The transcription factor NHR-8: A new target to increase ivermectin efficacy in nematodes.

Resistance to the anthelmintic macrocyclic lactone ivermectin (IVM) has a great impact on the control of parasitic nematodes. The mechanisms by which nematodes adapt to IVM remain to be deciphered. We have identified NHR-8, a nuclear hormone receptor involved in the xenobiotic response in Caenorhabditis elegans, as a new regulator of tolerance to IVM. Loss-of-function nhr-8(ok186) C. elegans mutants subjected to larval development assays and electropharyngeogram measurements, displayed hypersensitivity to IVM, and silencing of nhr-8 in IVM-resistant worms increased IVM efficacy. In addition, compared to wild-type worms, nhr-8 mutants under IVM selection pressure failed to acquire tolerance to the drug. In addition, IVM-hypersensitive nhr-8(ok186) worms displayed low transcript levels of several genes from the xenobiotic detoxification network and a concomitant low Pgp-mediated drug efflux activity. Interestingly, some pgp and cyp genes known to impact IVM tolerance in many nematode species, were down regulated in nhr-8 mutants and inversely upregulated in IVM-resistant worms. Moreover, pgp-6 overexpression in nhr-8(ok186) C. elegans increased tolerance to IVM. Importantly, NHR-8 function was rescued in nhr-8(ok186) C. elegans with the homolog of the parasitic nematode Haemonchus contortus, and silencing of Hco-nhr-8 by RNAi on L2 H. contortus larvae increased IVM susceptibility in both susceptible and resistant H. contortus isolates. Thus, our data show that NHR-8 controls the tolerance and development of resistance to IVM in C. elegans and the molecular basis for this relates to the NHR-8-mediated upregulation of IVM detoxification genes. Since our results show that Hco-nhr-8 functions similarly to Cel-nhr-8, this study helps to better understand mechanisms underlying failure in drug efficacy and open perspectives in finding new compounds with NHR-8 antagonist activity to potentiate IVM efficacy.

The relative resistance to gastrointestinal nematode infection of three British sheep breeds.

The relative resistance of Manx Loaghtan, Shetland and Southdown sheep to naturally acquired gastrointestinal nematode infection was assessed over a ten week period. Thirty shearling ewes, ten from each of the three breeds, were co-grazed on an infective pasture. The animals were initially treated with an anthelmintic to minimise previous nematode infection, and faecal samples were collected from individual animals every two weeks. Southdown sheep had significantly higher faecal egg counts (FEC) than Shetland by week 6, and than Manx Loaghtan by week 10. After ten weeks there was an 86-fold difference in FEC between Shetland and Southdown sheep, and a 14-fold difference between Manx Loaghtan and Southdown sheep. These preliminary results suggest that primitive Shetland and Manx Loaghtan sheep may have greater resistance to gastrointestinal parasites, a trait that could be of value to the UK livestock industry.

[Parasitic metazoans of Stenella coeruleoalba (Cetacea: Delphinidae) stranded along the coast of Latium, 1985-1991]. / Metazoi parassiti di Stenella coeruleoalba (Cetacea: Delphinidae) spiaggiata lungo le coste laziali dal 1985 al 1991.

The striped dolphin represents the most common species of cetacean stranded along the Italian coasts. A parasitological survey on 17 specimens of Stenella coerulecaiba stranded along coasts of Latium from 1985 to 1991, has been carried out. The morphological study enabled the identification of the following parasites. The sites are reported in brackets. DIGENEA: Campula rochebruni (liver), Campula palliata (liver), Pholeter gastrophilus (pyloric stomach). CESTODA: Tetrabothrium forsteri (intestine), Strobilocephalus triangularis (intestine), Monorygma grimaldii, larvae (abdominal cavity, mesentery, testes), Phyliobothrium delphini, larvae (subcutaneous fat). NEMATODA: Skrjabinalius sp. (lungs). COPEPODA: Pennella sp. (skin). ISOPODA: Ceratothoa parallela (mouth, stomach). AMPHIPODA: Syncyamus aequus (blowhole).