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Haemonchus contortus Global Somatic Proteome

ABSTRACT: Parasitic nematodes cause diseases that adversely impact on animal health and production. Although advances in genomics and transcriptomics are revolutionising the way we explore these parasites, there is a dearth of proteomic data to underpin or support fundamental discoveries. Here, using a high throughput LC-MS/MS-based approach, we undertook the first large-scale (global) proteomic investigation of Haemonchus contortus (the barber's pole worm), one of the most important parasitic nematodes of livestock animals worldwide. In total, 2487 unique H. contortus proteins, representing five key developmental stages [i. e. eggs, third-stage (L3) and fourth-stage (L4) larvae; female (Af) and male adults (Am)] were identified and quantified with high confidence. Bioinformatic analyses of the somatic proteome of H. contortus discovered substantial alterations in protein profiles during the life cycle, particularly in the transition from the free-living to the parasitic phase, and identified groups of key proteins involved specifically in feeding, digestion, metabolism, development, parasite-host interactions (including immunomodulation), structural remodelling of the body wall and other adaptive processes during the parasitic phase. This global proteomic data set will likely facilitate future molecular, biochemical and physiological investigations of H. contortus and related nematodes, and should underpin the discovery of novel intervention targets against haemonchosis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Haemonchus Contortus (barber Pole Worm)

TISSUE(S): Whole Body, Somatic Cell

DISEASE(S): Parasitic Infectious Disease

SUBMITTER: Tao Wang

LAB HEAD: Robin Beat Gasser

PROVIDER: PXD009956 | Pride | 2019-03-01

REPOSITORIES: Pride

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Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.

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Haemonchus contortus Global Somatic Proteome

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