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H11-induced immune protection is predominantly linked to N-glycan moieties

ABSTRACT: Parasitic nematodes of humans, animals and plants cause significant economic losses worldwide. Control of these pathogens is currently challenging due to the widespread problem of nematode anthelmintic resistance. Unfortunately, most efforts to develop anti-nematode vaccines for use in animals and humans have not succeeded. However, one effective (dead) anti-nematode vaccine (Barbervax) has been developed to protect livestock animals against the socioeconomically important parasitic nematode Haemonchus contortus (barber’s pole worm). This vaccine contains a major native antigen, termed H11. In its native form, H11 alone consistently induces high immunoprotection (75-95%) in animals, but recombinant forms thereof do not. Here, to test the hypothesis that post-translation modification of H11 is responsible for achieving the immunoprotection. We explored the N-glycoproteome and N-glycome of H11 using high-resolution mass spectrometry and assessed the roles of N-glycosylation in protective immunity against H. contortus. We demonstrated that N-glycans are a predominant protective component that induces protection and an associated IgG antibody response in immunised animals. We also showed that anti-H11 IgG antibodies confer specific, passive immunity in naïve animals. This study is the first detailed investigation of the relevance of protein glycosylation in protective immunity against a parasitic nematode, and should have important implications for developing vaccines against metazoan parasites.

INSTRUMENT(S): Orbitrap Fusion

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

TISSUE(S): Whole Body

SUBMITTER: Chunqun Wang

LAB HEAD: Min Hu

PROVIDER: PXD037140 | Pride | 2022-10-20

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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H11-induced immune protection is predominantly linked to N-glycan moieties

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