Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis

Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness

Co-Administration of Adjuvanted Recombinant Ov-103 and Ov-RAL-2 Vaccines Confer Protection against Natural Challenge in A Bovine Onchocerca ochengi Infection Model of Human Onchocerciasis

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a neglected tropical disease mainly of sub-Saharan Africa. Worldwide, an estimated 20.9 million individuals live with infection and a further 205 million are at risk of disease. Current control methods rely on mass drug administration of ivermectin to kill microfilariae and inhibit female worm fecundity. The identification and development of efficacious vaccines as complementary preventive tools to support ongoing elimination efforts are therefore an important objective of onchocerciasis research. We evaluated the protective effects of co-administering leading O. volvulus-derived recombinant vaccine candidates (Ov-103 and Ov-RAL-2) with subsequent natural exposure to the closely related cattle parasite Onchocerca ochengi. Over a 24-month exposure period, vaccinated calves (n = 11) were shown to acquire infection and microfilaridermia at a significantly lower rate compared to unvaccinated control animals (n = 10). Furthermore, adult female worm burdens were negatively correlated with anti-Ov-103 and Ov-RAL-2 IgG1 and IgG2 responses. Peptide arrays identified several Ov-103 and Ov-RAL-2-specific epitopes homologous to those identified as human B-cell and helper T-cell epitope candidates and by naturally-infected human subjects in previous studies. Overall, this study demonstrates co-administration of Ov-103 and Ov-RAL-2 with Montanide™ ISA 206 VG is highly immunogenic in cattle, conferring partial protection against natural challenge with O. ochengi. The strong, antigen-specific IgG1 and IgG2 responses associated with vaccine-induced protection are highly suggestive of a mixed Th1/Th2 associated antibody responses. Collectively, this evidence suggests vaccine formulations for human onchocerciasis should aim to elicit similarly balanced Th1/Th2 immune responses.</jats:p

Onchocerca armillata contains the endosymbiotic bacterium Wolbachia and elicits a limited inflammatory response

Human onchocerciasis, also known as River Blindness, is a debilitating disease caused by the filarial nematode Onchocerca volvulus. Many, but not all, filarial nematodes carry within their tissues endosymbiotic, Rickettsia-like bacteria of the genus Wolbachia. Onchocerca spp. infections in cattle offer the most relevant, analogous host–parasite model system. West African cattle are commonly co-infected with four Onchocerca spp.; two of these are Wolbachia-positive (Onchocerca gutturosa and Onchocerca ochengi), and the remainder are of unknown Wolbachia status (Onchocerca dukei and Onchocerca armillata). Previous studies have suggested that worm survival is dependent on this bacterium. O. armillata, an abundant parasite of African cattle that has received little attention, is a primitive species that may lack Wolbachia. The objectives of this study were to determine if O. armillata carries Wolbachia and to provide preliminary descriptions of the host inflammatory cell environment around the adult worms. The findings may support or refute the hypothesis that a prime contribution of Wolbachia is to permit long-term survival and reproduction of certain Onchocerca spp. (including O. volvulus in humans). O. armillata adult worms were found in the aorta of 90.7% of cattle (n = 54) slaughtered at an abattoir in Ngaoundéré, Adamawa Region, Cameroon. The presence of Wolbachia in O. armillata was confirmed by a specific anti-Wolbachia surface protein antibody detected using a peroxidase conjugate (immunohistochemistry) and PCR for detection of Wolbachia-specific sequences within DNA extracts from frozen worms. Tissue sections stained with haematoxylin and eosin showed the host cell response to be dominated by macrophages and fibroblasts. This is unusual compared with nodule-dwelling Wolbachia-positive Onchocerca spp., where the host response is typically characterised by granulocytes, and suggests that the mechanisms for worm survival employed by this species (which is probably motile) may differ