The effect of Haemonchus contortus infection on the pregnant and lactating ewe.
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Haemonchus contortus: the uptake and metabolism of closantel.
Closantel is an anthelmintic which associates with plasma albumin and is useful for the control of sheep parasites, such as Haemonchus contortus, that ingest blood. However, the utility of closantel for parasite control has been threatened by the emergence of resistance. The mechanisms of resistance are unknown. A closantel-resistant and a closantel-susceptible isolate of H. contortus were compared with respect to the distribution and metabolism of closantel. Neither strain appeared to metabolise closantel in vitro or in vivo. Following treatment of infected sheep with radioactively labelled closantel, isotope levels in closantel-resistant adult H. contortus were significantly lower than in susceptible worms. This reduced accumulation of drug could contribute to closantel resistance by mechanisms such as reduced feeding, failure to dissociate the drug-albumin complex in the gut or increased efflux of closantel from resistant worms.
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Are the 26-kDa somatic and the 24-kDa excretory/secretory antigens of Haemonchus contortus one and the same?
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Animals↗
Novel sources of anthelmintics.
The G-series of naturally occurring compounds from Eucalyptus species contain representatives that are endoperoxides and Mannich bases. Mannich bases have been shown to be effective in killing protozoa in vitro. Previous studies of the role of cells of the immune system reveal that helminth parasites are susceptible to free radical attack. A 3-year research project studied the anthelmintic potential of endoperoxides and/or Mannich bases derived from G-compounds. Results from 1 series of synthetic analogues which show a positive relationship between chemical structure and anthelmintic activity are reported here. A G-Mannich base with an aromatic ring side chain as well as a long aliphatic side chain was the most active analogue in the series with an LD 50 < 0.1 mM in an in vitro larval motility assay. This work showed that Mannich bases are a potential source of compounds for parasite control. More work on formulation and pharmacokinetics is required to advance these compounds to the threshold of commercial production.
Animals↗
The effect of infection with the abomasal nematode, Haemonchus contortus, on the avoidance behaviour of sheep in a motivational-choice test.
The behaviour of immune and non-immune sheep infected with H. contortus and undergoing a variety of experimental treatments was investigated in a motivational-choice test, the arena test. This test evaluates motivational state in sheep by pitting the motivation of test animals to approach a small flock of sheep against the motivation to avoid a human decoy located directly in front of the small flock. Approach distance is decreased by infection in immune ewes but was unaffected by infection in non-immune weaner lambs in the present study. Experimental drug-treatments with the opiate-antagonist nalorphine, the antihistamine chlorpheniramine, and the immunosuppressive glucocorticoid dexamethasone, affected avoidance behaviour but did not shed light on possible mechanisms involved in the changes observed when immune sheep are infected with the parasite. These substances may affect motivational state directly and not through a pharmacological action on processes triggered by infection in immune sheep. Arena tests conducted in immune ewes at 4, 7 and 11 days after challenge infection showed a fluctuating locomotor behaviour, which may arise from either the dynamics of a standard secondary immune response or particular antigens released during larval development. The immune-mediated changes in behaviour in the arena test will have entailed information-processing or cognitive pathways, but it is not known whether they also involved the physiological manifestations of emotion.
Animals↗
Effects of adult and larval Haemonchus contortus on abomasal secretion.
Abomasal pH and serum pepsinogen and gastrin were increased in parasite-naive sheep by infection with either larval or adult H. contortus. Four sheep received 10000 larvae intraruminally and 9000 adult worms were given directly via an abomasal cannula to another 4 sheep. The latter animals were dosed orally with 0.4 mg kg-1 ivermectin 4 days after worm transfer and their recovery was monitored for a further 8 days. Whereas the presence of adult worms rapidly induced changes in the secretory activity of the abomasum, the early larval stages had minimal effects up to the 4th day post-infection. After either larval or adult infection, the initial hypergastrinaemia began at the same time as the increase in abomasal pH, but serum gastrin continued to increase after abomasal pH had reached a maximum and returned more slowly to normal values after drenching. The increase in serum pepsinogen did not precede those in the other parameters, unlike the earlier hyperpepsinogenaemia which occurs with Ostertagia infection. Three of the 8 infected sheep had no detectable serum pepsinogen increase during the parasitism while showing typical effects on abomasal pH and serum gastrin. The rapidity of the responses to the transfer of adult worms and to their removal by treatment with anthelmintic supports a role for worm excretory/secretory (ES) products which possibly are not produced by the early larval stages. The similarity of responses to H. contortus and O. circumcincta infection suggests the involvement of the same or very similar ES products.
