Irridiated schistosome vaccines.
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Journal Article↗
Biomedical subjects
M G Taylor
Publications and source records attributed to M G Taylor.
Studies on heterologous resistance between Schistosoma bovis and Fasciola gigantica in Sudanese cattle.
Using the local strains of Schistosoma bovis and Fasciola gigantica, it was shown that Sudanese zebu calves with mature primary infections of F. gigantica were highly resistant to challenge with S. bovis cercariae, and vice versa. Liver enzyme tests showed that, in both cases, the primary infections had caused some liver damage. Primary infection with irradiated S. bovis cercariae, which did not cause significant liver damage, did not protect significantly against challenge with F. gigantica.
Animals↗
Immunization of zebu calves against Fasciola gigantica, using irradiated metacercariae.
The pathogenesis of unirradiated, 3 krad-irradiated and 20 krad-irradiated metacercarial infections was compared in zebu calves studied over a 10-week period. Calves exposed to 1000 unirradiated metacercariae (mc) became hypoalbuminaemic, and showed elevated serum concentrations of liver enzymes, whereas neither of the other groups was significantly affected. At slaughter, a mean of 332 flukes was recovered from the 0 krad group, while only 23% and 12% of this number were recovered from the 3 krad and and 20 krad groups, respectively. All the worms recovered from the 20 krad group were stunted, and found in biliary ductules, but a mean of 13% of the flukes recovered from the 3 krad group were large, and dwelling in main bile-ducts. Liver lesions typical of acute fascioliasis were present in the 0 krad group, but lesions in the other groups, and particularly the 20 krad group, were far less severe. Judged on clinico-pathological criteria, a single vaccination of calves with 1000 3 krad-irradiated mc induced partial resistance to a challenge with 1000 normal mc eight weeks later, but the reduction in worm recovery was not statistically significant. There was less evidence of protection when two vaccinating doses of 3 krad mc were given within four weeks, with challenge at week 8, and a single vaccination was ineffective against a challenge four weeks later. However, when the irradiation dose was increased to 20 krad, a hgh level of resistance (69% worm reduction) was induced by a single vaccination, given eight weeks before challenge, and liver pathology was strikingly reduced in the vaccinated animals.
Animals↗
Schistosoma mansoni: characterization of two protective monoclonal antibodies.
Two monoclonal antibodies against the surface of S. mansoni schistosomula were found to confer significant passive protection to mice (M7B3A, range 28-70%; M22H12C, range 14-58%). No additive effect was observed when both were transferred together. Neither McAb bound to the cercarial surface but both bound to the surface of in vitro derived schistosomula and schistosomula recovered from mouse skin up to 3 days after infection. The McAbs were species specific, but not S. mansoni strain specific. M22H12C immunoprecipitated an 125I-labelled surface antigen of relative molecular weight (mol. wt) 32 000. In Western blotting of an NP40 schistosomular extract, M7B3A recognized an antigen smear of 13 000-18 000 with a dominant band at 16 000. This 16 000 antigen was recognized by serum from demonstrably immune mice and rats vaccinated with highly irradiated carcariae but not by sera from mice with chronic single sex or bisexual infections.
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Effect of Plasmodium berghei infection on benzoic acid metabolism in mice.
The metabolism of benzoic acid was studied in Plasmodium berghei infected mice both in vitro and in vivo. Results of in vitro studies showed a considerable decrease in the ability of the infected liver to detoxify benzoic acid by hippuric acid formation. The in vivo study showed that hippuric acid formation decreases with increasing parasitemia and the emergence of benzoyl-glucuronide. This new pathway stops operating with further increase in parasitemia.
Animals↗
Protection of sheep against Schistosoma bovis using cryopreserved radiation-attenuated schistosomula.
