Interactions of Ostertagia species with their bovine and ovine hosts

Inrrmac,onalJourncll/or Prrnred m Grear Brrrarn

Porasrrology

Vol. 23. No. 4, pp. 451462,

c

INTERACTIONS

002&7519/93 $6.00 + 0.00 Pergamon Press Lfd .Sorrer~/br Purusitology

1993

1993 Ausrralion

OF OSTERTAGL4 SPECIES WITH THEIR BOVINE AND OVINE HOSTS Q. A. MCKELLAR

Department

of Veterinary

Pharmacology, University of Glasgow Veterinary Glasgow G61 lQH, Scotland, U.K.

School,

Bearsden

Road,

Bearsden,

Abstract-Mckm_m Q. A. 1993 Interactions of Ostertagiu species with their bovine and ovine hosts. International Journal fbr Parasitology 23: 45 1462. Ostertagia spp. affect their hosts in several complex interactions involving structural, biochemical, hormonal, nutritional and immunological mechanisms. Following infection with Ostertugia spp. the specialised secretory function and junctional integrity ofgastric epithelial cells is lost. The pH of the abomasal contents is elevated and pepsinogen concentration in the plasma increases. There is a concurrent elevation in the concentration of blood gastrin. The effects may be a response to the physical interaction of parasite with epithelial cells, may be mediated through parasite excretory/secretory products, or by neural mechanisms. There may also be interactions between the responses since elevated abomasal pH stimulates secretion of gastrin. Hormonal changes may also have a role in the increased susceptibility of host to parasite during the periparturient period. Prolactin was considered the most likely hormone candidate although there is now a body of evidence to suggest that elevated prolactin concentrations are not solely responsible. Infection with Ostertugiu spp. causes a marked inappetance, negative nitrogen balance and reduction in apparent gross energy digestion. The level of nutrition may also affect the response of the host to the parasites and establishment of 0. circumcincta is lower in animals on a low plane of nutrition than those on a high plane. Immunity of Osterfugiu spp. develops slowly and once established is manifest following challenge by an initial hypersensitivity response, followed by a cell mediated response and then an antibody response. Parasites may fail to establish or may be expelled from immune animals and if they do establish may be stunted with small vulva1 flaps and lower

biotic potential and may become inhibited at the early fourth stage of development. INDEX KEY WORDS: response;

effect of nutrition;

Ostertagiu ostertagi; Ostertagiu circumcincta; biochemical immune response.

INTRODUCTION THE pathogenesis

of ostertagiasis in cattle and sheep appears to be qualitatively similar although there are differences in time course of the disease and morphology of pathological changes which principally relate to differences in structure of the normal gastric mucosal epithelium. Detailed pathological studies on single infections with Ostertagia ostertagi in cattle (Ross & Dow, 1965a; Ritchie, Anderson, Armour, Jarrett, Jennings & Urquhart, 1966) and 0. circumcincta in sheep (Armour, Jarrett AC Jennings, 1966) demonstrated the gross and histological changes which occur. Infective third stage Ostertugiu larvae exsheath in the rumen and may penetrate gastric glands within 6 h of ingestion (Osborne, Batte & Bell, 1960). By 2 days after infection nodules with umbilicated centres can be identified where the gastric gland containing the larva becomes dilated. The nodules become enlarged as the larvae within the glands grow until the mucosa has a corrugated appearance. As mature parasites emerge from the glands, cytolysis and sloughing of the

response;

endocrine

superficial epithelium enhances the umbilicated appearance and superficial mucosal erosions may become confluent. Histopathologically, cells lining glands occupied by parasites lose their specialised secretory function such that parietal (acid secreting) and zymogenic (pepsinogen secreting) cells are replaced by irregular cuboidal epithelium. As the parasites emerge damage spreads to neighbouring glands which also lose their cellular differentiation. BIOCHEMICAL CHANGES INDUCED BY THE PARASITES Biochemical changes occur in lumen fluid of the abomasum and in the circulation of infected animals. Following a single primary infection with 0. ostertugi in calves a moderate increase in circulating pepsinogen concentration occurs approximately 5 days after infection and a much more substantial increase occurs from day 15 after infection. These changes have been attributed to damage caused by penetration and 451