Abomasum↗
The interaction of Trypanosoma congolense and Haemonchus contortus in Djallonké sheep.
The interaction between Trypanosoma congolense and Haemonchus contortus was studied in 5 groups of 8 Djallonké sheep. Two groups received a single infection with either H. contortus or T. congolense, and 2 groups were infected with T. congolense followed by H. contortus (TH) or vice versa (HT). One group was kept as uninfected controls. Mortality due to infection was observed only in the dual infection groups. In the TH group, the effects were more acute whereas in the HT group they were more chronic. No significant differences in weight gain could be demonstrated between infected and control groups. Djallonké sheep are able to withstand a single infection with either T. congolense or H. contortus, which confirms their trypanotolerant nature and provides preliminary indication of resistance against helminth infections. However, when exposed to successive infections with both parasites, some of the animals lose this tolerance.
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Selection for high levamisole resistance in Haemonchus contortus monitored with an egg-hatch assay.
To investigate the characteristics of selection for levamisole resistance in Haemonchus contortus, the consecutive nematode generations of an in vivo selection were monitored with a newly developed egg-hatch assay. The in vivo selection was started with a population not previously exposed to any anthelmintics (SHS). At first, the levamisole resistance progressed gradually in successive nematode generations by treating sheep with increasing doses of levamisole, the initial dose being 1 mg kg-1. Treatment with 5 mg kg-1 levamisole resulted, however, in a steep increase of resistance. The selection was ended after six generations, since a level of 30 mg kg-1 levamisole, which is not far from the toxic level for sheep, was reached. The final population, RHS6, was studied in a controlled test. Treatment of RHS6-infected sheep with 30 mg kg-1 levamisole caused an 80% decrease of faecal egg output, and a reduction of 34% in worm numbers. It was remarkable that only the number of female adults was reduced. RHS6 showed a reduced viability, but a fertility similar to the starting population SHS.
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Host range and the maintenance of Haemonchus spp. in an adverse arid climate.
Three Haemonchus species (Haemonchus contortus, Haemonchus placei and Haemonchus longistipes) live in sympatry in Sahelian areas such as Mauritania (West Africa). Four host species (dromedary, zebu cattle, sheep and goats) share the same pastures for several months per year. Experimental infection by H. contortus or H. placei was achieved only poorly in dromedaries, and H. contortus or H. longistipes infection failed to establish in zebu cattle. Conversely, H. placei and H. longistipes successfully infected sheep and goats. Under field conditions, mixed congeneric infections were very rare in dromedaries but frequent in zebu cattle (H. contortus represented 16% of Haemonchus spp. burden), in sheep (H. placei: 15%) and in goats (H. placei: 9% and H. longistipes: 6% of worms). The importance of the different host species was evaluated for Haemonchus spp.: small ruminants are the main hosts of H. contortus, dromedaries harboured the large majority of H. longistipes worms but 5% of them were found in goats which seemed to be additional hosts. The most striking finding was the role played by the small ruminants in the survival strategy of H. placei in Sahelian regions: 56% of the total of H. placei worms were found in sheep, 34% in goats and only 10% in zebu cattle. These results are consistent with the hypothesis that the extension of host range plays an important role in the survival strategy of H. placei, whereas H. longistipes or H. contortus might well survive utilising their usual hosts.
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Evidence of multiple mechanisms of avermectin resistance in haemonchus contortus--comparison of selection protocols.
Three isolates of Haemonchus contortus selected for avermectin resistance in sheep were compared in three in vitro pharmacological tests previously shown to discriminate between field isolates of H. contortus resistant and susceptible to the avermectins. Two isolates, F7-A and IVC, were selected for avermectin resistance in the laboratory from a reference susceptible isolate using suboptimal doses of ivermectin (LD95) for 7 and 16 generations, respectively. In these isolates avermectin resistance was not associated with a decreased sensitivity to avermectin inhibition of larval development or L3 motility but was associated with an increased sensitivity to paraherquamide. The third isolate, Warren, was derived from an overwhelmingly avermectin-susceptible, mixed species field isolate in a single generation by propagating the small number of survivors of a 0.2 mg/kg ivermectin treatment (i.e. 10 x LD95). This isolate, like previously characterised avermectin-resistant H. contortus isolates derived from the field in South Africa and Australia, showed a markedly reduced sensitivity to avermectin inhibition of larval development and L3 motility, as well as an increased sensitivity to paraherquamide. These results suggest that avermectin resistance can manifest itself in different ways and that the two selection protocols used to generate the F7-A, IVC and Warren isolates have resulted in the selection of different resistance phenotypes.
