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Stage-Specific Proteomes from Onchocerca Ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to A

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Stage-Specific Proteomes from Onchocerca Ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to A Edinburgh Research Explorer Stage-specific proteomes from Onchocerca ochengi, sister species of the human river blindness parasite, uncover adaptations to a nodular lifestyle Citation for published version: Armstrong, SD, Xia, D, Bah, GS, Krishna, R, Ngangyung, HF, LaCourse, EJ, McSorley, HJ, Kengne-Ouafo, JA, Chounna-Ndongmo, PW, Wanji, S, Enyong, PA, Taylor, DW, Blaxter, ML, Wastling, JM, Tanya, VN & Makepeace, BL 2016, 'Stage-specific proteomes from Onchocerca ochengi, sister species of the human river blindness parasite, uncover adaptations to a nodular lifestyle', Molecular and Cellular Proteomics. https://doi.org/10.1074/mcp.M115.055640 Digital Object Identifier (DOI): 10.1074/mcp.M115.055640 Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Molecular and Cellular Proteomics Publisher Rights Statement: Author's Choice—Final version free via Creative Commons CC-BY license. General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 11. Oct. 2021 crossmark Research Author’s Choice © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is available on line at http://www.mcponline.org Stage-specific Proteomes from Onchocerca ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to a Nodular Lifestyle*□S Stuart D. Armstrong‡, Dong Xia‡, Germanus S. Bah§, Ritesh Krishna¶, Henrietta F. Ngangyung§a, E. James LaCourseʈ, Henry J. McSorley**, Jonas A. Kengne-Ouafo‡‡, Patrick W. Chounna-Ndongmo‡‡, Samuel Wanji‡‡, Peter A. Enyong‡‡§§, David W. Taylor‡¶¶, Mark L. Blaxterʈʈ, Jonathan M. Wastling‡ ‡‡‡b, Vincent N. Tanya§, and Benjamin L. Makepeace‡c Despite 40 years of control efforts, onchocerciasis (river intradermal nodules. In addition, 135 proteins were de- blindness) remains one of the most important neglected tected from the obligate Wolbachia symbiont. Observed tropical diseases, with 17 million people affected. The protein families that were enriched in all whole body etiological agent, Onchocerca volvulus, is a filarial nem- extracts relative to the complete search database in- atode with a complex lifecycle involving several distinct cluded immunoglobulin-domain proteins, whereas re- stages in the definitive host and blackfly vector. The dox and detoxification enzymes and proteins involved in challenges of obtaining sufficient material have pre- intracellular transport displayed stage-specific overrep- vented high-throughput studies and the development of resentation. Unexpectedly, the larval stages exhibited novel strategies for disease control and diagnosis. Here, enrichment for several mitochondrial-related protein we utilize the closest relative of O. volvulus, the bovine families, including members of peptidase family M16 parasite Onchocerca ochengi, to compare stage-spe- and proteins which mediate mitochondrial fission and cific proteomes and host-parasite interactions within fusion. Quantification of proteins across the lifecycle the secretome. We identified a total of 4260 unique O. using the Hi-3 approach supported these qualitative ochengi proteins from adult males and females, infec- analyses. In nodule fluid, we identified 94 O. ochengi tive larvae, intrauterine microfilariae, and fluid from secreted proteins, including homologs of transforming growth factor-␤ and a second member of a novel 6-ShK toxin domain family, which was originally described From the ‡Institute of Infection & Global Health, University of Liv- erpool, Liverpool L3 5RF, UK; §Institut de Recherche Agricole pour le from a model filarial nematode (Litomosoides sigmodon- De´veloppement, Regional Centre of Wakwa, BP65 Ngaounde´re´, tis). Strikingly, the 498 bovine proteins identified in nod- Cameroon; ¶Institute of Integrative Biology, University of Liverpool, ule fluid were strongly dominated by antimicrobial pro- Liverpool L69 7ZB, UK; ʈDepartment of Parasitology, Liverpool teins, especially cathelicidins. This first high-throughput School of Tropical Medicine, Liverpool, L3 5QA, UK; **The Queens analysis of an Onchocerca spp. proteome across the Medical Research Institute, University of Edinburgh, Edinburgh, EH16 lifecycle highlights its profound complexity and empha- 4JT; ‡‡Research Foundation for Tropical Diseases and Environment, sizes the extremely close relationship between O. PO Box 474 Buea, Cameroon; §§Tropical Medicine