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Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Wilson RA, Langermans JA, van Dam GJ, Vervenne RA, Hall SL, Borges WC, Dillon GP, Thomas AW, Coulson PS - PLoS Negl Trop Dis (2008)

Bottom Line: Using immunoproteomics, gut digestive enzymes, tegument surface hydrolases and antioxidant enzymes were identified as targets of IgG in the high responder animals.It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes.We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operating in rhesus macaques, would have both prophylactic and therapeutic potential as a human vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York, York, United Kingdom. raw3@york.ac.uk

ABSTRACT

Background: Among animal models of schistosomiasis, the rhesus macaque is unique in that an infection establishes but egg excretion rapidly diminishes, potentially due to loss of adult worms from the portal system via shunts or death by immune attack.

Principal findings: To investigate this, six rhesus macaques were exposed to Schistosoma mansoni cercariae and the infection monitored until portal perfusion at 18 weeks. Despite a wide variation in worm numbers recovered, fecal egg output and circulating antigen levels indicated that a substantial population had established in all animals. Half the macaques had portal hypertension but only one had portacaval shunts, ruling out translocation to the lungs as the reason for loss of adult burden. Many worms had a shrunken and pallid appearance, with degenerative changes in intestines and reproductive organs. Tegument, gut epithelia and muscles appeared cytologically intact but the parenchyma was virtually devoid of content. An early and intense IgG production correlated with low worm burden at perfusion, and blood-feeding worms cultured in the presence of serum from these animals had stunted growth. Using immunoproteomics, gut digestive enzymes, tegument surface hydrolases and antioxidant enzymes were identified as targets of IgG in the high responder animals.

Significance: It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes. We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operating in rhesus macaques, would have both prophylactic and therapeutic potential as a human vaccine.

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Related in: MedlinePlus

Most surviving worms are morphologically degenerate.Confocal microscopy on selected tissues of adult worms recovered from the portal system of rhesus macaques (A, C, E) and mice (B, D, F), and stained with Langeron's carmine. A) female posterior lacking vitelline lobules (V) and with greatly simplified intestinal epithelium (E) versus B) abundant vitelline lobules and normal intestinal epithelium with lamellate extensions. C) female mid body showing shrunken ovary (O) with few recognizable oocytes versus D) normal ovary with large number of healthy oocytes. E) shrunken testes (T) with lacunae and few sperm versus F) normal testes structure. All images are the same magnification. Bar = 10 µm.
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pntd-0000290-g002: Most surviving worms are morphologically degenerate.Confocal microscopy on selected tissues of adult worms recovered from the portal system of rhesus macaques (A, C, E) and mice (B, D, F), and stained with Langeron's carmine. A) female posterior lacking vitelline lobules (V) and with greatly simplified intestinal epithelium (E) versus B) abundant vitelline lobules and normal intestinal epithelium with lamellate extensions. C) female mid body showing shrunken ovary (O) with few recognizable oocytes versus D) normal ovary with large number of healthy oocytes. E) shrunken testes (T) with lacunae and few sperm versus F) normal testes structure. All images are the same magnification. Bar = 10 µm.

Mentions: The declining values of the indirect indicators might reflect worm death or a more subtle deterioration in physiological function. In fact, when worms were counted a large proportion, particularly the females, had a pallid appearance as they lacked hematin pigment in their intestines. Many females were also shrunken compared to the mature equivalent from mice, with bodies approximately two-thirds the normal width. Confocal microscopy of the pallid female worms (n = 15) revealed that the intestinal epithelium was thinner and its luminal surface lacked the numerous lamellar extensions seen in normal female worms from mice (n = 9; Figure 2A cf. B). A decline in reproductive function of the pallid females was reflected by the greatly shrunken appearance of the ovary (Figure 2C) that contained very few oocytes compared to normal worms (Figure 2D). The vitelline lobules were strikingly absent in the pallid worms (Figure 2A cf. normal worms Figure 2B), as were forming eggs in the ootype (data not shown). The degeneration of the reproductive system was not confined to females. Pallid males (n = 7) had reduced numbers of spermatocytes in their testicular lobules, giving the contents a shrunken appearance with lacunae (Figure 2E) versus the tight packing of spermatocytes and maturing spermatozoa in the normal testis (n = 4; Figure 2F). A few females of normal appearance had an ovary with healthy oocytes, a forming egg in the ootype and sperm present in the proximal part of the oviduct that acts as a receptaculum seminis; this last is indicative of functionally active male worms.


Elimination of Schistosoma mansoni Adult Worms by Rhesus Macaques: Basis for a Therapeutic Vaccine?

