The

_{parasitological findings}

were the

_following:

a _{repeatability} of faecal _egg counts between successive _infections, a

negative

correlation between _{peak faecal egg} counts and self-cure

_intensity,

a _positive

correlation between faecal _egg counts and

_degree

of _anaemia, an _acquisition of _immunity

to the _{parasite by previous} contact with the _parasite and a reduction of this immunity

by anthelmintic treatment.

_According

to the

_genetic

_{investigations,} there were

_significant

sire effects on variables

_reflecting

the resistance. The faecal egg counts did not seem to be related to the

_haemoglobin

_system, but

_might

be affected

_by

1 or several genes located in

the OLA _complex or close to the latter. The humoral response to HSA showed a _negative

correlation to _parasite resistance.

sheep / Haemonchus contortus _/ humoral response _/ haemoglobin / OLA system

R.ésumé - Résistance à des infestations expérimentales par Haemonchus contortus

en race ovine Romanov. Les réponses à une immunisation avec de la sérum albumine humaine

_agrégée

_(SAH)

et à des

_infestations

_{expérimentales répétées} avec H contortus ont été étudiées chez 51 _agnelles de race _Romanov, issues de _{8 pères} et de 36 mères. Les _{8 pères} étaient _{hétérozygotes} AB pour le système

hémoglobine

(Hb)

et les 51

_agnelles

*

étaient _réparties en tmis groupes de 17 correspondant aux trois _génotypes Hb _AA, Hb AB

et Hb BB. Par _ailleurs, les _agnelles

_{expérimentales}

ont été _typées pour le système majeur

d’histocompatibilité

(OLA).

Sur le

plan parasitologique,

les résultats obtenus mettent en

évidence: une

_{répétabilité}

du taux d’excrétion des _oeufs entre

_infestations

_successives, une

corrélation _négative entre niveaux des pics d’excrétion et intensité de l’autostérilisation

(&dquo;self-cure&dquo;),

une corrélation _positive entre taux d’excrétion et _{degré d’anémie,} une

acquisition de l’immunité parasitaire par contact préalable avec le parasite et une réduction de cette immunité par

vermifu ation.

Sur le plan

génétique,

on observe des

_effets

_père

significatifs

sur des variables

rejetant

la résistance. Le _{système hémoglobine} ne semble pas

lié au taux d’excrétion mais _pourrait être lié au _degré d’anémie

_consécutif

à

_{l’infestation.}

La résistance à H contortus _pourmit être _influencée par un ou _{plusieurs gènes} situés dans le

complexe OLA ou à sa _proximité. La _réponse humorale à la SAH _présente une corrélation

négative

avec la résistance au _parasite.

ovin Haemonchus contortus / réponse humorale / hémoglobine / système OLA

INTRODUCTION

Since the

_publications

of Warwick et al

_(1949),

Whitlock

_{(1955, 1958)}

and Whitlock and Madsen

_(1958),

the existence of a

_{genetic variability}

in the resistance to

Haemonchus contortus has been shown in several studies: the

_heritability

estimates range around 0.25-0.30

(Le

Jambre,

1978;

Albers et

al,

1984, 1987;

Piper,

1987).

As there are almost no

_genetic

correlations between the resistance and various

production

traits

_(Alberts

et

_al,

_{1984, 1987; Piper,}

_1987),

selection on resistance to

H contortus would be

_possible

and

_{economically justified}

in conditions where this

type of

_parasitism

leads to

_large

_productivity

losses

_{(Holmes, 1986).}

_However,

it does

not seem to be

_possible

to use the _{response to} an

_experimental

infection as a

large-scale selection criterion because of the difficulties of such an

_{experimentation.}

It would therefore be

_interesting

to

_identify

resistance

_predictors,

either

_{immunological}

traits or

_genetic

markers

(Courtney,

1986;

Alberts and

_Gray,

_1987;

Cabaret and

Gruner,

1988).

Several studies _suggest that

_haemoglobin

A allele

_provides

a

_higher

resistance to

H contortus than the

_haemoglobin

B allele

_(Evans

et

_al,

_1963;

Jilek and

_Bradley,

1969;

Radhakrishnan et

_al,

_1972;

_Allonby

and

_{TJrquhart, 1976;}

Altaif and

_Dargie,

1976, 1978a,

b;

Preston and

_Allonby,

_1979;

_Dally

et

_al,

_1980;

Luffau et

_{al, 1981a,}

_b;

Courtney

et

_al,

_1985).