Three sheep were vaccinated with two doses of 3 krad-irradiated cryopreserved Schistosoma bovis schistosomula containing 20,000 and 17,000 organisms respectively, injected intramuscularly 23 days apart after storage in liquid nitrogen for between 9 and 46 days. A challenge of 5360 S. bovis cercariae was administered percutaneously approximately four weeks after the last vaccine dose to these animals and to three controls. Post-challenge the vaccinated animals gained significantly more weight (27% v. 9%), produced fewer eggs in their faeces, showed a smaller reduction in PCV values (-18% v. -27%) and were over-all in better condition than control animals. At perfusion 49.1% fewer adult worms were found in the vaccinated sheep than in controls. The tissue egg burdens were similar in both groups. Histopathologically both groups were similar except that fewer and smaller egg lesions were observed in the livers of vaccinated animals.
Animals↗
Resistance against Schistosoma mansoni induced by highly irradiated infections: studies on species specificity of immunization and attempts to transfer resistance.
Significant levels of resistance against Schistosoma mansoni challenge were developed by mice exposed to highly irradiated (20 krad.) cercariae of the homologous species (53-67%), whereas vaccination with S. bovis, S. haematobium or S. japonicum failed to confer significant levels of resistance (-5-12%), thus confirming the specificity of the immunizing procedure. Attempts to transfer resistance to naive recipients by injection of serum and of spleen or lymph node cells from donor mice vaccinated with highly irradiated cercariae were largely unsuccessful. However, significant levels of resistance could be transferred to mice by injection of serum from rabbits exposed to irradiated cercariae. Comparable levels of resistance were conferred by injection of serum at the time of challenge (34-69%) or 5-6 days later (31-56%). In contrast, sera from rabbits injected with soluble egg antigen or homogenized cercariae failed to confer protection upon recipient mice. Sera from vaccinated mice, vaccinated rabbits and antigen-injected rabbits all caused cell adherence to skin-transformed schistosomula but neither the level of adherence nor the serum titre correlated with the ability to confer protection to mice.
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The pathogenesis of experimental Schistosoma bovis infections in Sudanese sheep and goats.
The pathogenic effects of experimental Schistosoma bovis infection in Sudanese sheep and goats were investigated by a variety of clinical, parasitological, physiological and histopathological techniques; uninfected animals of each species were used as controls. Infected animals of both species lost or failed to gain weight and developed a haemorrhagic diarrhoea, inappetence, marked anaemia, hypoalbuminaemia, hyperglobulinaemia, hyperproteinaemia and eosinophilia. These changes first became noticeable around the time of onset of oviposition and their severity was generally related to faecal egg counts. Red cell breakdown and albumin catabolism were much higher in infected than in control animals of the same species, and it was concluded that these changes were due to haemorrhage resulting from the extrusion of large numbers of eggs through the intestinal mucosa. Although all the animals were infected with the same number of cercariae, both the number of worms reaching maturity and the tissue egg counts tended to be higher in sheep than in goats. On the other hand, goats had significantly higher faecal egg counts than sheep and it is suggested that this was the reason for the generally more severe disease in the former species.
Animals↗
Erythrokinetics and albumin metabolism in primary experimental Schistosoma bovis infections in Zebu calves.
Red cell kinetics and albumin metabolism were studied in calves infected with either 100 or 200 Schistosoma bovis cercariae per kg body weight, by the use of 59Fe-labelled transferrin, 51Cr-labelled erythrocytes and 125I-labelled albumin; a third group of worm-free animals acted as controls. The anaemia which developed in the infected calves was shown to be due basically to an accelerated rate of red cell loss from the circulation, and became evident around the seventh week of infection, increased in severity during the following two months, and subsequently subsided. In view of its close similarity to the pattern of faecal egg excretion, it was concluded that haemorrhage into the intestine caused by the exit of eggs was the principal aetiological factor: haemolysis was excluded by the absence of both splenomegaly and hyperferraemia . Erythropoiesis was also accelerated in infected animals, but could not keep pace with the rate of red cell breakdown to which the animals were concurrently subjected. Haemodilution was involved, but not to a significant extent. The hypoalbuminaemia associated with infection was caused by an increased rate of albumin catabolism, and a plasma volume expansion, and was accompanied by marked depletion of all albumin pools, but particularly the extravascular pool. The pattern of albumin catabolism closely followed that of red cell loss, suggesting that passage of plasma as whole blood into the intestine was the basic cause of hypoalbuminaemia. Red cell losses and albumin hypercatabolism were more severe in the more heavily infected group, and although both subsided as egg counts fell, they remained evident even 1 year after infection. This may partly explain the failure of infected animals to regain the weight lost during earlier stages of disease.
