24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 425

24 Host Resistance to
Gastrointestinal Parasites
of Sheep
S.J. MCCLURE, D.L. EMERY AND J.W. STEEL
CSIRO Animal Production, McMaster Laboratory, Prospect, New South Wales,
Australia

Introduction

Sustainable parasite control requires an understanding of the mechanisms involved in

the immunological resistance, and of how such mechanisms can be induced.
We will concentrate here on those nematodes whose parasitic stage is solely
restricted to the gastrointestinal tract. Relatively isolated from the systemic immune
system, this presents a particular set of problems to the host immune system and to
livestock managers. Some of the aspects of the acquisition of immunity and mechan-
isms of resistance to these species may also operate in infections with parasites such as
lungworm (Dictyocaulus) and tapeworms (Taenia) which have a gastrointestinal stage to
their life cycle.
The most common pathogenic nematode species of the ruminant gastrointestinal
tract are Teladorsagia (Ostertagia), Haemonchus (H) (abomasum), Trichostrongylus (T)
(abomasum and small intestine), Nematodirus, Cooperia (small intestine) and
Oesophagostomum (large intestine). Some occur and are equally pathogenic in more
than one ruminant species, while others are host specific. These parasites have a direct
life cycle consisting of free-living stages on pasture (egg to infective larvae, L3) and,
after ingestion, parasitic stages (L4 to adult) in the host gastrointestinal tract. They do
not have a tissue migratory phase. There are, however, some differences in their rela-
tionship with the host gut tissue, and therefore with the host immune system.
Haemonchus attaches to the mucosa of the abomasum and sucks blood. Ostertagia and
Oesophagostomum larvae penetrate into the abomasal glands or colonic mucosa before
emerging and residing on the mucosal surface. Trichostrongylus live in mucus-covered
tunnels eroded on the surface of intestinal villi or abomasal folds.

© CAB International 2000. Ruminant Physiology: Digestion, Metabolism,

Growth and Reproduction (ed. P.B. Cronjé) 425
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426 S.J. McClure et al.

Gastrointestinal defence mechanisms to parasitic nematodes of sheep

Inductive and effector phenomena

Most adult ruminants exhibit naturally-acquired protective immunity to the endemic-

species of gastrointestinal nematodes. However, immunologically naive animals are vul-
nerable to infection and disease for a period, as protective immunity to most worms
takes several months to develop. The speed with which immunity develops is influ-
enced by the dose of larvae ingested (Dobson et al., 1990). As protection develops,
animals sequentially acquire the ability to reject incoming larvae (after 5–7 weeks of
continuous exposure), depress fecundity (after 10–12 weeks), and finally to expel adult
worms (16–20 weeks later). The development of immunity against worms may require
the reversal of an active mechanism (termed oral tolerance) which suppresses immune
reactivity to ingested proteins in food. Reversal of oral tolerance allows the induction of
hypersensitivity responses associated with worm rejection. It is most likely that the
mucosal inflammation induced by parasites and the presence of infectious microorgan-
isms (e.g. bacteria) are central to the induction of acquired mucosal immunity.
However, the mucosal immune system is slower to invoke hypersensitivity responses
than antimicrobial immunity and restricts these to the site of worm establishment.
While our knowledge may be deficient concerning precisely how mucosal-dwelling par-
asites induce protective immunity, there is no reason to think that there are significant
differences between species of worms in the type of host immune response they induce,
although the relative importance of various components of that response may differ.
Despite considerable research and understanding about the responses occurring at the
time of immune rejection of worms, most of these responses are associations or correla-
tions only at this stage – we do not know whether they are causal or casual. A few have
been examined in in vivo depletion studies in an attempt to address this question of
which responses are protective. It is known that immunity to re-infection is triggered
by antigens on incoming worms to which the animal is sensitized. This induces the
release of inflammatory mediators which can cause rejection of the target species or
unrelated worms attempting to establish in the same location or downstream of it
(Dineen et al., 1977).
Sheep that are fully immune to a roundworm species and which have been
exposed within the previous 7 weeks (‘hyper-immune’) can mount a ‘rapid rejection’
response, preventing establishment of Haemonchus third-stage larvae within 30 min
(Jackson et al., 1988) and eliminating incoming Trichostrongylus larvae from the entire
15 m of the small intestine within 2 h (Wagland et al., 1996). This is thought to be a
mucosal mast-cell-mediated hypersensitivity response, and is associated with large
numbers of mucosal mast cells and globule leucocytes, and with local production of
mast cell protease. If this hyperimmune state has lapsed, or previous exposure was
insufficient to generate this degree of immunity, rejection takes somewhat longer –
approximately 5–14 days (McClure et al., 1992). It is then associated with increases in
local lymphocytic and humoral immune responses, in addition to the mast cell involve-
ment.
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Host Resistance to Gastrointestinal Parasites 427

