Résumé : Human Onchocerciasis is a neglected tropical disease of debilitating consequences caused by the nodule dwelling nematode Onchocerca volvulus. Excretory Secretory Products (ESPs) help the parasite to establishing infection in an immunocompetent host and thus make O. volvulus ESPs potential sources of diagnostic, therapeutic or immunomodulatory markers. Here, a blend of bioinformatics, biochemical, analytical and immunologic methods were employed to identify one such ESP as a GM2 activator protein orthologue. The cDNA of OvGM2AP was detected in most parasite stages and the protein was detected in ESPs of adult males, adult females and L3 stage. Recombinant OvGM2AP was expressed in Sf21 insect cells and was found to be glycosylated at Asn 173 by mass spectrometry analysis. The recombinant OvGM2AP could significantly differentiate infected from non-infected individuals on total IgG ELISA. No improvement in diagnostic indices was observed when IgG sub-classes were used to detect OvGM2AP by ELISA. A drop in IgG titre was observed to correlate with increased rounds of ivermectin administration. However, as observed from alignment of OvGM2AP sequences with other nematode species, recombinant OvGM2AP was found to cross react with sera from patients with other nematode infections such as Loa loa, Mansonella perstans and Brugia malayi. GM2 degradation to GM3 could not be mediated by OvGM2AP in the presence of human β-hexosaminidase A. However, when examined for competitive inhibition with artificial GM2 substrates such as MUG and MUGs, OvGM2AP was found to competitively inhibit the degradation of MUG by β-hexosaminidase A as opposed to the human GM2AP. Due to the genetic intractability of O. volvulus, Caenorhabditis elegans was used as a model to study the function of OvGM2AP. The C. elegans orthologous gene cpp-1 was found to be expressed predominantly in the hypoderm, with a paralogous form confined to specialized hypodermis such as seam cells. CRISPR-CAS9 mediated knock-out of a 1515 bp sequence on the cpp-1 locus generated mutant strains with altered permeability to chemicals including deionized water. The cpp-1(ulb13) mutant strains were also found to be significantly more permeable to Hoechst 33342 dye intake compared to WT worms and previously described strains with cuticle permeability. The cpp-1 phenotype was successfully rescued by cDNAs of cpp-1 and the human GM2AP (HsGM2AP) but not by the cDNA of OvGM2AP. Analysis of lipid binding abilities of baculovirus produced recombinant CPP-1 and OvGM2AP revealed a preferential lipid binding ability between the two proteins, with CPP-1 failing to recognize di and tri-phosphorylated phosphoinositides which are readily recognized by OvGM2AP on lipid overlay assays. Thus, with the information gathered so far, we conclude that OvGM2AP is an ESP of O. volvulus, is immunogenic and could assist in the diagnosis of onchocerciasis by determining ivermectin treatment endpoints. The C. elegans orthologous gene cpp-1 is essential for cuticle impermeability/integrity. Although the effects of OvGM2AP on immune cells is yet to be studied, we hypothesized based on the preferential lipid binding observed and the lack of rescue of the cpp-1 phenotype by OvGM2AP that OvGM2AP could utilize a preferential lipid binding mechanism to contribute in enabling parasite survival in the host.