452

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MCKELLAR

emergence respectively of parasites from the glands which have impaired cell junctional integrity associated with the hyperplastic changes in mucosal epithelium (Jennings, Armour, Lawson & Roberts, 1966; Murray, 1969). A rapid and substantial rise in pH sf abomasal contents also occurs at the time of parasite emergence and is associated with loss of functional activity of parietal cells and has been implicated in the elevated pepsinogen response since pepsinogen is converted to pepsin most effectively at low pH (Jennings et al., 1966). Hypoalbum~naemia ~Martin, Thomas & Urquhart, 1957) and raised gamma globulin (Andersen, Graff, Hammond, Fitzgerald & Miner, 1960; Ross & Todd, 1965) are consistent findings during ostertagiasis and are associated with a ‘leakage’ of albumin into the gastrointestinal tract (Mulligan, Dalton & Anderson, 1963). The enhanced permeability of the bowel wall to macromolecules was demonstrated ultrastructurally when dilated intracellular spaces between epithelial cells with separation of the zonulae occludentes were seen in parasitised gastric mucosa (Murray, 1969). However, the aiterations in blood pepsinogen and albumin concentrations cannot be completely explained by leakage out of and into the abomasum through the separated junctional complexes of the damaged epithelium. Albumin turnover rate has been shown to decline between days 14-22 after infection with 0. c~r&urn~~n~ta in sheep, whereas serum pepsinogen remained elevated and could not be directly related to continuing plasma leak (Holmes & MacLean, 197 1). Also, plasma proteins were found to be reduced in the abomasal contents of calves infected with 0. ostertagi and it has been shown that horseradish peroxidase, which is considered to be a suitable marker for pepsinogen on the basis of their similar molecular weight, leaked from the circulation into gastric contents to a similar degree in infected and non-infected calves (Stringfellow & Madden, 1979). This work suggested that pepsinogen, secreted by zymogen cells, was released directly into the circulation rather than leaked from the abomasal contents through damaged epithelium and is supported by a number of recent studies, Firstly circulating pepsinogen concentration has been shown to rise following transplantation of mainly adult populations of 0. circumcincta into the abomasa of sheep (Anderson, Hansky & Titchen, 1985) and exclusively adult populations of 0. nstertagi into the abomasa of calves (McKellar, Duncan, Armour & McWilliam, 1986; McKellar, Duncan, Armour, Lindsay & McWilliam, 1987). Following transplantation of adult parasite burdens the hyperplastic epithelial changes typical of Iarval infections with Ostertagia spp. do not occur and

leakage is likely to be minimal. Secondly, the antimuscarinic drug atropine caused a marked fall in plasma pepsinogen concentration within two hours of administration to Iambs with burdens of 0. circumcincta. This suggested that the production or secretion of pepsinogen by zymogenic cells was more critical in ostertagiasis than leakage from the abomasum since atropine is unlikely to affect epithehal integrity (Mostofa & McKellar, 1989). Finally, secretions from Ostertugia spp. significantly stimulated isolated preparations of dispersed gastric glands from bovine and ovine abomasal mucosa to secrete pepsinogen (McKellar, Mostofa & Eckersall, 1990a). The exact mechanism for the elevated blood pepsinogen is not yet completely defined and it may be that it is multifactorial involving direct stimulation of zymogenie ceils by factors released from the parasite, indirect stimulatjon via elevated circulating concentrations of hormones such as gastrin (ride infi-a) and leakage from abomasal fluid between poorly differcntiated epithelial cells. Although a number of different types and subtypes of pepsinogen exist in cattle and sheep the relative concentrations of each subtype in the blood do not appear to differ when cattle are infected with third stage larvae, when adult 0. ostertagi are transplanted directly into the abomasum or when previously cxposed cattle are challenged with infective larvae. Nor do there appear to be differences in the circulating pepsinogen subtypes in sheep challenged with 0. c~r~urn~~ncta or ~uem~nchus ~~nt~rtus which is a blood sucking abomasal nematode (Eckersall, Macaskill, McKellar & Bryce, 1987; McKellar. Eckersall, Duncan & Armour, 1988; Mostofa, McKellar, Eckersall & Gray, 1990). The elevated abomasat pH demonstrated following infection with 0. ostertagi was associated with rapid replacement of parietaf cells by undifferentiated cells as parasites emerged from the gastric glands (Jennings et al., 1966). Although Stringfellow and Madden (1979) identified parietal cells in the fundus, even at 30 days after infection they were sparse in the immediate vicinity of infected gastric glands and carbonic anhydrase activity was negligible throughout the tissue from day 26 onwards suggesting that these parietal cells were inactive. In rats an injected extract of homogenised 0. ostrrtagi has been shown to elevate the pH of gastric secretion and it has been suggested that hypochlorhydria during ostertagiasis may be mediated partially by a chemical released from the parasite (Eiler. Baber, Lyke & Scholtens, 1981). The interactions of parasite secretory factors and hormones have been studied in 0. circumcincta infected sheep. (McLeay, Anderson, Bingley & Titchen, 1973). Sheep surgically prepared with separated fundic