_According

to

_Cuperlovic

et al

_(1978),

this enhanced resistance

might

be related to a

_higher

humoral immune response.

From a

_genetic

_point

of

_view,

the main

objective

of the _present

_experiments

was to confirm or invalidate this

_hypothesis.

Because the

_typing

of animals in the

major

histocompatibility

system

( OLA)

was

_{performed retrospectively,}

a search for

_{relationships}

between resistance to H contortus and the OLA marker was also

included in this

_study.

From a

_{parasitological}

_point

of

_view,

the

_experimental

_goals

were to

_supply

additional information on the

_following

_{phenomena: repeatability}

of faecal _egg

counts between successive

_{infections, relationship}

_{between egg} counts and

_self-cure,

relationship

between _egg counts and

_degree

of

_anaemia,

_acquisition

of

_immunity

to the

_parasite

_by

_previous

contact with the

_parasite

and effect of anthelmintic

treatment on this

_{acquired immunity.}

MATERIALS AND METHODS Animals

Several studies have shown that females

_develop

_stronger

immunity

against

H contortus than males

_(Colglazier

et

_al,

_1968;

Yazwinski et

_al,

_1980;

Luffau et

al, 1981a; Courtney

et

_al,

1985; Watson,

1986):

hence

_only

females were used in

the _present

_study,

ie 51 female lambs of the Romanov breed born from 8 sires and 36 dams. The

_breeding

animals were chosen

according

to their

_haemoglobin

genotype.

All sires were Xb AB

_{heterozygotes.}

The dams

belonged

to

genotypes

Hb

_AA,

Hb AB or Hb BB. The 51 lambs fell into 3 groups of

17,

each

representing

1 of the 3

_haemoglobin

_genotypes.

The number of animals in the 3

_haemoglobin

genotypes

was balanced within each sire progeny so as to reduce risks of confusion between a

possible haemoglobin

_genotype

effect and a

possible

sire effect.

Fifty

lambs and 24 of their 35 dams were

typed

for

antigens

of the OLA

_system.

The sires were not

_typed

but their

_genotypes

could be inferred and transmission of markers determined in many cases.

The

_experimental

female lambs were chosen so as to form a _group as

homoge-neous as

possible

for age,

weight,

maintenance conditions and health in order to reduce uncontrolled factors of variation. The animals were maintained on a _grass

free diet from birth to avoid environmental exposure to H contortus.

Typing

methods for

_haemoglobin

and OLA

_systems

Haemoglobin

types

were determined

_by

electrophoresis

(Nguyen

and

Bunch,

1980).

Class I

_antigens

of the

_major

_{histocompatibility}

_system were tested

by

the

micro-cytotoxicity

method on blood

lymphocytes;

the test was carried out over a

period

of 2h 30 min

_(Cullen

et

_al,

_1985).

_Lymphocytes

of each animal were tested with

120 antisera

_against

22

_provisional

_{specificities,}

&dquo;OLA-P&dquo;. Nine

_haplotypes,

each

carrying

1 or 2

_{specificities,}

were identified in the tested animals.

Immunization

_experiments

with

_aggregated

human serum albumin

The 51

_experimental

lambs were immunized at the _age of about 6 months with heat

aggregated

human serum albumin

(HSA:

200

mg/animal)

by

intravenous

injection.

Their serum was collected before and 14 d after the administration of the

antigen,

titred

_{by passive haemagglutination using}

red blood cells tanned and sensitized with HSA

_{(Weir, 1978).}

The

_technique

used to determine the serum

agglutination

titre has been described

_previously

_{(Nguyen, 1984).}

Experimental

infections with H contortus

According

to various

_{studies, sheep develop immunity against}

H contortus from the age of about 7 months

(Jarrett

et

al, 1961;

Manton et

al,

1962;

Urquhart

et

al,

1966a, b;

Knight

and

_Rodgers,

_1974;

Wilson and

_{Samson, 1974;}

Benitez-Usher et

al,

1977; Duncan

et

_{al, 1978;}

Riffkin and

_{Dobson, 1979;}

Smith and

_Angus,

_1980).

