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Altered patterns of gene expression underlying the enhanced immunogenicity of radiation-attenuated schistosomes

18 Jun 2008

Marcia Triunfol

Source: PLoS Neglected Tropical Diseases (see original article)

Citation: Dillon GP, Feltwell T, Skelton J, Coulson PS, Wilson RA, et al. Altered patterns of gene expression underlying the enhanced immunogenicity of radiation-attenuated schistosomes. PLoS Negl Trop Dis 2008 May 21; 2(5): e240. doi:10.1371/journal.pntd.0000240

While a number of effective vaccines against bacterial and viral pathogens have been developed in the last 200 years, no fully-effective vaccine against multicellular parasites has ever been created.

Among the parasites for which no effective vaccine has been developed are the schistosomes (Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum), which have been infecting humans for more than 3000 years, as evidenced by schistosome-infected Egyptian mummies dating back 1200 BC. Nowadays, schistosomiasis affects 200 million people and kills around one million every year, mostly in Africa, South America, and Southeast Asia.

Parasites have complex life cycles. Some have more than one species as a host while others may remain silent for years within the host, before causing any pathology. For most parasites, each developmental stage of the life cycle is characterized by a different collection of antigens, which become a challenge for the host’s immune system. As soon as the host’s immune system starts to eliminate a certain set of antigens, the parasite presents a different one or, in some cases, become silent.

It has already been established that vaccines made with irradiated larvae of schistosomes induce an immunological protection in rodents and primates that is stronger than the one induced by non-irradiated larvae. This stronger effect is believed to be caused by a longer exposure of the irradiated larvae to the host’s immune system, which facilitates the differentiation of CD4+ T lymphocytes. CD4+ T lymphocytes are the cells responsible for an effective immunity against schistosomes.

This recently published work by Dillon and colleagues aimed to shed light on the enhanced immunogenicity found in irradiated larvae. To do so, the researchers analyzed a number of genes that are differentially expressed in irradiated and in non-irradiated larvae. They found that some of the genes showing lower levels of expression in irradiated larvae are those possibly associated to the parasite motility, namely cytoeskeletal genes, neuroreceptors and channel genes. The lower expression of these genes could lead to a slower motility of the irradiated larvae, resulting in a prolonged antigenic stimulation of the host. But because the study was done in vitro, it is possible that the differential expression observed in some of the parasites’ genes behave differently when in the host’s organism. It is also possible that the host itself may send the cues that the parasite uses to module its own gene expression.

Nevertheless, the study does provide some early insights on the immunity-evasion strategies of the schistosome fluke, such as the requirement for a prolonged antigen exposition, rather than for antigen abundance. This is certainly a finding to be further investigated when developing vaccines against schistosomiasis.

© 2008 Dillon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Source

Title:
Altered patterns of gene expression underlying the enhanced immunogenicity of radiation-attenuated schistosomes.

Authors:
Dillon GP, Feltwell T, Skelton J, Coulson PS, Wilson RA, Ivens AC

References:
PLoS Negl Trop Dis 2008: Vol. 2 no. 5, pp. e240

Abstract:
BACKGROUND: Schistosome 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 FINDINGS: We 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/SIGNIFICANCE: The 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.

PMID: 18493602
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