Cellular responses

Observations of infections with various worm species suggest that in immune sheep
which have not mounted a ‘rapid rejection’ of incoming larvae, worm challenge
induces a rapid increase (3–5 days after challenge) in lymphoid cell availability to the
gut (especially those lymphocytes expressing the gamma delta T-cell receptor, granulo-
cytes and antigen-presenting dendritic cells) and rapid sequestration and activation of
memory cells in lamina propria (Dawkins et al., 1989; Buddle et al., 1992; McClure et
al., 1992; Bendixsen et al., 1995; Pfeffer et al., 1996; S.J. McClure, unpublished obser-
vations). This appears to be followed by increased activation of lymphocytes in the
draining node and return of memory cells, initially activated and later (> 7 days) rest-
ing, to the blood (Adams and Cripps, 1977; Haig et al., 1989; Emery et al., 1991; S.J.
McClure, unpublished observations).
There are also changes in the local nerves. The autonomic innervation of the gas-
trointestinal tract is complex and extensive, consisting of both extrinsic and intrinsic
nerves. The density of intrinsic nerve cell bodies within the gut is very high, with num-
bers comparable to the total number of neurons within the spinal cord. Sheep immune
to Trichostrongylus colubriformis showed increases in the number and metabolic activity
of enteric nerve fibres following challenge infection, suggesting that the nervous system
can be primed by exposure to nematodes in a similar manner to the priming of the
immune system (Stewart et al., 1995b). In addition, immune and nervous systems can
synthesize and respond to shared chemical mediators. Thus it is probable that the local
and central nervous systems have a role in integrating the anamnestic immunological,
muscular and physiological changes that follow worm challenge into a coordinated and
flexible protective response.
It is not yet clear which of the many associated cellular responses are protective,
and some have been depleted in vivo in an attempt to further define the protective
mechanism. Depletion of CD4+ helper T-cells during challenge of sheep or goats
immunized by viable infection or non-viable vaccines impaired the rejection of
Haemonchus contortus, suggesting a role for CD4+ cells in protection (Gill et al., 1993;
Karanu et al., 1997). Depletion of CD8+ or WC1/Tcrgd+ T-cells during induction of
immunity to T. colubriformis both resulted in enhanced rejection of worms, suggesting
that these cells may be involved in the slowness of normal induction (McClure et al.,
1995). The conventional method for reducing resistance to worms is administration of
glucocorticoids, but a range of cellular responses is affected, and a specific mechanism
has not been identified.

Humoral responses

Systemic
Protective immunity in sheep against abomasal and intestinal worm species is associ-
ated with early increases in worm-specific antibody and IgA concentrations in local
efferent lymph (Smith et al., 1984, 1985; S.J. McClure, unpublished observations),
and with elevated levels of all isotypes of antibody in serum (McClure et al., 1992;
Pfeffer et al., 1996; Shaw et al., 1998). However, with the possible exception of IgA
antibody in Ostertagia infection (Stear et al., 1996), serum antibody level in sheep
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428 S.J. McClure et al.

exposed to viable infection is not consistently predictive of protective immunity. It may

be that serum antibody is particularly relevant for protection against the blood-sucking
worms, as immunity to H. contortus can be transferred passsively with serum in sheep
vaccinated with novel antigens (Smith, 1993).
Rapid rejection is associated with a temporary decrease in serum antibody level
coinciding with a rise in mucus levels of IgG antibody (McClure et al., 1992), presum-
ably reflecting a protease-induced exit of blood proteins into the gut (Miller, 1996).

Local
Immune sheep after challenge have increased concentrations of worm-specific antibody
in gut tissue and mucus, with all isotypes represented in the increase, and an increase in
the number of cells with surface-bound IgE (McClure et al., 1992; Pfeffer et al., 1996).
There are suggestions that IgG1 and IgE correlate best with protection against
Trichostrongylus species, but more studies are required to confirm this.