Our

_experiments

therefore

_began

when the lambs were about 8 months old.

During

sheepfold

fitted with a slatted

floor,

diets based on

compound

feed _{concentrates,}

hay

and straw ad libitum. Five infection

_experiments

were conducted

_successively

_using

3-week old larvae. Animals were infected with larvae obtained

by

faecal cultures

according

to the method of FJS Robert and PJ O’Sullivan and collected with Baerman’s _apparatus

_(Luffau

et

_al,

_1981a,

_b).

The

_required

number of larvae were

counted

_{microscopically}

and

_suspended

in 20 ml of

_ordinary

water. This

suspension

was administered

orally.

The strain maintained at the Station of

Virology

and

Immunology

was

_supplied

initially by

Professors GM

Urquhart

and EW

Allonby

(Glasgow).

Experiment

1

In

_experiment

_1,

lambs were divided into 3 _groups:

-

18 animals were

_given

3 infections

successively:

a

_primary

infection on DO with

5 000

_larvae,

a

_secondary

one on D32 with 10 000 larvae and a 3rd one on D64 with

20 000 larvae

_{(group 1);}

-

18 animals were

_given

2 infections

successively:

a

_primary

infection on D32 with

10 000 larvae and a

secondary

one on D64 with 20 000 larvae

(group 2);

- 15 animals

were

_given

an infection of 20 000 larvae on D64

(group 3).

The 3 _groups were formed so as to obtain a balanced distribution of the various

paternal origins

and

_haemoglobin

_genotypes.

The kinetics of faecal _egg counts was established for each animal.

Eggs

laid

by

H contortus females and eliminated with the faeces were counted

_using

faecal

samples

of

_3g

_using

the Mc Master method. Measurements were made on the

following

40 dates:

_{D17, D21, D24, D28, D31, D35, D37, D39, D42, D44, D46, D49,}

D51, D53, D56, D58, D60,

D63, D65,

D67, D70, D72,

D74, D77,

D79, D81, D84,

D86,

D88, D91, D95, D98, D107,

D114,

D119, D126, D133, D140,

D147 and D156. Each measure

_(number

of _{eggs per}

gram)

was the mean _egg count of 3 different

samples. These egg

counts were

good

indicators of the worm burdens of the animals

(Roberts

and

_Swan,

_1981).

The

_following

3

_{haematological}

_parameters were recorded in all animals: number of red blood

_{cells, packed}

cell volume and

_haemoglobin

content. These

measure-ments were made on the

_following

dates:

_{D9, D16, D23, D30, D39,}

D45, D53, D58,

D67,

D74,

D88, D95, D102, D109,

D116, D123,

D130, D137, D144,

D151 and D158. The number of red blood cells

_(per

_pl

of

_blood)

was determined

_by

_measuring

the variation in the

_potential

difference

_(Celloscope

401 -

_{Ljungberg - Stockholm,}

Sweden)

induced

_{by the passage}

of red blood cells

_(blood

dilution

_1/800)

in an

electric field. The _apparatus was

periodically

checked

according

to the

_{microscopical}

method of Malassez.

For

_measuring

haematocrit

_(packed

cell

_volume),

blood was

_centrifuged

in

heparinized capillary

tubes

_(inner

diameter: 0.55 _mm;

_length:

75

_mm)

_using

Janetzki’s TH-12

_centrifuge

at 1500

_r/min

for 5 min.

For

_measuring

the

_haemoglobin

content

_(g/100

ml

_blood),

_haemoglobin

of the red blood cells

_{lysed by saponin}

was fixed and transformed into

_{cyanmethaemoglobin.}

The

_haemoglobin

content was measured

_by

spectrophotometry

(absorption

at

Experiment

2

The

_surviving

49 animals were divided into 2 groups,

_irrespective

of the _group

they

were _part of in

experiment

1:

- the 26 animals of

group 1 were not drenched

_prior

to

_experiment

2;

hence

_they

were carriers of a residual H contortus

_population;

- before

starting

experiment

2 the 23 animals of group 2 were drenched with a

highly

effective

anthelmintic,

Thibenzole MSD

_powder

_(thiazolyl

benzimidazole-thiabendazole

_ND,

_Paris,

_France).