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Attempts to generate immunity against Trichostrongylus colubriformis and Haemonchus contortus in young lambs by vaccination with viable parasites.
The ability of young Merino lambs to achieve protective immunity following vaccination via viable nematode infections was assessed. Lambs were infected from 1 month of age by repeated continuous low dose (trickle) administration of Trichostrongylus colubriformis or Haemonchus contortus infective larvae (L3), or by truncated infections with high doses of viable T. colubriformis L3. After 7 weeks all groups were drenched with anthelmintic and at 3 months of age they were re-infected with the homologous species. Protection was assessed by faecal egg counts at 3, 4, 5, 6 and 7 weeks after challenge, and worm count at 7 weeks after challenge. Young lambs were partially protected by 3 months of age against Trichostrongylus by trickle infection. This protection correlated with local mast cell and T-cell priming, increased numbers of local antigen-presenting cells and T-cells and increased worm-specific antibody titres in the intestine. However, there was no evidence that young lambs were capable of immunologically recognising H. contortus antigens following trickle infection, nor did trickle infection significantly protect young lambs against Haemonchus challenge.
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Protein supplementation improves the performance of parasitised sheep fed a straw-based diet.
A study was made of the benefits of protein supplementation for parasitised and non-parasitised lambs. Sixty, 5-month-old crossbred wether lambs were placed in individual pens indoors for 9 weeks. Half of the animals were experimentally dosed with 1500 Haemonchus contortus larvae per head per week and were fed ad libitum and the other half were worm-free, pair-fed controls. Diets were formulated to be iso-energetic (9.0 MJ of calculated metabolisable energy per kg dry matter) with five levels of protein (10, 13, 16, 19 and 22% crude protein). These diets were based on oaten chaff, with barley, cotton-seed meal, urea and mineral mix (except for the 22% crude protein diet which did not contain barley). Dietary crude protein content increased live-weight gain, feed intake, rumen fluid ammonia-N, packed cell volume, eosinophil counts and antibody responses to H. contortus L3 antigen and decreased faecal worm egg counts significantly. Infection did not significantly affect packed cell volume of animals on diets with 16, 19 and 22% crude protein content. We conclude that extra dietary protein can prevent the adverse effects of H. contortus infection on animal production.
Ammonia↗
Genetic resistance to gastrointestinal nematode parasites in Polish long-wool sheep.
A study was undertaken from 1991 to 1994 on a farm in southern Poland to evaluate the genetic parameters of resistance to gastrointestinal nematodes. The predominant species were Teladorsagia circumcincta and Haemonchus contortus. A total of 32 sires were evaluated, around 15 per year. Faecal egg counts were measured twice during the 4-month grazing season for lambs (total 659 lambs) and three times for their mothers (total 327 ewes). Infection levels were high during the first 2 years and low during the last 2 years. Using an animal model, the heritability of log10(epg+25) increased from 0.20 in August to 0.33 in September for lambs, and from 0.18 in May to 0.25 in September for ewes. The repeatability of ewe faecal egg count between years was 0.25. A genetic correlation of 0.58 was found between faecal egg count in ewes and in 6-7-month-old lambs. A negative genetic correlation (-0.61) was estimated between faecal egg count in September and daily weight gain of lambs from 70 days of age to the end of grazing season (7 months of age). The results confirm the feasibility of genetic selection of sheep for resistance to nematode parasites in an environment where T. circumcincta and H. contortus are the dominant species.
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Influence of ruminal bypass on the pharmacokinetics and efficacy of benzimidazole anthelmintics in sheep.
