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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 proteins exposed on the adult worm tegument.Western blots of separated TSP, probed with individual rhesus sera. A) 1DE separation showing that the complexity of serum reactivity is inversely proportional to final worm burden. B) 2DE separation probed with serum from the most reactive animal (R6). Targets identified by matching the 2D blot to an identical gel are 1. α2 macroglobulin, 2. Sm200, 3. unknown function, 4. unknown function, 5. HSP70, 6. Alkaline phosphatase, 7. Sm22.6, 8. LMWP.
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pntd-0000290-g006: Antibodies recognize proteins exposed on the adult worm tegument.Western blots of separated TSP, probed with individual rhesus sera. A) 1DE separation showing that the complexity of serum reactivity is inversely proportional to final worm burden. B) 2DE separation probed with serum from the most reactive animal (R6). Targets identified by matching the 2D blot to an identical gel are 1. α2 macroglobulin, 2. Sm200, 3. unknown function, 4. unknown function, 5. HSP70, 6. Alkaline phosphatase, 7. Sm22.6, 8. LMWP.

Mentions: A relatively simple mixture of proteins was revealed by 2D separation of TSP, some sufficiently abundant for identification by tandem MS (Figure S3). TSP is a more scarce resource than SASP so probing with individual sera was restricted to Western blots of 1D separations (Figure 6A). The complexity of serum reactivity increased in inverse proportion to the final worm burden. Both high (280 kDa) and low (14, 10, 8 kDa) molecular weight bands were strongly recognized by all animals whilst more numerous bands were evident in the four with medium to low burdens, especially R6. Sufficient material was accumulated to perform a second 2D separation, under identical conditions to the gel in Figure S3, for blotting and probing with R6 serum (Figure 6B). The principal reactive targets identified by tandem MS were Sm200, alkaline phosphatase, α2 macroglobulin, LMWP and Sm22.6.


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 proteins exposed on the adult worm tegument.Western blots of separated TSP, probed with individual rhesus sera. A) 1DE separation showing that the complexity of serum reactivity is inversely proportional to final worm burden. B) 2DE separation probed with serum from the most reactive animal (R6). Targets identified by matching the 2D blot to an identical gel are 1. α2 macroglobulin, 2. Sm200, 3. unknown function, 4. unknown function, 5. HSP70, 6. Alkaline phosphatase, 7. Sm22.6, 8. LMWP.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0000290-g006: Antibodies recognize proteins exposed on the adult worm tegument.Western blots of separated TSP, probed with individual rhesus sera. A) 1DE separation showing that the complexity of serum reactivity is inversely proportional to final worm burden. B) 2DE separation probed with serum from the most reactive animal (R6). Targets identified by matching the 2D blot to an identical gel are 1. α2 macroglobulin, 2. Sm200, 3. unknown function, 4. unknown function, 5. HSP70, 6. Alkaline phosphatase, 7. Sm22.6, 8. LMWP.
Mentions: A relatively simple mixture of proteins was revealed by 2D separation of TSP, some sufficiently abundant for identification by tandem MS (Figure S3). TSP is a more scarce resource than SASP so probing with individual sera was restricted to Western blots of 1D separations (Figure 6A). The complexity of serum reactivity increased in inverse proportion to the final worm burden. Both high (280 kDa) and low (14, 10, 8 kDa) molecular weight bands were strongly recognized by all animals whilst more numerous bands were evident in the four with medium to low burdens, especially R6. Sufficient material was accumulated to perform a second 2D separation, under identical conditions to the gel in Figure S3, for blotting and probing with R6 serum (Figure 6B). The principal reactive targets identified by tandem MS were Sm200, alkaline phosphatase, α2 macroglobulin, LMWP and Sm22.6.

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