Ostertngiaspecies and host interactions

pouches were orally infected with 0. circumcincta. An increased volume of secretion and increased acid output was obtained from the pouch 4 days after infection and parietal cells of the pouch had the appearance ultrast~cturally of cells subjected to strong secretory stimuli. Coincident with pouch changes, acid secretion from the infected part of the abomasum decreased and parietal cells had features of inactivity. Two different mechanisms were thought to be operating. First, a factor released locally from the parasites was considered responsible for inhibition of parietal cell function and second, it was suggested that increased concentrations of circulating gastrin might account for the increased secretion of hydrochloric acid from the pouches. The effect of 0. ostertagi secretions on dispersed bovine abomasal gland cells has been determined iti vitro using aminopyrine a~umulation in parietal cells as a marker of acid production. Parasite secretions did not directly affect the production of acid by parietal cells (McKellar, Mostofa & Eckersall, 1990b). This finding suggests that the elevated abomasal pH observed during 0. ostertagi infection is not a response to parasite secretions but reflects a loss of mature acidsecreting parietal cells as reported by Murray, Jennings & Armour (1970) and that these cells are unable to respond to the stimulatory effect of elevated gastrin concentrations (vi& @a). It is, however, possible that factors released locally by parasites could act indirectly through neural mediation to cause the reduction in acid production. It is also possible that the mechanisms of acid inhibition differ between Ostertagia spp. infection in sheep and cattle or that the response is related to the number of parasites present and consequently the amount of secretory product produced. The elevated abomasal pH which occurs during ostertagiasis may create a more favourable environment for the survival of the parasites since 0. osfertagi have been shown to survive longer at pH 7.0 than at pH 2.2 (Eiler et al., 1981) and 0. ostertagi parasites suspended in cages within a normal abomasum (pH approximately 2.2) rapidly die (Q. A. McKellar, Unpublished Ph.D. Thesis, University of Glasgow, 1984). Nevertheless when adult parasites are transplanted into animals with normal abomasa they survive for prolonged periods and they do not markedly alter the pH of the abomasal contents (McKellar et al., 1987). It may be that they live in the mucus layer on the mucosa where the microenvironment differs markedly from that of the abomasal lumen. Also, adult 0. ostertagi are still active in peptic digests of low pH for up to six hours following collection and other factors may have caused their death in the studies of Eiler et al. (1981) and Q. A. McKellar (1984 Thesis cited above). The consequences of the biochemical changes in

453

plasma protein concentrations are of more relevance to nutritional alterations which occur during ostertagiasis and most other biochemical changes are of minor importance or have not been investigated in detail. Nematode cholinesterase activity has aroused interest and acetylcholinesterase secretion has been described from a number of parasite species (Ogilvie, Rothwell, Bremner, Schnitzerling, Nolan & Keith, 1973). Cholinesterase activity has been determined in 0. circumcincta and it was shown that sheep with high faecal egg counts had higher cholinesterase activity than sheep with low faecal egg counts. Female parasites had higher cholinesterase activity than males and cholinesterase activities declined with the age of the host sheep @ouch, Harrison, Buchanan & Greer, 1988). Cholinesterase activity could markedly affect cell secretions and gastrointestinal motility although in Ustertagia spp. infections this seems unlikely since it appears to be confined to the parasite and much less is released or secreted into gut lumen than from other intestinal nematodes such as 7’richostrongyfus species (McKeand J., personal communication). BIOCHEMICAL CHANGES IN THE HOST WNICH AFFECT THE PARASITE

Studies have been carried out in which the normal biochemistry of the host has been altered experimentally and consequent effects on parasite burdens or challenge have been assessed. The intra-abomasal administration of arachidonic acid in lambs with 0. circumcincta burdens resulted in expulsion of a large proportion of the worms (Dakkak & Daoudi, 1985). Arachidonic acid is a precursor of prostanoids and leukotrienes which have been implicated in expulsion of and resistance to gastrointestinal parasites (Kelly & Dineen, 1976; Douch, Harrison, Buchanan & Brunsdon, 1984). It is also possible that a change in abomasal pH could have been associated with expulsion of the worms since the administration of arachidonic acid caused a temporary exacerbation of the elevated abomasal pH associated with the parasites which lasted for about 24 h (Dakkak & Daoudi, 1985). Prostaglandins are thought to exert direct actions on the metabolism of gastrointestinal parasites as well as indirect effects on the host such as increased vascular permeability, gut peristalsis and degranulation of myeioid cells which facilitate worm expulsion (Kelly & Dineen, 1976). Concentrations of endogenous prostaglandins in the wall of the gastrointestinal tract have been shown to rise during parasitic infection (Dineen & Kelly, 1976) and inhibitors of prostaglandin synthesis such as the non-steroidal antiinflammatory drug aspirin have been shown to prevent