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Immunization of rats against Schistosoma mansoni using irradiated cercariae, lung schistosomula and liver-stage worms.
In PVG rats a single immunizing infection with Schistosoma mansoni cercariae exposed to 0, 5, 10 or 20 krad. gamma radiation failed to induce more than minimal resistance (17-29%) to challenge 4 weeks later, whereas 4 immunizations with 20 krad.-irradiated cercariae, over several months, induced substantial resistance (75%). In contrast, significant protection was induced in Fischer rats by a single immunization with unirradiated cercariae or cercariae irradiated with up to 80 krad. Comparable resistance was induced by unirradiated and by 2, 5 and 20 krad.-irradiated cercariae (67-74%) and lower levels by 10, 40 and 80 krad.-irradiated infections (57, 48 and 33%, respectively). Although the resistance induced by a single dose of 1000 20 krad.-irradiated cercariae could be boosted by a second (88%), further immunizations failed to enhance this resistance. Also, increasing the number of immunizing cercariae in single or multiple vaccinations from 1000 to 3000 failed to increase the resistance. While the resistance induced by 20 krad.-irradiated cercariae persisted undiminished for at least 25 weeks (67%), the resistance induced by normal cercariae declined to insignificant levels by 25 weeks (21%). Comparison of the migration and survival of unirradiated and of 20 and 40 krad.-irradiated cercariae revealed dramatic differences in their fate: parasites exposed to 40 krad. remained in the skin, while the majority of 20 krad.-irradiated parasites died in the lungs after a sojourn of at least 14 days. Thus, although skin schistosomula alone could induce significant protection, optimal resistance was induced only by parasites which migrated to the lungs or beyond. The immunizing potential of these older parasites was investigated by exposing rats to lung- and liver-stage larvae injected into the tail and mesenteric veins, respectively. Irradiated 4-day lung schistosomula induced comparable resistance (79%) to that induced by a complete unattenuated cercarial infection (78%), whereas less resistance was induced by irradiated and unirradiated 11-day-old liver worms (30 and 27%) and by 25-day-old pre-adult worms (48%).
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Passive transfer of resistance and the site of immune-dependent elimination of the challenge infection in rats vaccinated with highly irradiated cercariae of Schistosoma mansoni.
The immune-dependent elimination of a challenge infection in rats vaccinated with highly-irradiated cercariae of Schistosoma mansoni was analysed by passive transfer of serum, recovery of the challenge from the lungs and liver and by transferring lung-stage schistosomula. Recipients of serum from rats immunized with either unirradiated, 20 or 40 krad.-irradiated cercariae, most of which die in the liver, lungs and skin, respectively, were equally resistant if the serum was injected on the day of infection or 5-7 days after infection. In addition, vaccinated rat serum transferred to mice and vaccinated rabbit serum transferred to rats conferred comparable protection when injected on day 0 or 5 days after infection of the recipients. This apparent susceptibility of the lung schistosomula to immune attack was confirmed by challenging 20 or 40 krad.-irradiated cercariae vaccinated rats with lung-stage schistosomula derived either from mice or rats. All the detectable attrition of a cercarial challenge in vaccinated rats occurred between 7 and 10 days post-challenge, before the parasites reached the liver. Since there was no evidence of damage or attrition in the skin or lungs before day 7 it was concluded that immune-dependent elimination occurred rapidly following a 'window of sensitivity' coinciding with the migration of the parasites from the lungs to the liver.
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The conformations of nitroxide-labelled fatty acid probes of membrane structure as studied by 2H-NMR.
The electron spin resonance (ESR) spectrum of a nitroxide spin probe intercalated in a membrane is influenced by the amplitude of anisotropic motion of the nitroxide group and by the geometry of the oxazolidine ring of the nitroxide. In the analysis of the ESR spectra of nitroxide-labelled fatty acid probes, it is generally assumed that the five-membered oxazolidine ring system is oriented rigidly perpendicular to the long molecular axis of the probe. This assumption is tested in the present study, using 2H-NMR of specifically deuterium-labelled nitroxide spin probes. Evidence is presented that the nitroxide does not display the assumed geometry in membranes. The departure from this geometry depends on the position of the nitroxide label on the acyl chain, with a more pronounced departure for position 5 relative to position 12. These and previous data provide an explanation for the discrepancies between spin-probe ESR and 2H-NMR order parameters in membranes.
