Ch24 - Host Resistance To Gastrointestinal1
Ch24 - Host Resistance To Gastrointestinal1
Ch24 - Host Resistance To Gastrointestinal1
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
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al., 1992; Bendixsen et al., 1995; Pfeffer et al., 1996; S.J. McClure, unpublished obser-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McClure, unpublished observations).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
24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 428
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.
24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 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.
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.
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
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
24 Ruminant Phys Ch24 1/9/00 12:37 pm Page 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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