Wilson RA, Langermans JA, van Dam GJ, Vervenne RA, Hall SL, Borges WC, Dillon GP, Thomas AW, Coulson PS - PLoS Negl Trop Dis (2008)

Most surviving worms are morphologically degenerate.Confocal microscopy on selected tissues of adult worms recovered from the portal system of rhesus macaques (A, C, E) and mice (B, D, F), and stained with Langeron's carmine. A) female posterior lacking vitelline lobules (V) and with greatly simplified intestinal epithelium (E) versus B) abundant vitelline lobules and normal intestinal epithelium with lamellate extensions. C) female mid body showing shrunken ovary (O) with few recognizable oocytes versus D) normal ovary with large number of healthy oocytes. E) shrunken testes (T) with lacunae and few sperm versus F) normal testes structure. All images are the same magnification. Bar = 10 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2553480&req=5

pntd-0000290-g002: Most surviving worms are morphologically degenerate.Confocal microscopy on selected tissues of adult worms recovered from the portal system of rhesus macaques (A, C, E) and mice (B, D, F), and stained with Langeron's carmine. A) female posterior lacking vitelline lobules (V) and with greatly simplified intestinal epithelium (E) versus B) abundant vitelline lobules and normal intestinal epithelium with lamellate extensions. C) female mid body showing shrunken ovary (O) with few recognizable oocytes versus D) normal ovary with large number of healthy oocytes. E) shrunken testes (T) with lacunae and few sperm versus F) normal testes structure. All images are the same magnification. Bar = 10 µm.
Mentions: The declining values of the indirect indicators might reflect worm death or a more subtle deterioration in physiological function. In fact, when worms were counted a large proportion, particularly the females, had a pallid appearance as they lacked hematin pigment in their intestines. Many females were also shrunken compared to the mature equivalent from mice, with bodies approximately two-thirds the normal width. Confocal microscopy of the pallid female worms (n = 15) revealed that the intestinal epithelium was thinner and its luminal surface lacked the numerous lamellar extensions seen in normal female worms from mice (n = 9; Figure 2A cf. B). A decline in reproductive function of the pallid females was reflected by the greatly shrunken appearance of the ovary (Figure 2C) that contained very few oocytes compared to normal worms (Figure 2D). The vitelline lobules were strikingly absent in the pallid worms (Figure 2A cf. normal worms Figure 2B), as were forming eggs in the ootype (data not shown). The degeneration of the reproductive system was not confined to females. Pallid males (n = 7) had reduced numbers of spermatocytes in their testicular lobules, giving the contents a shrunken appearance with lacunae (Figure 2E) versus the tight packing of spermatocytes and maturing spermatozoa in the normal testis (n = 4; Figure 2F). A few females of normal appearance had an ovary with healthy oocytes, a forming egg in the ootype and sperm present in the proximal part of the oviduct that acts as a receptaculum seminis; this last is indicative of functionally active male worms.

Bottom Line: Using immunoproteomics, gut digestive enzymes, tegument surface hydrolases and antioxidant enzymes were identified as targets of IgG in the high responder animals.It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes.We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operating in rhesus macaques, would have both prophylactic and therapeutic potential as a human vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of York, York, United Kingdom. raw3@york.ac.uk

ABSTRACT

Background: Among animal models of schistosomiasis, the rhesus macaque is unique in that an infection establishes but egg excretion rapidly diminishes, potentially due to loss of adult worms from the portal system via shunts or death by immune attack.

Principal findings: To investigate this, six rhesus macaques were exposed to Schistosoma mansoni cercariae and the infection monitored until portal perfusion at 18 weeks. Despite a wide variation in worm numbers recovered, fecal egg output and circulating antigen levels indicated that a substantial population had established in all animals. Half the macaques had portal hypertension but only one had portacaval shunts, ruling out translocation to the lungs as the reason for loss of adult burden. Many worms had a shrunken and pallid appearance, with degenerative changes in intestines and reproductive organs. Tegument, gut epithelia and muscles appeared cytologically intact but the parenchyma was virtually devoid of content. An early and intense IgG production correlated with low worm burden at perfusion, and blood-feeding worms cultured in the presence of serum from these animals had stunted growth. Using immunoproteomics, gut digestive enzymes, tegument surface hydrolases and antioxidant enzymes were identified as targets of IgG in the high responder animals.

Significance: It appears that worms starve to death after cessation of blood feeding, as a result of antibody-mediated processes. We suggest that proteins in the three categories above, formulated to trigger the appropriate mechanisms operating in rhesus macaques, would have both prophylactic and therapeutic potential as a human vaccine.

Show MeSH
Related in: MedlinePlus