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Spatial proteomics of Onchocerca volvulus with pleomorphic neoplasms show local and systemic dysregulation of protein expression

ABSTRACT: Onchocerca volvulus is the agent of onchocerciasis or river blindness and targeted by WHO for elimination. The main strategy is mass drug administration with ivermectin for the duration of the life span of the adult worms. The drug is mainly microfilaricidal, but weak macrofilaricidal effects, after several rounds of treatment, were observed. A small percentage of adult O. volvulus females contain pleomorphic neoplasms and the rate of worms with neoplasms increases with the number of ivermectin treatments. Within a clinical trial of drug combinations that included ivermectin we identified 24 (5.6%) adult females with neoplasms. We assessed the protein inventory of these neoplasms to identify proteins that may be associated with tumor development. We used laser capture microdissection and highly sensitive mass spectrometry analysis to determine the protein inventory of neoplasms. Neoplasm tissue from female worms was analyzed, and compared to normal tissue from the body wall, uterus and intestine from the same worms, and to tissues from females without neoplasms. One female with neoplasms had a few normal stretched microfilariae in the vagina, but no normal embryogenesis was seen in the other two worms. The healthy females showed all intact embryogenesis. In the worms with neoplasms, 151 proteins were detected in the body wall, 215 proteins in the intestine, 47 proteins in the uterus and 1,577 proteins in the neoplasms. Only in the uterus of the female with intrauterine microfilariae an elevated number of proteins (601) was detectable, while in the uteri of the healthy females 1,710 proteins were detected. The majority of the 20 most abundant proteins identified in neoplasms was highly conserved and only two nematode specific proteins were observed. Among the most abundant proteins that were found in neoplasms but not in the other analyzed tissues, were peroxiredoxin, proteases, and proteins related to signal transduction, ribosomal and proteasome activity. Immunolocalization of a calcium binding protein that was detected in neoplasms confirmed the mass spectrometry results. In conclusion, we have developed a system to analyze the proteome of O. volvulus from nodule sections and identified proteins that are potentially linked to the development of neoplasms and may contribute to worm mortality.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Onchocerca Volvulus

SUBMITTER: Byoung-Kyu Cho

LAB HEAD: Young Ah

PROVIDER: PXD056237 | Pride | 2025-02-26

REPOSITORIES: pride

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			Action	DRS
	20221015_bkc_23-0126_Weil_Fischer_G1.raw	Raw
	20221015_bkc_23-0126_Weil_Fischer_HT1.raw	Raw
	20221015_bkc_23-0126_Weil_Fischer_IN1.raw	Raw
	20221015_bkc_23-0126_Weil_Fischer_ON1.raw	Raw
	20221015_bkc_23-0126_Weil_Fischer_U1.raw	Raw

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Project description:In spite of 40 years of control efforts, onchocerciasis (river blindness) remains one of the most important neglected tropical diseases, with 17 million people affected. The aetiological agent, Onchocerca volvulus, is a filarial nematode with a complex lifecycle involving several distinct stages in the definitive host and blackfly vector. The challenges of obtaining sufficient material have prevented high-throughput studies and the development of novel strategies for disease control and diagnosis. Here, we utilise the closest relative of O. volvulus, the bovine parasite Onchocerca ochengi, to compare stage-specific proteomes and host-parasite interactions within the secretome. We identified a total of 4,260 unique O. ochengi proteins from adult males and females, infective larvae, intrauterine microfilariae, and fluid from intradermal nodules. In addition, 135 proteins were detected from the obligate Wolbachia symbiont. Observed protein families that were enriched in all whole body extracts relative to the complete search database included immunoglobulin-domain proteins, whereas redox and detoxification enzymes and proteins involved in intracellular transport displayed stage-specific overrepresentation. Unexpectedly, the larval stages exhibited enrichment for several mitochondrial-related protein families, including members of peptidase family M16 and proteins which mediate mitochondrial fission and fusion. Quantification of proteins across the lifecycle using the Hi 3 approach supported these qualitative analyses. In nodule fluid, we identified 94 O. ochengi secreted proteins, including two homologs of transforming growth factor and a second member of a novel 6 ShK toxin domain family, which was originally identified from a model filarial nematode (Litomosoides sigmodontis). Strikingly, the 498 bovine proteins identified in nodule fluid were strongly dominated by antimicrobial proteins, especially cathelicidins. This first high-throughput analysis of an Onchocerca spp. proteome highlights its profound complexity and emphasises the extremely close relationship between O. ochengi and O. volvulus. The insights provided here provide new candidates for vaccine development, drug targeting and diagnostic biomarkers.

Project description:Male-derived accessory gland proteins (Acps) that are transferred to females during mating have profound effects on female reproductive physiology including increased ovulation, mating inhibition, and effects on sperm utilization and storage. The extreme rates of evolution seen in Acps may be driven by sperm competition and sexual conflict, processes which may ultimately drive complex interactions between female- and male-derived molecules and sperm. However, little is known of how gene expression in female reproductive tissues changes in response to the presence of male molecules and sperm. To characterize this response, we conducted parallel genomic and proteomic analyses of gene expression in the reproductive tract of 3-day-old unmated and mated female Drosophila melanogaster. Using DNA microarrays, we identified 539 transcripts that are differentially expressed in unmated vs. mated females and revealed a striking peak in differential expression at 6 hrs postmating and a marked shift from primarily down-regulated to primarily up-regulated transcripts within 3 hrs after mating. Combining two-dimensional gel electrophoresis and liquid chromatography mass spectrometry analyses, we identified 84 differentially expressed proteins at 3 hrs postmating, including proteins which appeared to undergo post-translational modification. Together, our observations define transcriptional and translational response to mating within the female reproductive tract and suggest a bimodal model of postmating gene expression initially correlated with mating and the final stages of female reproductive tract maturation and later with the declining presence of male reproductive molecules and with sperm maintenance and utilization. Experiment Overall Design: Three-day-old mated and unmated females were dissected to remove the lower reproductive tract (upper uterus, sperm-storage organs, and accessory glands). Mated females were dissected either immediately following mating (0 hr) or at 3, 6, or 24 hrs following the termination of mating. Tracts of 12-40 females of like category were pooled and total RNA extracted via a TRIzol-based protocol. Processing and labeling of transcript was performed by the Molecular Biology Core Facility at the Medical College of Georgia. Arrays from mated females at the different timepoints were compared to unmated females.

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Spatial proteomics of Onchocerca volvulus with pleomorphic neoplasms show local and systemic dysregulation of protein expression

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