In these _{2 groups,} each animal was

_given

10 000 larvae on DO of

_experiment

2

(263

days

after DO of

_experiment

_1).

Faecal egg counts were made on the

_following

20 dates:

_{Dl, D0,}

_D17,

_{D20, D24,}

_D27,

_{D31, D34,}

_D38,

_D41,

_{D45, D48,}

_D56,

_D59,

D80, D83,

D88,

D91,

D95 and D98.

Experiment

3

Experiment

3 was a

_replication

of

_experiment

2. The infection on DO took

place

366

days

after DO of

_experiment

1. The faecal _egg counts were made on the

_following

18 dates:

_{D5, D8,}

_{D9, D12,}

_{D15, D19, D22, D26,}

_D29,

_{D33, D36,}

_{D40, D43, D47,}

D50, D54,

D57 and D64.

Experiment

4 .

In

_experiment

_4,

each animal was drenched and

_given

10 000 larvae on DO

(485

days

after DO of

experiment

1).

The faecal _egg counts were made at the

_following

19 dates:

_{D5, D0, D3, D6, D10, D15, D19, D22, D26, D29, D33, D36, D40, D44,}

D47, D50, D55,

D65 and D72.

Experiment

5

Experiment

5 was a

_replication

of

_experiments

2 and 3. The animals of each _group

(drenched

and not

_drenched)

were

_given

10 000 larvae on DO

₍₅₆₀

_days

after DO of

experiment

1).

The faecal egg counts were made on the

_following

41 dates:

_D0,

D17,

D21, D24, D28, D31, D35, D38,

D42, D45,

D49,

D52, D56,

D59,

D63,

D70,

D73, D77, D80, D84, D87, D91,

D94,

D98, D101, D108, D115, D119, D123, D126,

D129,

D140,

D143,

D147, D150, D154,

D157, D161, D164,

D168 and D172. Statistical

_analysis

Choice of variables and factors Variables

The

_{immunological, parasitological}

and

_{haematological}

variables used are

_given

in

table I. The

_{parasitological}

variables were defined from decimal

_logarithms

of mean

egg

counts

over certain

_periods

_(in

order to normalize distributions and obtain more

Thus,

in each of the 3 _groups of

_experiment

_1,

a

_peak

faecal _egg count was

observed after the

_primary

infection

_{(fig 1).}

This

_peak

was located from D24-D37 in

group 1, from D56-D57 in group 2 and from D88-D107 _{in group} 3: the PRIMPEAK

variable reflects this

_peak.

In groups 1 and 2 of

_{experiment 1,}

the

_secondary

infection was followed

by

a _very

group

2):

this was the classical self-cure

phenomenon.

Variable SELFCURE reflects

this

_phenomenon;

it is defined as the difference between the

_primary

peak

and

the

_depression

_subsequently

to the self-cure. A

_{secondary peak}

could be observed

immediately

after this

_depression

_(D46

to D53 _{in group 1} and D84 to D88 in group

2):

variable SECPEAK reflects this

peak.

In

_{experiments 2, 3, 4}

and

_5,

the faecal _egg counts increased after the infection

_(fig

2).

Variables

_{PEAKEXP2, PEAKEXP3, PEAKEXP4}

and PEAKEXPS reflect the

high

egg counts after the infection

_(from

D27-D48 in

_experiment

_2,

D26-D54 in

ex-periment 3,

D26-D55 in

_experiment

4 and D28-D52 in

_experiment

_5).

The

_synthetic

variable PEAK2,35 is the mean of the 3 variables

_previously

defined in

_expriment

2

and in its 2

_{replications,}

ie

_experiments

3 and 5 also

_involving

_{2 groups} of animals

(a

group drenched before infection and a non-drenched

group).

The

synthetic

vari-able PEAK235 does not include

_experiment

4 in which all animals were drenched

prior

to infection.

The

_{haematological}

_parameters are defined as means of

_given

measures over

certain

_periods.

The choice of

_periods

here is

_again

based on a kinetic examination.