Oxfendazole, fenbendazole and albendazole were each administered at 5mgkg(-1) to sheep fitted with abomasal cannulae as a single bolus intra-ruminally or infused intra-abomasally at a declining exponential rate, with half-life equivalent to the rate of rumen fluid outflow. The pharmacokinetic disposition of parent compound and metabolites in plasma and abomasal fluid was determined by high performance liquid chromatography. Compared with intra-ruminal administration, intra-abomasal infusion of fenbendazole lowered the area under the concentration-time curve of drug in both plasma and abomasal fluid; intra-abomasal infusion of albendazole substantially increased maximum drug concentration and the concentration-time curve in abomasal fluid and lowered the plasma concentration time curve of the sulphoxide metabolite; intra-abomasal infusion of oxfendazole increased maximum concentration and the concentration-time curve of drug in plasma and abomasal fluid. The greater availability in abomasal fluid of oxfendazole and albendazole when given at commercial dose rates of 5 mg kg(-1) and 3.9 mg kg(-1), respectively, by intra-abomasal infusion correlated with increased efficacy of both drugs against benzimidazole-resistant Trichostrongylus colubriformis and of albendazole against benzimidazole-resistant Haemonchus contortus over that achieved by intra-ruminal administration as a single bolus.
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Long-term effects of short-term provision of protein-enriched diets on resistance to nematode infection, and live-weight gain and wool growth in sheep.
Weaner sheep that had been hand-fed on diets containing increasing concentrations of protein for a 9-week period (when uninfected, or infected with Haemonchus contortus) were studied during the next 69 weeks when put on to pasture as a single, unsupplemented flock. During the 9-week period, groups of 12 sheep (six infected, six uninfected) were offered one of five iso-energetic (9.0 MJ kg(-1)) diets containing 10, 13, 16, 19 or 22% crude protein. All sheep were treated with anthelmintic at the end of the 9 weeks and then put out to pasture for 69 weeks, where they were all subject to the same environmental variables including nematode larval challenge. During the grazing period, animals that had previously received the higher protein diets consistently had higher live-weight gain and wool production, higher antibody responses to both H. contortus and Trichostrongylus colubriformis antigenic challenge in vitro, and lower faecal nematode egg counts than did the lambs previously offered the lower protein diets. Faecal egg counts of the grazing sheep that had been artificially infected with H. contortus while being hand-fed were similar to those of the uninfected sheep and there was no interaction between previous infection and dietary protein concentration. We conclude that short periods of enhanced post-weaning nutrition can have long-term and perhaps life-long effects on production.
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The intramammary inflammatory response of genetically resistant Merino ewes infected with Haemonchus contortus.
The mammary glands of 103 pasture-reared non-lactating, non-pregnant Merino ewes were infused via the teat canal with antigens prepared from the nematode Haemonchus contortus, and the inflammatory response to infusion assessed by washing the gland of its contents after 24 h and 14 days. The ewes were of two genotypes: one with proven high levels of resistance to infection with the nematode H. contortus, the other random-bred animals with relative susceptibility to infection. On day 0 of a H. contortus infection, one gland of the subgroups of both genotypes was infused with the antigen preparation. At the same time, the other gland of the random-bred ewes was infused with sterile physiological saline. A third group of infected random-bred ewes was infused with only sterile physiological saline. Similar infusions were performed on other subgroups on days 12, 21 and 35 of infection, which was then terminated with anthelmintic. A fourth group of uninfected random-bred control ewes was given both infusions 35 days after the other groups were infected. Sheep of the resistant genotype had lower worm egg counts and smaller reductions in blood packed cell volumes from day 21 of infection. Infusion of antigen had no effect on the course of infection and no effect on the response of the other gland, which had been infused with saline alone. The dominant leukocyte response from the antigen-infused gland was eosinophilia. On all days of infusion, and after both 24 h and 14 days, eosinophil counts from the resistant genotype were higher than those from their random-bred counterparts. The sheep mammary gland provides a source of eosinophils whose number is related to host genotype and stage of infection and may provide a model for the investigation of cellular responses in mucosal immunity to nematode infections.
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Peroxide-supported in-vitro cytochrome P450 activities in Haemonchus contortus.