Neuropeptides

The role of neuropeptides in immunity to worms has not been investigated in vivo.
However, the neuropeptides employed by the enteric nervous system (Substance P,
somatostatin, vaso-intestinal peptide and b-endorphin) rendered mucosal mast cells
more sensitive to limiting concentrations of worm antigens in vitro. These peptides also
enhanced the in vitro proliferation to worm antigen of lymphocytes from mesenteric
lymph node and prefemoral efferent lymph of immune sheep but did not affect specific
antibody production by these cells (Stewart et al., 1995a, 1996).

Inflammatory mediators

Local tissue concentrations and secretion into the intestine of mediators such as leu-
cotrienes, 5-hydroxytryptamine and histamine increase during immune rejection of T.
colubriformis (Steel et al., 1990; Jones et al., 1990). The administration of glucocorti-
coids immediately before challenge abrogates immunity to H. contortus and T. colubri-
formis; however, injection of more specific antagonists of leucotrienes, histamine,
platelet-activating factor or phosphodiesterases failed to affect worm rejection (Adams,
1988; Jackson et al., 1988; Emery and McClure, 1995).

‘Non-specific’ mechanisms

A number of local mechanisms important in the rejection of gut parasites are non-spe-
cific in effect but immunologically specific in induction. They are thus adaptive
responses, developing after exposure to the antigens, and possibly only after exposure to
the viable parasite. They may partly explain the observation that, to date, non-viable
vaccines are less protective against browsing worms than are viable infection or irradi-
ated larval vaccines.
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Host Resistance to Gastrointestinal Parasites 429

Mucus
Mucus per se has been proposed to have a protective role in trapping incoming worms
and preventing their establishment (reviewed by Rothwell, 1989). Protective immunity
to T. colubriformis in Merinos is associated with increased numbers of goblet cells and
increased quantities of mucus in the jejunum (R.G. Windon, personal communica-
tion). The quality of the mucus also changes in sheep immune to gastrointestinal
nematodes, with altered composition of the muco-polysaccharides and -proteins, the
leucotriene content (Douch et al., 1983; Jones et al., 1990, 1994), and the content of
various as yet unidentified molecules with inhibitory effects on nematodes. Mucus also
stabilizes and prolongs the biological activity of inflammatory mediators (W.O. Jones,
unpublished observations). The induction of these mechanisms is not well understood.

Peristalsis
Immunity in sheep to gut worms appears to be associated with increased enteric nerve
fibre number and metabolic activity (Stewart et al., 1995b), and with hypertrophy and
hyper-contractility of local smooth muscle (Tremain and Emery, 1994; S.J. McClure,
unpublished observations). In rodents, gut smooth muscle function is subject to modu-
lation by the immune system, with T lymphocytes, particularly those expressing CD4,
implicated in the alteration of smooth muscle contractility seen by 6 days after infec-
tion with Trichinella spiralis (Vallance and Collins, 1998). These adaptive changes in
gastrointestinal motility persist for some time after exposure to worms, and in addition
to hustling incoming larvae, may have wider and more long-term repercussions in the
physiology and function of the gastrointestinal tract.

Epithelial sloughing and proliferation

If immediate rejection of incoming larvae does not occur, expulsion of T. colubriformis
from immune sheep is associated with transient loss of the jejunal epithelium at 4–5
days after intra-duodenal infection, effectively dislodging the larvae, which do not
embed in the sub-epithelial mucosa (McClure et al., 1992). The epithelium is repaired
within approximately 24 h.

Fluid and electrolyte movement into lumen

Mediators such as mast cell protease disrupt cell junctions, increasing mucosal perme-
ability (Miller, 1996). This both increases the fluid content of the lumen and allows
access of potentially protective host molecules to the worm.

Thus the host mounts a wide range of immune and inflammatory responses to a chal-
lenge infection with worms, and probably no one response is essential or sufficient on
its own for protection.

Influences of parasites on gastrointestinal function of host

Effects of gastrointestinal parasitism on the digestive physiology of ruminants have

been reviewed most recently by van Houtert and Sykes (1996) and Coop and Holmes
(1996) with particular emphasis on quantitative aspects of digestion and absorption.
Depression in food consumption is frequently, but not invariably, observed, and is
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430 S.J. McClure et al.

dependent on the level of intake of infective larvae of small-intestinal (Steel et al.,