The number of red blood

_cells,

the

_packed

cell volume and

_haemoglobin

content

Factors

The factors of variation considered are

_given

in table II. Two of these factors

(HBALLELE,

the

_haemoglobin

allele received from the sire and

_OLALLELE,

the

OLA

_haplotype

received from the

_sire)

are nested within sire.

_According

to

_analyses,

the _response to immunization with HSA was considered as a variable or a factor.

Method of

_analysis

Analysis of

the humoral immune response

Two methods were used for the statistical

_analysis

of the humoral immune _response, ie

_x

₂

test and

_analysis

of variance.

Chi-square

tests of

_independence

were carried out between the RESPOND factor

(accounting

for the immunization

_{&dquo;responder&dquo;}

or

_{&dquo;non-responder&dquo;}

_character)

and various other factors of variation of table II

_{(sire, haemoglobin}

_genotype and OLA

, haplotypes).

including

all factors of

_variation;

there would have been numerous either _empty or

low cells.

_Accordingly,

several

_analysis

of variance models were used each

_involving

a small number of factors. This can also be

_applied

to the

_analyses

of variance of the

parasitological

and

_{haematological}

variables,

treated in the

_following

_paragraphs.

Analysis of

the

_{parasitological}

and

_{haematological}

variables

_of

_experiment

1 Table IV shows the

_analysis

of variance models

_applied

to the

_{parasitological}

and

haematological

variables of

_experiment

1. When the factors did not include

RE-SPOND

_{(immunization}

&dquo;responder&dquo;

or

_{&dquo;non-responder&dquo;}

trait)

or TITRE

(category

of anti-HSA

_antibody

_titre),

the ANTIHSA variable

_(reflecting

the humoral

re-sponse)

was added in order to

_study

its correlation with the

_{parasitological}

and

haematological

variables. The same

_procedure

was used for

_analysis

of the vari-ables of

_{experiments 2, 3,}

4 and 5.

Analysis of

the

_{pana,sitological}

variables

_of

_{experirrzents 2,}

3, 4

and 5

Table V

_gives

the models of the

_analyses

of variance

_performed

on the

_{parasitological}

of the variable of

_{experiment 4,}

since in this

_experiment

all animals were

_given

the

anthelmintic treatment before infection.

Analysis

of

various

_{parasitological}

variables considered as

_repeated

measures

_of

the same character

A new

_approach

consists of

_considering

that the

_{parasitological}

variables

experiments

1, 2,. 3,

4 and

_5,

_{respectively)}

constitute

_repeated

measures of the

same

_{parasitological}

overall variable OVERALL. Table VI

_gives

models of

analyses

- the EXPGROUP factor

corresponding

to the

_experiment

and

_group

combination in which the OVERALL variable was

_measured;

- the ANIMAL factor

corresponding

to the

_experimental

animal in which the

measure was made.

RESULTS

Analysis

of the humoral immune response

Chi-square

tests of

_independence

between the

_{&dquo;responder&dquo;}

character and various other factors

_(sire,

_haemoglobin

_genotype

and OLA

_haplotypes)

No x

2

was

_significant

at the 0.05

_level,

with the

_exception

of the test

_{of independence}

between the

_{&dquo;responder&dquo;}

character and the OLA -P14+9

haplotype

_(xi!

=

_5.953,

significant

at the 0.02

_{level) :}

this

_x

₂

resulted from a

_preferential

association between the

_{&dquo;responder&dquo;}

character and the OLA -P14 + 9

_haplotype.

Analyses

of variance of the ANTIHSA variable

_reflecting

the humoral immune _response

Among

the 23

_analyses

of variance described in table

_{III, only analyses}

no 8 and 19 showed a

_significant

effect at the 0.05

_level;

in both cases, it was the effect of the

OLA -P14 +9

_haplotype

whose presence in the studied

sample

was related to an

Analysis

of the

_{parasitological}

and

_{haematological}

variables of

experi-ment 1

Table VII summarizes the results of the

_analyses

of variance whose models are

described in table IV. Table VIII

_gives

the residual correlations calculated on

the

_{parasitological}

and

_{haematological}

variables relative on the

_primary

peak

of

experiment

1 and on the

_{immunological}

ANTIHSA variable. Table IX

gives

the

residual correlations calculated on all

_{parasitological}

variables of

experiment

1

(relative

to the

_primary

_{peak, secondary peak}

and to the

_self-cure)

as well as on

the

_{immunological}

ANTIHSA variable.