454

Q. A.

MCKELLAR

the expulsion of Nippostrongylus brasiliensis in rats (Dineen, Kelly, Goodrich & Smith, 1974). However, the potent prostaglandin inhibitor meclofenamic acid did not significantly affect the establishment of 0. cjrcumcjncta in lambs or in adult immune ewes during challenge with third stage 0. ejr~~~~c~~c~~ larvae (Mitchell, McKellar & Bogan, 1990). The direct artificial elevation of abomasal pH with the histamine receptor antagonist cimetidine has also been shown to cause expulsion of 0. circurncincta in sheep (Hall & Oddy, 1984) ahhough a direct anthelmintic effect of the cimetidine could not be discounted. The effect of the antacid drug omeprazole which acts by blocking the hydrogen ion pump in the parietal cells has also been investigated. Omeprazole was administered to sheep which had been previously exposed to 0. circumcincta and treated with an anthelmintic. It was given just before and for three days after a challenge with 200,000 0. circumcincta larvae and did not significantly reduce the establishment of the parasites compared to sheep which were not given the omeprazole (Mitchell, McKellar, Bogan & Moqbell, unpublished data). It is dilTicult to interpret the results from studies designed to determine the effects of biochemical changes since the chemicals used to induce the changes may directly affect the parasites or may cause secondary changes such as hormonal and motility alterations with adverse effects on the parasites (Fox, Gerrelli, Shivalkar & Jacobs, 1989). HORMONAL CHANGES INDUCED BY PARASITES Interest in hormonal changes induced by Ostertagia spp. was stimulated by the hypothesis that blood gastrin concentrations became elevated in 0. circumcincta infections in sheep (McLeay et al., 1973). Gastrin is a peptide hormone which has a positive role in abomasal acid secretion, and exocrine (pepsinogen) secretion, and which inhibits motility of the reticulum, rumen and abomasum (McLeay & Titchen, 1975; Grovum & Chapman, 1982; Bell, Titchen & Watson, 1977). It is also known to have trophic effects on gastrointestinal mucosa (Johnson, 1980). Elevated circulating concentrations of gastrin have been confirmed by radioimmunoassay in 0. circumcincta infected sheep (Anderson, Blake & Titchen, 1976; Anderson, Hansky & Titchen, 1981) and in 0. ostertagi infected cattle (Entrocasso, McKellar, Parkins, Bairden, Armour & Kfoosterman. 1986; Fox. Gerrelli, Pitt, Jacobs, Hart & Simmonds, 1987). The aetiology of the etevated gastrin concentrations is uncertain. In cattle it occurs coincident with the period of elevated abomasal pH and since gastric acid inhibits gastrin release it has been suggested that it is a response to the pH change (Entrocasso et al., 1986: Fox ef al.. 1987).

Furthermore there was no significant gastrin response in calves into which adult 0. ostertagi were transplanted surgically and in which there was no rise in abomasal pH values (McKeIlar et al., 1987). However, elevated gastrin concentrations occurred before abomasal pH values increased and were observed following infection with larval and adult stages of 0. circumcincta in sheep (Anderson et al., 1985). It is as yet unclear whether the stimulus for the early elevation in circulating gastrin in sheep is a direct physical stimulus by the parasites on gastrin secreting cells or a chemical stimulus released by the parasites. In sheep with surgically prepared fundic pouches and orally infected with 0. circumcincta there is a marked increase in acid secretion within the pouch and it has been suggested that this was attributable to the stimulating effect of elevated circulating gastrin. The fundic pouch hypersecretion was not observed in sheep infected with 0. circumcincta after surgical removal of the abomasal antrum indicating that the hypergastrinaemia is of antral origin (Anderson, Hansky & Titchen, 1975). Gastrin has also been shown to rise in cattle with Type II ostertagiasis (Entrocasso, McKellar, Parkins, Bairden, Armour & Kloosterman, 1986) but not in immune adult dairy cattle challenged with single or trickle infections of 0. ostertagi which do show a marked pepsinogen response (Q. A. McKellar, 1984, Thesis cited above). Gastrin exists in two forms which differ in number of amino acids and which have been called big gastrin and little gastrin. Recent work has demonstrated that during infection of the calf with 0. ostertagi the elevated concentrations of gastrin are principally attributable to big gastrin and suggest a failure in processing and reduction in storage of the larger molecule (Fox M. T., personal communication). The trophic effects of gastrin on gastrointestinal mucosa may have a role in the aetiology of the hyperplastic changes seen in abomasal epithelium during ostertagiasis. Serum gastrin immunoreactivity has been shown to correlate with the degree of mucosaf hyperplasia in calves infected with 0. ostertagi and it has been suggested that this could be a parasite survival mechanism (Snider, Williams, Karns, Markovits & Romaire, 1988). Changes in circulating concentrations of other hormones have been studied following Ostertagiu spp. infections. Pancreatic polypeptide is a peptide hormone which suppresses pancreatic secretion and may also inhibit gastric secretion and gastric and intestinal motility (Titchen, 1986). It is at least partly under vagal control mediated by a muscarinic cholinergic mechanism which may be blocked by atropine. The concentration of pancreatic polypeptide was shown to