Electron Spin Resonance Spectroscopy↗
Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. IV. Preliminary observations on the mechanism of naturally acquired resistance.
Suppression of egg production is the main parasitological manifestation of naturally acquired resistance to Schistosoma bovis in Sudanese cattle. In preliminary investigations on the mechanisms involved, 700-4,000 "suppressed" adult worms were surgically transplanted from six "resistant" donor cattle with very low fecal egg counts (0-8 eggs/g, epg) into six normal recipients. After transplantation, large numbers of eggs were excreted in the feces of the recipient cattle, beginning at between 5 and 16 days after operation, and reaching counts of 55-405 epg at between 6 and 20 days post transplantation. In the cattle with the highest egg counts, egg counts soon fell sharply from peak levels, whereas in cattle with lower peak counts, more steady counts were maintained. All the recipients were perfused at days 46-56, when between 0.1% and 78.5% of the transplanted worms were recovered. In the second experiment, 1,000-ml quantities of pooled sera from "resistant" donors were injected intraperitoneally into each of four normal recipient calves, while another four were injected with pooled sera from uninfected cattle. All the calves were challenged percutaneously the next day with 7,500 cercariae each, and the course of infection was followed by parasitological and clinical measurements until perfusion 18 weeks later. The results showed that the "immune" sera had a negligible effect on the numbers of worms which developed, and had no significant effect on the fecal egg counts or clinical parameters studied. There was, however, some evidence from the tissue egg counts of a reduction in the fecundity of the worms in calves injected with "immune" sera.(ABSTRACT TRUNCATED AT 250 WORDS)
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Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. V. The effect of praziquantel therapy on naturally acquired resistance to Schistosoma bovis.
Studies in the White Nile area of the Sudan have shown that Zebu cattle acquire a high degree of resistance to Schistosoma bovis as a result of repeated natural exposures without, however, being able to eliminate their populations of adult schistosomes, although these do show greatly suppressed fecundity. To test whether these adult worms are necessary for the maintenance of resistance we cured six "naturally resistant" cattle (TC group) with a double treatment of 25 mg/kg praziquantel and compared their response to a 70,000 cercariae challenge with groups of "naturally resistant" but untreated cattle (UC group) and with previously unexposed, challenged cattle (CC group). Challenge was carried out 7 weeks after the second dose of praziquantel. The results confirmed that untreated cattle are "naturally resistant" and also showed that resistance was not abrogated by cure of the naturally-acquired infections. Thus, fecal egg counts after challenge reached mean maxima of 2,432 eggs per gram (epg) in the CC, but only 5 epg and 28 epg in the TC and UC groups, respectively. Similarly, mean worm counts were 85% and 69% lower in the TC and UC groups, respectively, and mean tissue egg densities were reduced by 72-99%, and 56-80%. Histopathologically, the TC and UC groups were also far less affected than the CC. Effective praziquantel treatment does therefore not destroy naturally acquired resistance to S. bovis, and may benefit infected livestock even in the absence of transmission control. The situation in human schistosomiasis is less clear, but there are several epidemiological and experimental indications of a similar conclusion for S. mansoni.
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Age specific prevalence and intensity of Schistosoma bovis infection in Sudanese Desert sheep in the White Nile Province.
A survey of ovine schistosomiasis was carried out in a Schistosoma bovis enzootic area in the central Sudan. Three hundred Desert sheep, representing different age groups, were screened for infection, using Pitchford's faecal egg counting technique. No infection was detected in animals under one year old, but from the age of 18 months onward, the prevalence increased progressively from around 20 per cent to 60 per cent in six-year-old sheep, and this was accompanied by an increase in infection intensity, as determined by faecal egg counts. These findings, which suggest that these sheep did not develop an effective resistance to schistosomiasis, contrasted with those previously recorded in cattle from the same locality, studied in the same year.
