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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

Antibodies recognize adult worm secreted proteins.Western blots of 2DE separations of SASP probed with A) high titer, low worm burden serum (R6) and B) low titer, high worm burden serum (R5). Region X is a group of highly reactive protein spots not detected by Sypro Ruby or Coomassie staining of the corresponding gel. Region Y is a group of highly reactive protein spots present only in trace amounts on the gel. SASP proteins matched to the blot are 1. asparaginyl endopeptidase, 2. unknown function, 3. thioredoxin glutathione reductase, 4. Sm200 surface protein, 5. α2 macroglobulin, 6. thioredoxin peroxidase, 7. GST 28.
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pntd-0000290-g005: Antibodies recognize adult worm secreted proteins.Western blots of 2DE separations of SASP probed with A) high titer, low worm burden serum (R6) and B) low titer, high worm burden serum (R5). Region X is a group of highly reactive protein spots not detected by Sypro Ruby or Coomassie staining of the corresponding gel. Region Y is a group of highly reactive protein spots present only in trace amounts on the gel. SASP proteins matched to the blot are 1. asparaginyl endopeptidase, 2. unknown function, 3. thioredoxin glutathione reductase, 4. Sm200 surface protein, 5. α2 macroglobulin, 6. thioredoxin peroxidase, 7. GST 28.

Mentions: To determine whether the IgG response was directed against secreted and/or accessible surface proteins we developed two corresponding novel antigen preparations. Separation of SASP by 2D electrophoresis revealed a complex mixture of proteins, many of which could be identified by tandem MS (Figure S2). When blots were probed with individual rhesus sera, only a minority of constituents was immunoreactive, with largely quantitative rather than qualitative variations observed between the six animals. The same basic pattern was present but at a higher intensity in the animals with the low burden and high titre (Figure 5A), and vice versa (Figure 5B). Targets identified by tandem MS on gels matched to the higher intensity blot are annotated in the figure. Two groups of highly reactive spots on the blots were either not detected on the gels by Sypro Ruby or Coomassie staining (Figure 5 Region X), strongly indicative of glycan epitopes, or were present only in trace amounts that made tandem MS identification problematic (Figure 5 Region Y). The former group is likely to comprise high molecular weight mucins while the two identities obtained for the latter (Sm200 and α2 macroglobulin) are indicative of tegument surface components.


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)

Antibodies recognize adult worm secreted proteins.Western blots of 2DE separations of SASP probed with A) high titer, low worm burden serum (R6) and B) low titer, high worm burden serum (R5). Region X is a group of highly reactive protein spots not detected by Sypro Ruby or Coomassie staining of the corresponding gel. Region Y is a group of highly reactive protein spots present only in trace amounts on the gel. SASP proteins matched to the blot are 1. asparaginyl endopeptidase, 2. unknown function, 3. thioredoxin glutathione reductase, 4. Sm200 surface protein, 5. α2 macroglobulin, 6. thioredoxin peroxidase, 7. GST 28.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000290-g005: Antibodies recognize adult worm secreted proteins.Western blots of 2DE separations of SASP probed with A) high titer, low worm burden serum (R6) and B) low titer, high worm burden serum (R5). Region X is a group of highly reactive protein spots not detected by Sypro Ruby or Coomassie staining of the corresponding gel. Region Y is a group of highly reactive protein spots present only in trace amounts on the gel. SASP proteins matched to the blot are 1. asparaginyl endopeptidase, 2. unknown function, 3. thioredoxin glutathione reductase, 4. Sm200 surface protein, 5. α2 macroglobulin, 6. thioredoxin peroxidase, 7. GST 28.
Mentions: To determine whether the IgG response was directed against secreted and/or accessible surface proteins we developed two corresponding novel antigen preparations. Separation of SASP by 2D electrophoresis revealed a complex mixture of proteins, many of which could be identified by tandem MS (Figure S2). When blots were probed with individual rhesus sera, only a minority of constituents was immunoreactive, with largely quantitative rather than qualitative variations observed between the six animals. The same basic pattern was present but at a higher intensity in the animals with the low burden and high titre (Figure 5A), and vice versa (Figure 5B). Targets identified by tandem MS on gels matched to the higher intensity blot are annotated in the figure. Two groups of highly reactive spots on the blots were either not detected on the gels by Sypro Ruby or Coomassie staining (Figure 5 Region X), strongly indicative of glycan epitopes, or were present only in trace amounts that made tandem MS identification problematic (Figure 5 Region Y). The former group is likely to comprise high molecular weight mucins while the two identities obtained for the latter (Sm200 and α2 macroglobulin) are indicative of tegument surface components.

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