Ostertugiaspecies and host interactions fall in sheep following transfer of mixed larval and adult, and predominantly adult populations of 0. circumcincta directly into the abomasum, and this was followed by an apparent rebound elevation from day seven after transfer. Unfortunately fluctuations in concentrations of the peptide precluded definitive interpretation of these changes (Anderson et al., 1985). Endocrine mechanisms have been implicated in metabolic changes which occur during ostertagiasis, and include reduced feed intake, protein metabolism and energy utilisation. Thyroid hormones increase basal oxidative metabolism, stimulate gluconeogenesis and lipid catabolism, and alter protein metabolism. Thyroxine concentrations decrease in Trichostrongy/us colubriformis infected sheep (Prichard, Hennessy & Griffiths, 1974) and 0. circumcincta infected sheep (Sykes & Coop, 1977) and the effects of 0. ostertagi infection on selected adrenal, pituitary and thyroid hormones have been investigated in detail by Fox et al., (1987). No significant differences in cortisol or growth hormone were identified between infected and pair-fed control groups although over a 33-day infection period there was a reduction of 1.2 ng ml-’ in growth hormone in infected calves compared to an increase of 2.7 ng ml-’ in the control calves. A depression in total thyroxine concentration occurred and was attributed to reduced feed intake since it also occurred in the pair-fed controls; also significant decreases in insulin concentration were observed intermittently from day 17 in the infected calves and it was suggested that this reflected changes in protein metabolism. In a similar study designed to determine the effects of a trickle infection of 0. ostertagi, growth hormone concentrations increased significantly in the infected calves compared to controls. These animals had reduced appetite and significant increases in plasma urea, non-esterified fatty acid concentrations and an increase in the ratio of growth hormone: insulin (Fox, Gerrelli, Pitt, Jacobs, Gill & Simmonds, 1989). The differences in response by growth hormone in single and trickle challenge infections is as yet unexplained. HORMONAL CHANGES IN THE HOST WHICH AFFECT THE PARASITE Undoubtedly many of the hormonal changes which are induced in the host by the parasite will in turn affect the parasite; for instance, the abnormally high gastrin response will act as a constant stimulus for gastric zymogenic and parietal cells thus altering the environment for the parasite. There are, however, hormonal changes which occur in the host independent of infection but which may influence parasite establishment, growth, survival and reproductive physiology. Hormonal changes in ewes which occur at or around