Age Factors↗
Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. VI. Demonstration of resistance to Schistosoma bovis challenge after a single exposure to normal cercariae or to transplanted adult worms.
Calves were immunized with Schistosoma bovis by a single experimental exposure to 10,000 normal cercariae. Some of these calves were perfused 14 weeks later, and a part of their worm loads was surgically transplanted into groups of normal recipient calves: "WPR" group calves received 500 pairs of worms; "MR" group calves received between 650 and 1,000 male worms alone. All three groups were subsequently challenged 10 weeks after surgery with 20,000 cercariae, as were a previously unexposed group of controls ("CC"). Mean post-challenge fecal egg counts in the animals immunized with cercariae ("PC" group) rose to a maximum of only 60 eggs per gram (e.p.g.), compared to 376 e.p.g. in the CC, and maximum fecal egg counts in the WPR and MR groups were also somewhat lower than in the CC, at 152 and 250 e.p.g., respectively. In spite of the much lower fecal egg counts in the PC than in the CC group, calculated adult "challenge" worm recoveries were only reduced by 11%, but PC group tissue egg densities derived from the challenge were 78-100% lower than in the CC. The WPR and MR groups had 43% and 37%, respectively, fewer worms than the CC, and mean tissue egg densities were lower by 39-63% and 63-76%, respectively, though in most cases there were no statistically significant differences from the CC.(ABSTRACT TRUNCATED AT 250 WORDS)
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Direct observation of the properties of cholesterol in membranes by deuterium NMR.
The properties of cholesterol in bilayers of egg phosphatidylcholine (PC) were investigated directly by means of 2H-NMR of specifically-deuterated species (C3, C7, C26, C27). Quadrupole splittings were a measure of molecular ordering, and relaxation times T1 and T2e were indicators of rates of motion. The importance of the use of echoes for spectral acquisition is emphasised, particularly to obtain accurate values of the quadrupole splitting. In the case of overlapping powder patterns from two labelled positions, the use of the absolute value mode of spectral presentation is shown to yield reasonable estimates of the individual quadrupole splittings. Spectral properties were monitored as a function of cholesterol concentration and temperature. Increasing cholesterol concentration led to a high degree of ordering for the rigid ring system of cholesterol, approaching a molecular order parameter of 0.8 at 50 mol% cholesterol. The isopropyl methyl groups were in all cases less ordered and more mobile than the ring system, but responded in a similar fashion to variable cholesterol concentration and temperature. The observation of a minimum in the temperature dependence of T1 for cholesterol-7,7-d2 led to a direct estimate of its correlation time for molecular motion, 3.5 X 10(-9) S rad-1. This indicates that the overall rate of motion of cholesterol is considerably slower than that of the lipids in which it is located. The short T2e values suggest that the motional spectrum of cholesterol is rich in low frequencies. The parallel temperature and cholesterol dependences of quadrupole splittings for different positions on the rigid ring system of cholesterol indicate that the position of the axis of motional averaging of the molecule is not changing, and is the same as that determined in an earlier study. It is emphasised that the steep temperature dependence and small quadrupole splittings for the chain isopropyl methyl groups of cholesterol do not necessarily indicate a high degree of disorder, but may be due to their axes of motional averaging lying at angles close to 54 degrees with respect to the director of the ordered lipids.
Cholesterol↗
Effects of praziquantel and metrifonate on Schistosoma bovis infections in Sudanese cattle.
Twelve nine-month-old zebu calves were each experimentally infected with 10,000 Schistosoma bovis cercariae. Four were treated orally with 20 mg/kg praziquantel at weeks 9 and 14 after infection, and four were treated orally three times with metrifonate at week 11 (25 mg/kg) and again at week 14 (50 mg/kg). Praziquantel proved to be highly effective, reducing faecal egg counts near to zero; the mean live worm count in the treated calves at week 16 was only 32, compared to 2850 in the untreated group, a reduction of 98.9 per cent. In contrast, metrifonate treatment caused only a very short-lived, partial reduction in faecal egg counts, and no reduction in live worm counts.
Animals↗