Carcinogenic Parasite Secretes Growth Factor That Accelerates Wound Healing and Potentially Promotes Neoplasia

© 2015 Smout et al. Infection with the human liver fluke Opisthorchis viverrini induces cancer of the bile ducts, cholangiocarcinoma (CCA). Injury from feeding activities of this parasite within the human biliary tree causes extensive lesions, wounds that undergo protracted cycles of healing, and re-injury over years of chronic infection. We show that O. viverrini secreted proteins accelerated wound resolution in human cholangiocytes, an outcome that was compromised following silencing of expression of the fluke-derived gene encoding the granulin-like growth factor, Ov-GRN-1. Recombinant Ov-GRN-1 induced angiogenesis and accelerated mouse wound healing. Ov-GRN-1 was internalized by human cholangiocytes and induced gene and protein expression changes associated with wound healing and cancer pathways. Given the notable but seemingly paradoxical properties of liver fluke granulin in promoting not only wound healing but also a carcinogenic microenvironment, Ov-GRN-1 likely holds marked potential as a therapeutic wound-healing agent and as a vaccine against an infection-induced cancer of major public health significance in the developing world

Transcriptional responses of in vivo praziquantel exposure in schistosomes identifies a functional role for calcium signalling pathway member CamKII

Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with "Tegument/Muscle Repair" and "Lipid/Ion Regulation" functions and were followed by "Drug Resistance" and "Ion Regulation" associated genes. Prominent responses induced in female worms included upregulation of "Ca²⁺ Regulation" and "Drug Resistance" genes and later by transcripts of "Detoxification" and "Pathogen Defense" mechanisms. A subset of highly over-expressed genes, with putative drug resistance/detoxification roles or Ca²⁺-dependant/modulatory functions, were validated by qPCR. The leading candidate among these was CamKII, a putative calcium/calmodulin-dependent protein kinase type II delta chain. RNA interference was employed to knockdown CamKII in S. japonicum to determine the role of CamKII in the response to praziquantel. After partial-knockdown, schistosomes were analysed using IC₅₀ concentrations (50% worm motility) and quantitative monitoring of parasite movement. When CamKII transcription was reduced by 50-69% in S. japonicum, the subsequent effect of an IC₅₀ dosage of praziquantel was exacerbated, reducing motility from 47% to 27% in female worms and from 61% to 23% in males. These observations indicated that CamKII mitigates the effects of praziquantel, probably through stabilising Ca²⁺ fluxes within parasite muscles and tegument. Together, these studies comprehensively charted transcriptional changes upon exposure to praziquantel and, notably, identified CamKII as potentially central to the, as yet undefined, mode of action of praziquantel

Linear functional response by two pupal Drosophila parasitoids foraging within single or multiple patch environments

Functional response describes the number of prey or hosts attacked by a predator or parasitoid as a function of prey or host density. Using three different experimental designs, we found a linear functional response by two insect parasitoids (the pteromalid Pachycrepoideus vindemiae and the diapriid Trichopria drosophilae) to their hosts (the drosophilids Drosophila suzukii and D. melanogaster). A linear function response is considered unusual for insect parasitoids. The first design was a 'fixed time within patch experiment' where individual parasitoids were exposed to a range of host densities for 24 h; the second two designs were a 'variable time functional response' and a 'selective functional response' experiments where individual parasitoids were presented with a range of host patches and allowed to freely select and explore only one patch (variable time) or forage for 24 h (selective). In all experimental designs, the number of hosts parasitized increased linearly until reaching an upper limit. Under the laboratory conditions used, the functional response of P. vindemiae was limited by its egg supply and time (host handling time) whereas T. drosophilae was limited by time only. The linear functional response by both parasitoids likely resulted from a constant attack rate and an incremental foraging strategy where the parasitoids left a poor (low density) host patch or remained in a higher quality host patch when there was successful oviposition and adequate host density