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

Date Published: September 17, 2008

Publisher: Public Library of Science

Author(s): R. Alan Wilson, Jan A. M. Langermans, Govert J. van Dam, Richard A. Vervenne, Stephanie L. Hall, William C. Borges, Gary P. Dillon, Alan W. Thomas, Patricia S. Coulson, Jeffrey Bethony

Abstract: BackgroundAmong 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 FindingsTo 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.SignificanceIt 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.

Partial Text: Schistosomiasis remains a major public health problem in the Tropics, with tens of millions infected and many more at risk [1]. It has been estimated that greater than 250,000 deaths per annum are directly attributable to the disease [2], and the subtle morbidities associated with chronic infection have a more serious impact than hitherto credited [3]. Treatment relies on a single drug (praziquantel) to eliminate the adult worms but, as this has no prophylactic properties and is ineffective against larval schistosomes [4], a vaccine would augment efforts to control and ultimately eradicate the disease. Once established in the human portal tract adult Schistosoma mansoni are long-lived [5], revealing their ability to deploy effective immune evasion strategies. In pre-pubertal children there is little evidence for immune-mediated prevention of worm recruitment, as a result of which the prevalence and intensity of infection rise gradually with age [6]. Even in those adults who are apparently resistant to reinfection, suggesting the development of acquired immunity, no mechanisms have been defined on which a vaccine might be based [7].

In this study we have attempted to discover why the fate of a primary S. mansoni infection in the rhesus macaque differs from that in other permissive primate hosts [27]. A notable feature of our data was the wide range of worm recoveries at 18 weeks but the peak values for fecal egg output and level of circulating parasite antigens indicate that a substantial population established in all animals. Independent validation was provided by five adult rhesus macaques, infected under identical conditions by one of us and perfused at 8 weeks, where a mean of 43% parasite maturation was observed (range 152 to 718 worms) [28]. Perfusion data from earlier studies revealed 49% maturation at 6–7 weeks [29] and reduced primary burdens between 12 and 27 weeks relative to 8 weeks [10]. These data on actual worm numbers, together with the two indirect estimates of infection intensity, point to a gradual but appreciable loss of the established worm burden in some animals. This is contrary to the impression given by advocates of concomitant immunity that adult worms of a primary infection are unaffected by the response they provoke [11],[30].



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