About the Authors: Paul J. Brindley * E-mail: pbrindley@gwu.edu (PJB); alex.loukas@jcu.edu.au (AL) Affiliations Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & ...Health Sciences, The George Washington University, Washington DC, United States of America, Research Center for Neglected Tropical Diseases of Poverty, School of Medicine & Health Sciences, The George Washington University, Washington DC, United States of America ORCID http://orcid.org/0000-0003-1765-0002 Alex Loukas * E-mail: pbrindley@gwu.edu (PJB); alex.loukas@jcu.edu.au (AL) Affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Queensland, AustraliaCitation: Brindley PJ, Loukas A (2017) Helminth infection-induced malignancy. ...each of these helminth infections must be viewed holistically in the context of a perfect storm of risk for cancer (see 3). Mutations in p53 and smad4 directly affect the p53- and TGF-signaling pathways, both of which are involved in tumorigenesis. ...distinct causes of CCA induce discrete somatic alterations, even within the same cancer type 25. Secreted Ov-GRN-1 may promote angiogenesis and also wound repair of the bile ducts damaged by the liver fluke 11, 30 (Fig 2). ...Ov-GRN-1 may mimic the action of interleukin-33 (IL-33), an epithelial mitogen for cholangiocytes, in the development of CCA 31.
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The World Health Organization (WHO) currently classifies 20 diseases and conditions as neglected tropical diseases (NTDs). However, since its inception in 2007, PLOS Neglected Tropical Diseases has ...considered an expanded list that includes additional diseases with the chronic and/or debilitating, and poverty-promoting features of NTDs. Described here is an update of our current scope, which attempts to embrace all of the NTDs, and a discussion of the status of some of the more debated medical conditions in terms of whether or not they constitute an NTD.
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Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA) in the Mekong Basin countries of Thailand, Lao PDR, Vietnam, Myanmar and ...Cambodia. Using a novel model of CCA, involving infection with gene-edited liver flukes in the hamster during concurrent exposure to dietary nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We derived RNA-guided gene knockout flukes (ΔOv-grn-1) using CRISPR/Cas9/gRNA materials delivered by electroporation. Genome sequencing confirmed programmed Cas9-catalyzed mutations of the targeted genes, which was accompanied by rapid depletion of transcripts and the proteins they encode. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes. However, less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control gene-edited and mock-edited parasites. Specifically, immuno- and colorimetric-histochemical analysis of livers revealed markedly less periductal fibrosis surrounding the flukes and less fibrosis globally within the hepatobiliary tract during infection with ΔOv-grn-1 genotype worms, minimal biliary epithelial cell proliferation, and significantly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high-grade CCA compared to controls. The clinically relevant, pathophysiological phenotype of the hepatobiliary tract confirmed a role for this secreted growth factor in malignancy and morbidity during opisthorchiasis.
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Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than ...a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.
World neglected tropical diseases day Hotez, Peter J; Aksoy, Serap; Brindley, Paul J ...
PLoS neglected tropical diseases,
01/2020, Letnik:
14, Številka:
1
Journal Article
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January 30, 2020 is the first-ever World Neglected Tropical Diseases Day (World NTD Day), a day when we celebrate the achievements made towards control of the world's NTDs, yet recognize the daunting ...challenges we face in the control and elimination of these conditions.
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The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which ...chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov-GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma.
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Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and adjacent countries. In addition to infection-associated morbidity, infection with O. viverrini ...and the related Clonorchis sinensis are unarguable risk factors for cholangiocarcinoma (CAA, bile-duct cancer). Here we review the pathogenesis of opisthorchiasis and the association between O. viverrini infection and bile-duct cancer, focusing on the molecular parallels between wound healing, chronic inflammation, and cancer development. We review a schema for human disease progression from fluke infection, chronic opisthorchiasis, advanced periductal fibrosis, and cholangiocarcinogenesis, and present a rationale for biomarker discovery to facilitate early intervention. We conclude by addressing post-genomic advances with a view to developing new control strategies to combat this infectious cancer.
Infection with the food-borne liver fluke Opisthorchis viverrini causes cholangiocarcinoma (CCA). Whereas the cause of CCA in the West remains obscure, the principal risk factor in Thailand is ...opisthorchiasis. Here, we review recent findings on the pathogenesis of opisthorchiasis and CCA focusing on helminth molecules/toxic metabolites, host-parasite interaction, endocytosis, immunopathology/inflammatory responses, free radical production, molecular genetic alterations, and multifactorial including coinfections driving to CCA development.
Helminths are parasitic worms. They are the most common infectious agents of humans in developing countries and produce a global burden of disease that exceeds better-known conditions, including ...malaria and tuberculosis. As we discuss here, new insights into fundamental helminth biology are accumulating through newly completed genome projects and the nascent application of transgenesis and RNA interference technologies. At the same time, our understanding of the dynamics of the transmission of helminths and the mechanisms of the Th2-type immune responses that are induced by infection with these parasitic worms has increased markedly. Ultimately, these advances in molecular and medical helminth biology should one day translate into a new and robust pipeline of drugs, diagnostics, and vaccines for targeting parasitic worms that infect humans.
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