455

parturition have been implicated in the rise in faecal output of worm eggs at this time. This rise has been attributed to maturation of previously arrested larvae, increased establishment of newly acquired larvae and increased fecundity of female worms (Connan, 1968; O’Sullivan & Donald, 1970). It has also been suggested that expulsion of established parasites is reduced (Michel, 1974; 1976). The proximity of the rise in nematode faecal egg count with parturition and lactation suggested that hormonal changes in the host at this time could be responsible. Prolactin is a lactogenic hormone which is secreted during lactation and becomes further elevated in response to suckling (McNeilly, 1971). When the suckling stimulus was removed in ewes the periparturient rise in faecal egg output was largely negated (Salisbury & Arundel, 1970). Moreover elevated prolactin concentrations induced in non-pregnant ewes by injection of diethylstilboestrol or acepromazine caused increased nematode faecal egg output (Gibbs, 1967; Salisbury & Arundel, 1970; Blitz & Gibbs, 1972; Connan, 1973). Recent studies in which udder development and milk production were stimulated in non-pregnant ewes with dexamethasone, oestradiol 17p and progesterone and in which prolactin concentrations consequently rose there was no consistent increase in nematode egg output (Coop, Mellor, Jackson, Jackson, Flint & Vernon, 1990). Furthermore, the synthetic dopamine agonist, bromocryptine, was successfully used to suppress prolactin concentration in ewes during the post-partum period without affecting the dynamics of the periparturient egg rise (Jeffcoate, Fishwick, Bairden, Armour & Holmes, 1990). Progesterone (Lloyd, 1983) and cortisol (Connan, 1973) have also been implicated in the periparturient rise and it has been suggested that the effector mechanism is one of immunosuppression. However, administration of exogenous progesterone and dexamethasone had no effect on the faecal egg output in the study by Coop et al. (1990). Cell mediated and humoral immunity were assessed by BCG inoculation and raised antibody titre against horse red blood cells respectively in ewes with inhibited prolactin response at lambing and neither were found to be impaired (Jeffcoate et al., 1990). It is apparent that the aetiology of the periparturient rise is still unknown but that hormonal changes are probably implicated. The resumption of development of inhibited or hypobiotic fourth stage Ostertagia spp. may also be related to hormonal status. It has been postulated that inhibited 0. ostertagi spontaneously and synchronously resume development in a manner resembling diapause in insects (Armour & Bruce, 1974). However, Michel (1974) suggested that a regular turnover of inhibited

456

Q.

A.

MCKELLAR

0. ostertagi proceeds in the host, regulated by the number of adults present. Hormonal changes in the host have been investigated as a trigger to the resumption of larval development. Treatment of cattle with pregnant mare serum, luteinising hormone and stilboestrol did not render inhibited larvae susceptible to anthelmintics in trials by Armour, Jennings, Reid & Selman (1975) nor did the luteinising hormone-like activity of human chorionic gonadotrophin (Cummins & Callinan, 1979). A rise in circulating oestrogens in adult cows near parturition has been associated with relaxation of immunity and maturation of inhibited larvae (Wedderburn, 1972) and may be similar to a component of the periparturient rise in 0. circumcincta in sheep. The changes in cows occurred at the time of year when inhibited larvae are maturing anyway and their significance is uncertain. It appears unlikely that a hormonally mediated depression of immunity alone is responsible for the maturation of inhibited fourth stage larvae, since J. Armour (Unpublished Ph.D Thesis, University of Glasgow, 1967) and Prichard, Donald & Hennessy (1974) could not demonstrate resumed development of inhibited larvae in calves treated with immunosuppressive doses of corticosteroid. NUTRITIONAL CHANGES INDUCED BY THE PARASITES The effects of gastrointestinal helminth parasites on ruminant nutrition have recently been comprehensively reviewed by Parkins & Holmes (1989). Ostertagia spp. have been shown to affect feed intake, feed utilization and wool and milk production. The reduction in feed intake is possibly the most important nutritional consequence of Ostertagia infection and may be associated with abdominal pain, altered abomasal pH, gastrointestinal motility, elevated circulating hormone concentrations, or direct neural effects on the central nervous system. Pain may be associated with local damage in the abomasum, although this is difficult to quantify. Elevated pH limits abomasal protein digestion and the consequent altered amino acid production could affect food intake since some amino acids are known appetite stimulants (Leng, 1981). Gastrointestinal motility is generally reduced as a result of nematode parasitism (Gregory, 1985) and the hormone gastrin becomes elevated during ostertagiasis (vide supra). Artificially elevated gastrin concentrations similar to those observed in ostertagia infected calves were induced using omeprazole and resulted in up to 40% reduction in food intake (Fox, Gerrelli, Shivalkar & Jacobs, 1989). Infections with 0. circumcincta in sheep have been shown to induce marked negative nitrogen balance