1980) and abomasal (Symons et al., 1981) parasites. The mechanisms responsible are
poorly understood although abdominal pain, gut inflammation, pH changes, changes
in digesta flow rate, changes in protein to energy ratios of absorbed nutrients together
with changes in cholecystokinin secretion have all been implicated (Symons, 1985), as
well as neuropeptides and possibly some cytokines (van Houtert and Sykes, 1996).
During continuous infections, appetite begins to return to normal after 10–12 weeks
of larval intake. Although anorexia clearly has a profound effect on overall nutrient
absorption, numerous pair-feeding studies have demonstrated that it does not entirely
account for the impaired productivity of parasitized animals.
Impaired uptake of nutrients at the site of small-intestinal parasite infections is
attributable to deficiencies in digestive enzymes, proliferation of undifferentiated non-
absorbing cells on the villi, and reduced surface area due to villous atrophy (Steel and
Symons, 1982). However, the overall capacity of the ruminant small intestine to digest
and absorb protein appears to be generally unaffected by parasitism at proximal sites
(Poppi et al., 1986; Kimambo et al., 1988a). The increased flow of nitrogen observed at
the ileum during the first 12 weeks of T. colubriformis infection (Steel, 1974; Poppi et
al., 1986; Kimambo et al., 1988a) and at the abomasum and terminal ileum during
Teladorsagia circumcincta (Steel, 1978) and H. contortus (Rowe et al., 1988) infection
have therefore been attributed to increased endogenous nitrogen secretion into the gas-
trointestinal tract. The principal sources of this endogenous nitrogen are increases at
the site of infection in gastroenteric plasma and blood protein loss, turnover and loss
into the gut of mucosal epithelia, and mucoprotein secretion by goblet cells. These
changes appear to be associated in turn, not surprisingly, with an increased rate of pro-
tein synthesis by gastrointestinal tissues (Steel and Symons, 1982) such that there is a
diversion of amino acids away from muscle, bone and wool growth into protein synthe-
sis for processes essential for survival. Although often termed ‘pathophysiological’ these
responses may indeed be an unavoidable component of the development of immune
competence, and it is significant to note that they appear to peak at a time (around 12–
14 weeks) when manifestations of resistance mechanisms in weaner lambs, such as
declining faecal egg count and the progressive expulsion of resident worms, are clearly
evident (Steel et al., 1980; Poppi et al., 1986; Kimambo et al., 1988a).

Cost to the host of protective immunity

The sequelae of physiological and immunological events responsible for the expulsion
of resident adult worm populations in primary infections of young sheep correlates
closely in time with maximal effects on liveweight gain and wool growth, particularly
for small-intestinal infections (Steel et al., 1980; Kimambo et al., 1988a). Continued
infection beyond this time is accompanied by a progressive recovery in productive per-
formance and gastrointestinal function. Whether animals which have acquired a pro-
tective immunity to worm establishment experience a physiological and production
cost during persistent exposure to infective larvae, because of hypersensitivity
responses, has been of considerable interest since reduced wool growth and elevated
plasma pepsinogen concentrations have been recorded in mature ‘resistant’ sheep
under challenge (Barger 1982). Daily challenge of immune sheep for 10 weeks with T.
24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 431

Host Resistance to Gastrointestinal Parasites 431

colubriformis larvae, following a 24-week parasite-free period, elicited a small increase in

plasma nitrogen loss into the gut during the first 9 days, but no other change in nitro-
gen flow in digesta, digestibility or retention, and no excretion of worm eggs in faeces
(Kimambo et al., 1988b). Other studies have recorded immediate but transient
increases in enteric plasma loss 4–6 days after a single challenge of T. colubriformis
given to lambs made solidly immune by vaccination with irradiated larvae (Steel et al.,
1990), and in ‘immune’ ewes taken off contaminated pasture and given daily challenge
with mixed trichostrongyle larvae, predominantly of Ostertagia circumcincta (Yakoob et
al., 1983). However, in young sheep made highly resistant to infection by vaccination
with irradiated larvae, continuous challenge with T. colubriformis larvae for 20 weeks
had no effect on rates of liveweight gain or wool growth, despite evidence of immuno-
logical reactivity in terms of elevated serum antibody levels and total absence of faecal
egg count (Wagland et al., 1982). Protective immunity in terms of larval exclusion and
prevention of worm establishment therefore seems to be effected through changes in
the composition of intestinal mucus, including the content of ‘larval migration
inhibitory factor’, without any detectable metabolic or production cost (Kimambo and
MacRae, 1988).