Analysis

of the

_{parasitological}

variables of

_experiments

_{2, 3,}

4 and 5 Table X summarizes the results of the

_analyses

of variance whose models are

described in table V. Table XI

_gives

the residual correlations calculated on the

parasitological

variables of

_{experiments 2, 3,}

4 and 5 as well as on the

immunological

Analysis

of the various

_{parasitological}

variables considered as

_repeated

measures of the same character

Table XII summarizes the results of the

_analyses

of variance whose models are

described in table VI.

The

_{repeatability}

of the character measured

_by

the OVERALL variable was

estimated in model No 71

_(including

the crossed EXPGROUP and ANIMAL

factors)

by

the intra-class coefficient of correlation

_(ratio

of &dquo;individual&dquo; variance to

the sum of &dquo;individual&dquo; variance and residual

_variance):

the estimated

_{repeatability}

was 0.26.

Figure

4 illustrates the effect of the TITRE factor

_(anti-HSA

_antibody

_titre)

on

the overall

_{parasitological}

OVERALL variable. DISCUSSION

the variable

_reflecting

the

_self-cure,

the correlation

_being

_{only highly}

_significant

(P

<

_0.001)

between the self-cure and the

_{secondary peak:}

in other

_words,

the animals with the lowest faecal _egg counts were also those that best

expelled

their

parasites.

Positive

_{(generally significant)}

residual correlations were observed in the

the _egg counts. The

_highly

_significant

effect of the ANIMAL factor on the overall

parasitological

OVERALL variable

_{(table XII)}

illustrates the

_{repeatability}

of the

mean _{egg output}

_during

the

_peaks

of the 5 successive infection

_experiments.

Phenotypic relationships

between faecal egg counts and

degree

of anaemia

There were

highly

significant (P

<

_0.001)

correlations between the mean number

of red blood cells per mm3 of

blood,

the _average

_packed

cell volume and the

mean level of

_{haemoglobin during}

the

_primary

_peak

of _eggs

_passed

in

_experiment

1

(table VIII).

The

_{PRIMPEAKvariable, reflecting}

the

_peak

faecal egg counts

_during

primary

infection was

_negatively

correlated with the 3

_{haematological}

variables.

This

_corresponds

to the

_phenomenon

of anaemia

_classically

associated to

_large

faecal _egg counts

_(Whitlock,

_{1955, 1958;}

Evan et

_{al, 1963;}

Pradhan and

_Johnstone,

1972;

Altaif and

_{Dargie, 1978a, b;}

Roberts and

_{Swan, 1982;}

Albers et

_al,

_1984).

Effect of

_primary

dose of infective larvae of faecal _egg counts and anaemia The factor GROUPl

_(group

in

_experiment

₁₎

had a

_significant

effect on all

parasitological

and

_{haematological}

variables measured

_during

the

primary

peak

of

_experiment

1

_{(table VII):}

as

_expected,

the

_larger

the larval

_intake,

the

_higher

the

faecal _egg counts and the

_degree

of anaemia

_(figures

1 and

_3).

Effect of vaccination on

_immunity

to the

_parasite

Considering

the kinetics of faecal egg output in group 1 of

_experiment

1

_{(figure 1):}

the

_peak

faecal _egg counts after the 1st infection

_(with

5000

_larvae)

was

_higher

than

the

peak

after the 2nd infection

_(with

10 000

_larvae)

which was

_higher

than the

_peak

after the 3rd infection

_(with

20 000

_larvae).

_{Likewise, in group 2}

of

_experiment

1

(figure 1),

the

_{primary peak}

exceeded the

_{secondary peak although}

the 2nd dose of infective larvae was 2-fold

_higher

than the 1st one

_{(20 000}

larvae instead of

_{10 000).}

With the same dose of infective larvae

(10

000 larvae on D32 or 20 000 larvae on

D64),

animals which had

_{previously experienced}

infection with H contortus reacted

by

eliminating

fewer _eggs than those infected with the

_parasite

for the first time.