and reductions in apparent gross energy digestion (Parkins, Holmes & Bremner, 1973; Sykes & Coop, 1977). Proteins are lost into the gastrointestinal tract during ostertagiasis from plasma and as a result of exfoliation of epithelial cells and mucus. Plasma losses of 90 ml per day in sheep infected with 0. circumcincta and 500 ml per day in calves infected with 0. ostertagi have been reported (Parkins & Holmes, 1989). A substantial amount of the nitrogen lost into the gut from the abomasum is re-absorbed along the small intestine and it has been suggested that nitrogen lost as a result of Ostertagiu spp. infection would be compounded if the host had concurrent intestinal nematode burdens (Steel, 1978; Steel, Jones & Symons, 1982). Concurrent infections with 0. circumcincta and T. vitrinus did not substantially increase the depression of growth rate in lambs compared to monospecific infections (Coop, Field, Graham, Angus & Jackson, 1986; Coop, Jackson, Graham & Angus, 1988). Gastrointestinal protein loss does not completely explain the negative nitrogen balance experienced during ostertagiasis since a rise in catabolic rate of albumin and increased plasma urea and urinary nitrogen excretion are features of the disease. These changes may be attributed to endogenous catabolism associated with inflammatory changes in the abomasum (Holmes & MacLean, 1971; Parkins et al., 1973). A trickle infection of 0. ostertagi in calves has also been shown to cause reduced nitrogen digestibility and caused reduced rate of passage of digesta which it was suggested may have been a response to hypergastrinaemia (Fox, Gerrelli, Pitt, Jacobs, Gill & Gale, 1989). Calves naturally infected with 0. ostertugi also had reduced nitrogen retention which was mainly attributed to increased urinary nitrogen excretion (Parkins, Bairden & Armour, 1982). Energy utilization is also compromised during ostertagia infections and Sykes & Coop (1977) demonstrated a 30% reduction in utilization of metabolisable energy in lambs infected with 0. circumcincta. It has been suggested that much of the reduced digestible energy of food in parasitised sheep and calves may be attributed to increased turnover of epithelial cells and plasma albumin (Sykes & Coop, 1977; Parkins, Taylor, Holmes, Bairden, Salman & Armour, 1990). Ostertagia circumcincta has been shown to affect mineral metabolism in lambs, reducing calcium and phosphorus deposition by 65% compared to noninfected pair-fed controls. The impaired deposition has been attributed to matrix osteoporosis resulting from protein deficiency rather than reduced absorption of the minerals (Sykes, Coop & Angus, 1977; Wilson & Field, 1983). The overall effect of altered nutrition as a result of

Osrertagiuspecies and host interactions Ostertagia spp. infection is poor carcass quality (Entrocasso, Parkins, Armour, Bairden & McWilliam, 1986) reduced wool production (Symons, Steel & Jones, 1981) and reduced milk production (Bliss & Todd, 1973; 1976; Leyva, Henderson & Sykes, 1982). There is some debate, however, whether gastrointestinal parasitism has a significant effect on milk production in mature lactating dairy cattle which may be highly resistant to parasitic damage (Parkins & Holmes, 1989). NUTRITIONAL

CHANGES

IN THE HOST WHICH

AFFECT THE PARASITE

The plane of nutrition on which parasitised animals are maintained undoubtedly affects their overall response to the parasites. Nutrition may influence the resistance of the host to the effects of infection or it may affect the establishment of the infection. Animals fed a high protein diet are less severely affected than those on low protein diet when infected with a variety of parasites (Kates & Wilson, 1955; Gibson, 1963; Orraca-Tetteh & Platt, 1964) and in sheep infected with 0. circumcincta a more severe negative nitrogen balance was observed in those infected animals fed lower amounts of crude protein (Parkins et al., 1973). The establishment of 0. circumcincta was also significantly lower in sheep on a low plane of nutrition than in those on a high plane (Brunsdon, 1964) although this study was complicated by the fact that the sheep had mixed trichostrongyle infestation. In a series of detailed studies the effect of nutrition was examined in sheep infected with the blood sucking abomasal nematode Haemonchus contortus. Following single infection high levels of dietary protein did not significantly affect the establishment of the parasites, however it did affect the ability of the animals to withstand the pathophysiological consequences of the infection. Lambs on a low protein diet had more severe anaemia, hypoproteinaemia and hypoalbuminaemia than those in the high protein group (Abbott, Parkins & Holmes, 1985; 1986). In lambs given continuous infections of H. contortus, a high protein diet did appear to positively affect the development of resistance although dietary protein did not influence the response to vaccination with irradiated H. contortus (Abbott, Parkins & Holmes, 1988; Abbott & Holmes, 1990). Similar studies would be of considerable interest in sheep or cattle infected with Ostertagi spp. in which the pathophysiological basis of the disease is fundamentally different. IMMUNE RESPONSES

INDUCED

BY THE

PARASITES

Effective immunity to infection with Ostertagia spp. develops slowly. Calves exposed to natural infection at

