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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

Cells internal to the body wall musculature are atrophied.Electron micrograph of a transverse section of the posterior of A) pallid female worm from rhesus macaque. The syncitial tegument (T), body wall musculature (M) and intestinal epithelium (E) are intact but cells of the parenchyma (P) and vitelline lobules (V) are devoid of content apart from prominent central nuclei. The gut lumen is virtually empty. B) posterior of female worm from mouse, with abundant vitelline lobules and gut lumen full of partly digested blood.
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pntd-0000290-g003: Cells internal to the body wall musculature are atrophied.Electron micrograph of a transverse section of the posterior of A) pallid female worm from rhesus macaque. The syncitial tegument (T), body wall musculature (M) and intestinal epithelium (E) are intact but cells of the parenchyma (P) and vitelline lobules (V) are devoid of content apart from prominent central nuclei. The gut lumen is virtually empty. B) posterior of female worm from mouse, with abundant vitelline lobules and gut lumen full of partly digested blood.

Mentions: These degenerative changes were further highlighted by an ultrastructural comparison. The cellular organization in the posterior half of the female body, comprising numerous individual vitelline cells packed with peripheral egg-shell precursor granules in worms from mice (Figure 3B), was absent in pallid worms from rhesus macaques (Figure 3A). The parenchyma appeared almost completely devoid of content, including glycogen and lipid stores, although individual cell membranes and isolated nuclei were evident. The absence of food in the gut lumen contrasted with the abundance of SEi-digested blood in the normal worm gut (Figure 3A cf. B). Electron microscopy confirmed the degenerative state of the intestinal epithelium in pallid worms. Although plasma membranes were intact, the cytoplasm was less dense, nuclei were more rounded, and endoplasmic reticulum and Golgi apparatus were lacking, implying little or no protein synthesis (Figure S1A). In contrast, the surface syncitial tegument of the parasite had a normal pitted appearance with the usual cytoplasmic inclusions (Figure S1B). The subtegumental circular and longitudinal muscles that make up the body wall, together with the muscles surrounding the gut epithelium, also appeared relatively intact.


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)

Cells internal to the body wall musculature are atrophied.Electron micrograph of a transverse section of the posterior of A) pallid female worm from rhesus macaque. The syncitial tegument (T), body wall musculature (M) and intestinal epithelium (E) are intact but cells of the parenchyma (P) and vitelline lobules (V) are devoid of content apart from prominent central nuclei. The gut lumen is virtually empty. B) posterior of female worm from mouse, with abundant vitelline lobules and gut lumen full of partly digested blood.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000290-g003: Cells internal to the body wall musculature are atrophied.Electron micrograph of a transverse section of the posterior of A) pallid female worm from rhesus macaque. The syncitial tegument (T), body wall musculature (M) and intestinal epithelium (E) are intact but cells of the parenchyma (P) and vitelline lobules (V) are devoid of content apart from prominent central nuclei. The gut lumen is virtually empty. B) posterior of female worm from mouse, with abundant vitelline lobules and gut lumen full of partly digested blood.
Mentions: These degenerative changes were further highlighted by an ultrastructural comparison. The cellular organization in the posterior half of the female body, comprising numerous individual vitelline cells packed with peripheral egg-shell precursor granules in worms from mice (Figure 3B), was absent in pallid worms from rhesus macaques (Figure 3A). The parenchyma appeared almost completely devoid of content, including glycogen and lipid stores, although individual cell membranes and isolated nuclei were evident. The absence of food in the gut lumen contrasted with the abundance of SEi-digested blood in the normal worm gut (Figure 3A cf. B). Electron microscopy confirmed the degenerative state of the intestinal epithelium in pallid worms. Although plasma membranes were intact, the cytoplasm was less dense, nuclei were more rounded, and endoplasmic reticulum and Golgi apparatus were lacking, implying little or no protein synthesis (Figure S1A). In contrast, the surface syncitial tegument of the parasite had a normal pitted appearance with the usual cytoplasmic inclusions (Figure S1B). The subtegumental circular and longitudinal muscles that make up the body wall, together with the muscles surrounding the gut epithelium, also appeared relatively intact.

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