These observations

_(based

on

figure

1 and confirmed

_{statistically by analyses}

of

variances not shown

_here)

illustrate the

_phenomenon

of

_immunity

to the

_parasite

(ie protection)

acquired by &dquo;vaccination&dquo;,

ie

_by

previous

infection with the

_parasite

(Clunies

Ross,

1932; Luffau,

1975;

Luffau et

_al,

_1981a,

_b).

Effect of anthelmintic treatment on

_immunity

to the

_parasite

In

_experiments

2 and

_3,

the _group drenched before infection eliminated

_{significantly}

more _eggs than the non-drenched group

(figure

2 and first line of table

X);

the anthelmintic treatment

_{substantially}

reduced the

_immunity

_{acquired previously by}

contact with the

_parasite.

The

_phenomenon

was more marked in

_experiment

3 which

was a

_replication

of

_experiment

2. In

_{experiment 5,}

the same trend was observed

of the

_{previous experiment}

_{(experiment 4)}

seemed to have reduced the difference between the 2 groups.

All these

_results,

which show the reduction of

_immunity

to the

_parasite

after anthelmintic _treatment, confirm those obtained

_by

Benitez-Usher et al

₍₁₉₇₇₎

according

to whom

_application

of such a treatment after vaccination with irradiated larvae lowered the

_immunity

to the

_parasite.

Phenotypic

relationships

between resistance to

_parasitism

and humoral

immunity

.

Factors

_relating

to the anti-HSA

_antibody

titre

_(RESPOND

and

_TITRE)

had

significant

effects on various

parasitological

variables of

_experiments

1

(table VII),

2, 3,

4 and 5

_{(table X)}

as well as the overall

_{parasitological}

OVERALL variable

(table XII).

The

_higher

the

_production

of anti-HSA antibodies the

_larger

the faecal egg counts, as shown

by adjusted

means in

figure

4. This

positive

relation between

faecal _egg count and humoral

_immunity

is also illustrated

_by

the

_positive

coefficients of correlation between various

_{parasitological}

variables

_reflecting

the faecal _egg

output and the variable ANTIHSA

_reflecting

the humoral

_immunity

_(tables

IX and

XI).

Contrary

to the

_hypothesis

_put forward

_{by Cuperlovic}

et al

_(1978),

response to an immunization with

_aggregated

human serum albumin is not a

_predictor

of resistance to H contortus. This

_negative

correlation between resistance to helminths and response to an immunization has

_already

_{been observed}

in mice

_(Blum

and

Cioli,

1978;

Deelder et

_{al, 1978;}

Perrudet-Badoux et

_{al, 1978; Wakelin,}

_1978).

In

sheep,

Albers et al

₍₁₉₈₄₎

did not find _any

_significant

correlation between resistance

to H contort and _response to an immunization with chicken red blood cells. Sire effect on resistance to H contortus

Significant

sire effects were evidenced on the PRIMPEAK variable

_accounting

for

the

_primary

_peak

_{faecal egg} counts in

_experiment

1

_{(table VII)}

and on the overall

parasitological

OVERALL variable

_pertaining

to all

_experiments

_{(table XII):}

these effects were

_significant

at the 0.05 and 0.10

_{level, respectively.}

The number of

experimental

animals

₍₅₁

_offspring

of 8

_sires)

was too small to make a

heritability

estimation.

_However,

our results are in favour of a sire effect on

_resistance;

_they

are in

_keeping

with those of Le Jambre

_(1978),

Albers et al

_{(1984, 1987)}

and

_Piper

(198?)

who found a

heritability ranging

from 0.25-0.30 for resistance to H contortus.

Relationships

between

_haemoglobin

_system

and

_{immunological,}

para-sitological

and

_{haematological}

variables

Neither the HBGENO factor

_(haemoglobin

_genotype)

or the

_HBALLELE

factor

(haemoglobin

allele received from the

_sire)

had _any

_significant

effect at the 0.05 level on the

immunological

or

_{parasitological}

variables,

although

the

_experiment

was

_designed

to

_verify

the existence of such effects.

and

_{Dargie, 1976, 1978a, b;}

Preston and

_Allonby,

1979;

Dally

et

_al,

_1980;

Luffau et

_{al, 1981a, b; Courtney}

et

_al,

_1985),

but

_they

are in

keeping

with the results of

Le Jambre

_(1978),

R,iffkin and Dobson

_(1979),

_Courtney

et al

_(1984),

Riffkin and

Yong

(1984)

and Albers and

_Burgess

_{reported by Piper}

_(1987),

who did not find

any

relationship

between resistance to H contortus and

_haemoglobin

_system.

