Abstract
BackgroundSchistosome cercariae only elicit high levels of protective immunity against a challenge infection if they are optimally attenuated by exposure to ionising radiation that truncates their migration in the lungs. However, the underlying molecular mechanisms responsible for the altered phenotype of the irradiated parasite that primes for protection have yet to be identified.Methodology/Principal FindingsWe have used a custom microarray comprising probes derived from lung-stage parasites to compare patterns of gene expression in schistosomula derived from normal and irradiated cercariae. These were transformed in vitro and cultured for four, seven, and ten days to correspond in development to the priming parasites, before RNA extraction. At these late times after the radiation insult, transcript suppression was the principal feature of the irradiated larvae. Individual gene analysis revealed that only seven were significantly down-regulated in the irradiated versus normal larvae at the three time-points; notably, four of the protein products are present in the tegument or associated with its membranes, perhaps indicating a perturbed function. Grouping of transcripts using Gene Ontology (GO) and subsequent Gene Set Enrichment Analysis (GSEA) proved more informative in teasing out subtle differences. Deficiencies in signalling pathways involving G-protein–coupled receptors suggest the parasite is less able to sense its environment. Reduction of cytoskeleton transcripts could indicate compromised structure which, coupled with a paucity of neuroreceptor transcripts, may mean the parasite is also unable to respond correctly to external stimuli.Conclusions/SignificanceThe transcriptional differences observed are concordant with the known extended transit of attenuated parasites through skin-draining lymph nodes and the lungs: prolonged priming of the immune system by the parasite, rather than over-expression of novel antigens, could thus explain the efficacy of the irradiated vaccine.
Highlights
The radiation-attenuated schistosome (RA) vaccine remains the most effective way of inducing high levels of protective immunity against Schistosoma mansoni in rodent and primate hosts [1]
A manufactured vaccine has yet to generate high levels of protection, this can be achieved with infective parasite larvae that have been disabled by exposure to radiation
How these weakened parasites are able to induce protective immunity when normal parasites do not, is the question addressed by our experiments
Summary
The radiation-attenuated schistosome (RA) vaccine remains the most effective way of inducing high levels of protective immunity against Schistosoma mansoni in rodent and primate hosts (reviewed by Coulson) [1]. Few differences have been reported between irradiated and normal larvae apart from an altered morphological phenotype at the lung stage of development [3] that produced subtle differences in motility. This accorded with a key feature of the vaccine that attenuated larvae must undergo a truncated migration, as far as the lungs, to prime the immune system [4]. The underlying molecular mechanisms responsible for the altered phenotype of the irradiated parasite that primes for protection have yet to be identified
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