The non-specific enhancement of immunity

Two features of immunity to worms, namely the role of inflammation in induction,

and the expulsion of parasites via a pharmacologically-mediated non-specific effector
response, raise the possibility of augmenting the levels of resistance to parasites. Feasible
means to increase mucosal inflammation include concurrent (controlled) infections or
infestations, immunomodulators or the judicious use of nutritional supplements. It is
already appreciated that Trichostrongylus and particularly Ostertagia reduce the estab-
lishment of Haemonchus (Dobson and Barnes, 1995) and that genetically-selected resis-
tant sheep mount more rapid and pronounced inflammatory responses to
gastrointestinal nematodes (GIN) parasites (Windon, 1996). Irradiated Haemonchus or
Trichostrongylus larval vaccines also induced about 30% protection against the heterolo-
gous parasite.
Several other manipulations have been found to reduce parasitism:
1. Ground navy beans, given as 10% of pelleted diets and constituting 50% of
digestible dietary protein, significantly (P < 0.05) reduced parasitism in sheep given T.
colubriformis L3 or harbouring a mature infection (Ad) (Fig. 24.1). Sheep were fed the
diet for up to 22 days from the day of infection (L3) or from 3 weeks into a primary
infection (Ad), and in both situations, parasitism was reduced by > 60%. It is hypothe-
sized that lectins within the navy beans increased mucosal inflammation in the same
way that soybean diets can induce diarrhoea in feedlot cattle.
2. Variable levels of resistance, ranging from 35 to 50%, can be achieved against chal-
lenge with T. colubriformis by oral delivery of attenuated Salmonella typhimurium aro A
(H.N. Brahmbatt, unpublished observations) or intraperitoneal inoculation of lipo-
somes (D.L. Emery, unpublished observations).
3. Supplementaton of sheep diets with Mo also decreased levels of parasitism following
challenge (Suttle et al., 1992a, b; McClure et al., 1999).
24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 432

432 S.J. McClure et al.

30,000
Day 15 Day 22
25,000
L3 Ad L3 Ad

20,000
Worm count

15,000

10,000

5,000

0
+ – + – + – + –
Beans (10% of diet; 50% of protein)

Fig. 24.1. A total of 32 sheep were fed a normal ration (2, 16 sheep) or a ration in
which navy beans (10% wt/wt) provided 50% of dietary protein (+, 16 sheep). Eight
sheep from each group were infected with 20,000 Trichostrongylus colubriformis L3
21 days prior to initiation of feeding, to examine effects on established adult worms
(Ad), and the remaining sheep were infected with 20,000 T. colubriformis L3
coincidentally with the diet. Four sheep from each of the four treatment groups were
killed for worm counts after 15 and 22 days of the two rations.

Although the ‘protective’ effects of these relatively diverse treatments could act
directly or indirectly on the gut immune responses of the host, the exact mechanisms
are not resolved at present.

Conclusions

Unlike some internal parasites, GIN of ruminants have a simple life-cycle, and during
their parasitic phase reside only in the gastrointestinal tract of the host. They therefore
present a difficult immunological problem for the host, requiring protective immunity
from an organ normally restrained from reacting to locally-presented molecules, and
one with a good barrier between local immune system and pathogen. The gut immune
responses associated with rejection of these parasites are physiologically complex and
appear to contain much redundancy in that there is no evidence that any one mecha-
nism is essential for protection. Protective immune responses against GIN parasites
which are allergic in nature are also highly regulated within the local mucosal environ-
ment to avoid systemic sequelae. Mucosal immune responses come at considerable cost
to the host in terms of cell and protein loss, reduced nutrient absorption and increased
metabolic demand for nutrients; a cost exacerbated by the damage to gastrointestinal
function due directly to the worm.
It should be remembered that these mechanisms are subject to a number of influ-
ences. These include physiological factors such as age, liveweight and sex, and external
factors such as nutrition and weaning stress. The nutritional requirements for optimal
mucosal immunity appear to be greater than currently recognized, and additional to
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Host Resistance to Gastrointestinal Parasites 433

those required to meet the demands of growth and production. The efficacy of the
mucosal immune responses can also be enhanced by altering the local immunological
environment, for example the degree of inflammation. Thus gut immunity is not an
isolated component of ruminant physiology, but is highly integrated with the nervous,
digestive and endocrine systems, and underlaid by a common cell biology regulating
signalling, activation, metabolism, replication and differentiation. In such a situation,
intervention which is directed towards addressing any single factor contributing to sus-
ceptibility will predictably have limited prospects of success.

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