Research Station, ochengi and O. volvulus. The insights presented here Kumba, Cameroon; ¶¶Division of Pathway Medicine, University of provide new candidates for vaccine development, drug Edinburgh, Edinburgh EH9 3JT, UK; ʈʈInstitute of Evolutionary Biol- targeting and diagnostic biomarkers. Molecular & Cel- ogy, University of Edinburgh, Edinburgh EH9 3JT, UK; ‡‡‡The Na- tional Institute for Health Research, Health Protection Research Unit lular Proteomics 15: 10.1074/mcp.M115.055640, 2554– in Emerging and Zoonotic Infections, University of Liverpool, Liver- 2575, 2016. pool L3 5RF, UK Author’s Choice—Final version free via Creative Commons CC-BY license. Received September 17, 2015, and in revised form, April 30, 2016 Despite 40 years of vector control and mass drug admin- Published, MCP Papers in Press, May 25, 2016, DOI istration programs, onchocerciasis (river blindness) remains 10.1074/mcp.M115.055640 one of the most important of the neglected tropical diseases, Author contributions: S.D.A., D.X., S.W., P.A.E., D.W.T., J.M.W., infecting nearly 17 million people in sub-Saharan Africa (1). V.N.T., and B.L.M. designed research; S.D.A., G.S.B., H.F.N., J.A.K., P.W.C., and B.L.M. performed research; S.D.A., D.X., R.K., E.J.L., The disease is caused by a filarial nematode, Onchocerca H.J.M., M.L.B., and B.L.M. analyzed data; S.D.A., E.J.L., H.J.M., and volvulus, which resides within subcutaneous nodules and B.L.M. wrote the paper. achieves a reproductive lifespan of Ͼ10 years (2). An adult 2554 Molecular & Cellular Proteomics 15.8 Stage-specific Proteomes from Onchocerca ochengi female worm releases ϳ1000 first-stage larvae (microfilariae, sion at the level of the vector by PCR of pooled blackflies (17). Mf)1 per day (3), which migrate to the skin and eyes, ultimately However, the desirability of a simple, noninvasive test to causing onchodermatitis and ocular pathology. Recent esti- determine if an individual harbors one or more viable adult mates of disease burden indicate that 4.2 million people are nematodes has spurred the hunt for onchocerciasis biomark- affected by severe itching, 746,000 experience poor vision ers in body fluids such as urine (18). and 265,000 individuals are rendered blind, resulting in a total Our understanding of filarial genomics and molecular biol- global morbidity of almost 1.2 million years lived with disability ogy has been shaped largely by the publication of the Brugia (1, 4). malayi genome (19) and follow-up studies of its transcriptome Historically, vector control was implemented on a massive (20–22), secretome (23–25), and structural proteome (26). scale, but the mainstay of current control efforts is a single This species is geographically restricted cause of lymphatic anthelminthic, ivermectin, which suppresses microfilaridermia filariasis in humans, but is also popular as a laboratory model, for several months following a single annual dose but does as it will complete its lifecycle in jirds and will undergo limited not kill the adult worms (5). However, resistance to ivermectin development in mice (27). Furthermore, its availability from may be emerging in West Africa (6, 7), and this drug is con- a central facility in Athens, Georgia, has greatly facilitated traindicated in individuals heavily co-infected with Loa loa (a genomic and post-genomic studies on this parasite (28). filarial parasite coendemic in Central Africa) because of the However, B. malayi differs greatly from O. volvulus in its much risk of severe adverse events, such as potentially fatal en- shorter lifespan, location of Mf (which circulate in peripheral cephalopathy (8). Two potential adulticidal treatments are un- blood rather than migrating through the skin), and the lifestyle der evaluation to accelerate elimination efforts: flubendazole, of the adult worms, which are located in the lymphatic vessels another anthelminthic used primarily for veterinary indications rather than nodules (27) and do not become heavily accreted (9); and antibiotics such as tetracycline derivatives, which with host material, unlike O. volvulus (29). The number of target the obligate Wolbachia endobacteria present in all available filarial genomes has expanded recently with the stages of O. volvulus (10). These drugs will have to overcome publication of draft assemblies for Loa (30), the canine heart- bioavailability and safety issues (in the case of flubendazole worm, Dirofilaria immitis (31), and the release of an unpub- (11)) or undergo a significant contraction in
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