Thus,

although

our data do not lead to detection of _any

_relationship

of humoral

responsiveness

(to

human serum

albumin)

or of resistance to H contortus with the

haemoglobin

system, there is evidence of a

statistically

significant

effect

(P

<

_0.05)

of the HBALLELE factor

_(haemoglobin

allele received from the

_sire)

on the mean

packed

cell volume

_{(table VII).}

Hence a

_relationship

between

_haemoglobin

_system

and

_{post-infection degree}

of anaemia cannot be excluded.

_According

to the

_adjusted

means, it seems that animals

_carrying

the HbA allele were less anaemic than the others. These results are in

_agreement

with those of Evans and Whitlock

(1964),

Radhakrishnan et al

_(1972),

Altaif and

_Dargie

_(1976,

_1978a,

_b)

and Albers and

Burgess

reported by Piper

(1987).

The

_{post-infection}

differences observed between animals of various

_haemoglobin

_genotypes

_{might simply}

be due to differences

existing

in non-infected animals

_(Agar

et

_al,

_1972).

These differences

_might

arise from _oxygen

_affinity

differences between

_haemoglobins

A and B.

_Haemoglobin

A has a

_higher

_oxygen

_affinity:

at

_equal

_{pressure, it} releases less oxygen, which

might

cause the creation of _compensatory mechanisms in

haemoglobin

A carriers

(Agar

et

_ad,

_1972).

Relationships

between the OLA

_system

with

_{immunological,}

parasito-logical

and

_{haematological}

variables

The results obtained show

_{statistically}

_significant

effects of various OLA

_haplotypes

on the humoral response as well as on the faecal egg counts and the

_degree

of anaemia after

_parasite

infections

_(tables

_VII,

X and

_XII).

_Thus,

we cannot exclude the

_existence,

within or close to the _{OLA system,} of _genes

_affecting

these various

phenomena.

These results

_disagree

with those of

_Cooper

et al

_{reported by Piper}

(1987),

who did not find any association between OLA system and resistance to H contortus. But

_they

do _agree with those of

_Outteridge

et al

_(1984,

_1985,

_1986,

1987 and

₁₉₈₈₎

who found an association between the OLA _system and the _response

to a vaccination

_against

_{Trichostrongylus colubrifo!rmas.}

A

_relationship

between the

major histocompatibility complex

and resistance to nematode

_parasites

has also been demonstrated in the case of the

_{guinea pig-Trichostrongylus}

_{colnbriformis}

system

(Geczy

and

_Rothwell,

₁₉₈₁₎

and the

_{mouse- Trichostrongylus spiralis}

_system

(Wassom

et

_al,

_1979).

CONCLUSION

In terms of

_{parasitology,}

the results obtained lead to a more accurate determination of a certain number of

_phenomena

such as

_{repeatability}

of faecal _egg counts between

infections, negative relationship

between faecal _egg count

_peaks

and self-cure

intensity, positive

relationship

between faecal _egg counts and

_degree

of

_anaemia,

In terms of

_genetics,

the results invalidate the

_hypothesis

that

_{homozygous sheep}

carriers of

_haemoglobin

A have lower faecal egg counts than the others as well as

the

_hypothesis

that animals with the _{best humoral immune response} are the most resistant to

_parasitism.

On the other

_{hand, they}

do not exclude the

_hypothesis

that

genes

within or close to the OLA _system

_might

affect the resistance to H contortus.

The latter

_conclusion,

in

_keeping

with those of other

studies, emphasizes

the role of the OLA _system as a

_potential

marker of resistance to

_parasitism.

ACKNOWLEDGMENTS

The authors are

grateful

to K R6rat

_(Unite

Centrale de

_{Documentation, INRA,}

Centre de Recherches de

_{Jouy-en-Josas)}

for the translation of the

_manuscript.

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