457

pasture are still susceptible to challenge mid-way through their first grazing season (Ross & Dow, 1965b). However, prolonged daily exposure over 5-8 months duration whether by natural acquisition (Ross & Dow, 1965b) or by experimental infection (Michel, Lancaster&Hong, 1973) confers protection. Similarly in lambs continuously infected with 0. circumcincta substantial immunity develops after about 2 months (Smith, 1988). The responses induced by parasite challenge differ somewhat in parasite naive animals and in animals which have been previously infected and have consequently developed immunity. In previously naive sheep challenged with 50,000 0. circumcincta larvae a lymphoblast response develops 8 days after infection and is maintained for at least 3 weeks (Smith, Jackson, Jackson & Williams, 1983). In immune sheep an initial hypersensitivity response is followed by a cell mediated and then an antibody response. The hypersensitivity response may reflect degranulation of sensitised mast cells and globule leukocytes in the gastric mucosa with release of protease, histamine and leukotrienes (Huntley, Gibson, Brown, Smith, Jackson & Miller, 1987; Smith, 1988). It has previously been suggested that vasoactive mediators released during the hypersensitivity response are responsible for the increased mucosal epithelial permeability and consequent leakage of pepsinogen out of, and protein into, the abomasum (Yakoob, Holmes & Armour, 1983). However, the mast cell stabilising agent cromoglycate did not reduce the pepsinogen response in previously infected adult ewes challenged with 0. circumcincta and the response may not be solely a result of mast cell degranulation (McKellar & Bogan, 1987). The maximum cellular response is seen in gastric lymph 3 days after challenge and consists of lymphoblastic and IgA containing cells which have been shown to confer immunity if transferred to genetically identical susceptible sheep (Smith, Jackson, Jackson, Williams, Willadsen & Fehilly, 1986). It was suggested that the effector mechanism of the immunity was indirect rather than associated with direct cytotoxic effects of the cells. A third component of the immune response to parasite challenge is a substantial increase in antibody concentration in gastric lymph peaking 6 days after challenge. Immunoglobulin A, produced by the abomasal mucosa, may be responsible for the retarded length of those worms which establish although transfer of antibodies in immune lymph plasma has not successfully conferred immunity upon susceptible recipients (Smith, Jackson, Jackson & Williams, 1985; Smith, 1988). Such detailed studies have not been carried out in the bovine although elevated levels of serum IgG, IgM and IgA have been demonstrated in bovine ostertagiasis (Jensen & Nansen, 1978).

458

Q. A. MCKELLAR

Immunity is acquired more rapidly to 0. ostertugi in adult cattle than calves (Michel, Lancaster & Hong, 1979) and to 0. circumcincta in adult sheep than lambs (Smith et al., 1985). The reason for the age related effect is obscure and not apparently due to an inability of the younger animals to mount protective immune responses per se. Smith et al. (1985) suggested that it may be an inability to mount a secondary mucosal immune response. Attempts have been made to vaccinate against 0. ostertagi in cattle using irradiated larvae (J. Armour, 1967. Thesis cited above); or the related and potentially more immunogenic species 0. leptospicularis administered orally (Q. A. McKellar, 1984, Thesis cited above). Ostertugiu ostertagi has also been administered intraperitoneally or exoantigens of 0. ostertagi intraperitoneally and intravenously (Herlich & Douvres, 1979). All these regimens and similar attempts with irradiated 0. circumcinctu in sheep (Smith, Jackson &Jackson, 1982) have proved unsuccessful. Despite the poor results obtained so far. the identification of specific protective antigens and the use of recombinant DNA and monoclonal antibody techniques may yet provide a vaccine (Smith, 1988). EFFECT OF IMMUNE

RESPONSES

ON THE

PARASITES

The most dramatic and important response by the parasite to host immunity is that it fails to establish or that it is expelled. More subtle responses have also been observed particularly relating to morphology of the parasites. In 0. ostertugi the development of the vulva1 flap is greatly reduced in resistant animals (Michel, 1967). The size of the parasites may also be reduced and Q. A. McKellar (1984), Thesis cited above, demonstrated large numbers of worms less than 0.55 cm long in previously infected 9%15-monthold-calves whereas all worms recovered from 5month-old parasite naive calves were greater than 0.55 cm long, both groups were infected with the same numbers of larvae and killed 21 days after challenge. Similarly the number of eggs in the uteri of female worms was much lower (mean 3.02) in the previously infected calves compared to the previously naive calves (mean 14.33) confirming the observation of Michel(l963) that acquired immunity affects the biotic potential of 0. ostertugiu females. Ostertugiu circumcinctu have also been shown to have reduced growth in immune sheep and this has been closely correlated with the size of the IgA response. It was suggested that IgA may block enzymes essential for the feeding of the growing parasites (Smith et al., 1985). Ostertagia larvae may also become inhibited or arrested in their development at the early fourth larval

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