Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses

Jennifer M. Fitzpatrick, Emily Peak, Samirah Perally, Iain Wyllie Chalmers, John Barrett, Timothy P. Yoshino, Alasdair C. Ivens, Karl Francis Hoffmann

Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

105 Dyfyniadau(SciVal)
151 Wedi eu Llwytho i Lawr (Pure)

Crynodeb

Background:
Novel methods to identify anthelmintic drug and vaccine targets are urgently needed, especially for thoseparasite species currently being controlled by singular, often limited strategies. A clearer understanding of thetranscriptional components underpinning helminth development will enable identification of exploitable moleculesessential for successful parasite/host interactions. Towards this end, we present a combinatorial, bioinformatics-ledapproach, employing both statistical and network analyses of transcriptomic data, for identifying new immunoprophylacticand therapeutic lead targets to combat schistosomiasis.

Methodology/Principal Findings:
Utilisation of a Schistosoma mansoni oligonucleotide DNA microarray consisting of 37,632elements enabled gene expression profiling from 15 distinct parasite lifecycle stages, spanning three unique ecologicalniches. Statistical approaches of data analysis revealed differential expression of 973 gene products that minimally describethe three major characteristics of schistosome development: asexual processes within intermediate snail hosts, sexualmaturation within definitive vertebrate hosts and sexual dimorphism amongst adult male and female worms. Furthermore,we identified a group of 338 constitutively expressed schistosome gene products (including 41 transcripts sharing nosequence similarity outside the Platyhelminthes), which are likely to be essential for schistosome lifecycle progression. Whilehighly informative, statistics-led bioinformatics mining of the transcriptional dataset has limitations, including the inabilityto identify higher order relationships between differentially expressed transcripts and lifecycle stages. Network analysis,coupled to Gene Ontology enrichment investigations, facilitated a re-examination of the dataset and identified 387 clusters(containing 12,132 gene products) displaying novel examples of developmentally regulated classes (including 294schistosomula and/or adult transcripts with no known sequence similarity outside the Platyhelminthes), which wereundetectable by the statistical comparisons.

Conclusions/Significance:
Collectively, statistical and network-based exploratory analyses of transcriptomic datasets haveled to a thorough characterisation of schistosome development. Information obtained from these experiments highlightedkey transcriptional programs associated with lifecycle progression and identified numerous anti-schistosomal candidatemolecules including G-protein coupled receptors, tetraspanins, Dyp-type peroxidases, fucosyltransferases, leishmanolysinsand the netrin/netrin receptor complex.
Iaith wreiddiolSaesneg
Rhif yr erthygle543.
CyfnodolynPLoS Neglected Tropical Diseases
Cyfrol3
Rhif cyhoeddi11
Dynodwyr Gwrthrych Digidol (DOIs)
StatwsCyhoeddwyd - 03 Tach 2009

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