The potential for cytochrome P450 from Haemonchus contortus to operate in the oxygen-poor intestinal environment was investigated by examining the ability of the cytochrome to act in vitro as a peroxygenase in utilising cumene hydroperoxide for substrate oxidations not requiring molecular oxygen. Peroxygenase and NADPH-supported monooxygenase activities were measured in microsomes prepared from L3 and adult nematodes. Both cumene hydroperoxide- and NADPH-supported ethoxycoumarin O-deethylase and aldrin epoxidase activities were detected in larval microsomes. Adult microsomes showed low levels of cumene hydroperoxide-supported ethoxycoumarin O-deethylase, as well as NADPH- and cumene hydroperoxide-supported aldrin epoxidase activities. The use of inhibitors in ethoxycoumarin O-deethylase assays with larval microsomes indicated that the peroxygenase pathway does not proceed via ferrous cytochrome P450 (no inhibition by carbon monoxide), did not require molecular oxygen, and did not depend on electron flow from cytochrome P450 reductase. Larval activity was inhibited by typical cytochrome P450 inhibitors (piperonyl butoxide, SKF-525A, chloramphenicol, metyrapone, n-octylamine) and was unaffected by the peroxidase inhibitor salicylhydroxamic acid. In contrast, adult microsomal cumene hydroperoxide-supported ethoxycoumarin O-deethylase activity was significantly inhibited by both cytochrome P450 inhibitors and salicylhydroxamic acid. Adult microsomes also contained potassium ferrocyanide peroxidase activity utilising cumene hydroperoxide. This activity showed a similar pattern of inhibition by both cytochrome P450 and peroxidase inhibitors. Whilst the ability of larval H. contortus cytochrome P450 to act as a peroxygenase in vitro was demonstrated, the inhibition results with adult microsomes showing both cytochrome P450 and peroxidase activities require further investigation to clarify the nature of the adult microsomal cumene hydroperoxide-supported O-deethylase activity.
7-Alkoxycoumarin O-Dealkylase↗
Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus.
Two morphologically marked strains of Haemonchus contortus, CAVRS (smooth-macrocyclic lactone resistant) and McMaster (linguiform-macrocyclic lactone susceptible), were used to investigate the selection for anthelmintic resistance following exposure to ivermectin (IVM), a non-persistent anthelmintic. and a more persistent anthelmintic, oral moxidectin (MOX). Three types of selection were investigated: (1) selection of resident worms at the time of treatment (Head selection); (2) selection of incoming-larvae post-treatment (Tail selection); and (3) selection of both resident population and incoming larvae (Head + Tail selection). The experimental animals were adult sheep and lambs. In the controls where there was no anthelmintic selection, the proportion of CAVRS in the adult worm population was the same as the proportion in larvae given to both adults and lambs indicating that CAVRS and McMaster H. contortus were equally infective. There was a significant effect of anthelmintic on total worm numbers in adult sheep with MOX treated adults having less worms, but selection type was non-significant. Anthelmintic type had a significant effect on numbers of resistant worms in adult sheep with less resistant worms in the MOX treated groups, but selection type had no effect. Analysis of variance of arcsine-transformed proportions of resistant worms found that the type of anthelmintic had a highly significant effect, with MOX treated adults having a higher proportion of resistant worms, while type of selection was not significant. In the lambs, nil treated controls and IVM Head + Tail and Tail selected groups had similar geometric mean total worm burdens while Head selected had less total worms. In the MOX treated lamb groups the worm burdens were similar within selection type but less than the IVM treated groups. In the lambs, the types of selection that resulted in more resistant worms were IVM Tail, MOX Head + Tail and MOX Tail. Resistant worm numbers were similar in both adult and lamb groups with Head selection by either MOX or IVM. Moxidectin selected out higher proportions of resistant worms than did IVM in the lambs, with Tail and Head + Tail being stronger selectors than Head. Computer simulations were used to estimate the rate at which resistance developed in the field using the information generated in the present study. The anthelmintic treatments used in the simulation followed a strategic parasite control program for H. contortus in which all sheep receive three Closantel (CLS) treatments in summer. all sheep receive a broad-spectrum (BS) drench or capsule at weaning and lambs receive an additional two BS drenches insummer or no further treatment in the case of the capsule. Moxidectin, IVM-capsule and IVM were the broad spectrum anthelmintics simulated. All simulations were run four times assuming high or low efficacy against resident resistant worms and in the presence or absence of CLS resistance. The simulations indicated that the presence of CLS resistance hastened selection for macrocyclic lactone (ML) resistance. While the IVM-capsule will select most rapidly for ML resistance, IVM oral is expected to be least selective. Moxidectin treatment is intermediate, except in simulations with no CLS resistance and when MOX is assumed to be highly effective against resident ML-resistant worms, in which case MOX can be expected to select more slowly than IVM oral treatments.
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