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Haemonchus Contortus ABC Transporters Linked to Macrocyclic Haemonchus contortus ABC transporters linked to Macrocyclic lactone resistance Pablo Godoy Rosas Institute of Parasitology, McGill University Montreal, CANADA March 2015 A thesis submitted to Faculty of Agricultural and Environmental Sciences, McGill University in partial fulfillment with the requirements of the degree of Doctor of Philosophy © Pablo Godoy 2015 0 Abstract. Haemonchus contortus is a parasitic nematode distributed all around the world where ruminants graze and it causes serious decreases in small ruminants production. In order to control this veterinary helminth as well as others, the administration of anthelmintic chemotherapeutics is still the main strategy used to overcome parasitosis in veterinary medicine. One particular anthelmintic class is the macrocyclic lactones (MLs), which since their launch more than thirty years ago have shown remarkable efficacy against endo and ectoparasites, being successful against parasitic pathogens resistant to older parasiticide drugs. Currently, they represent the cornerstone of antiparasite chemotherapy in animal health and are also important in humans. Unfortunately, due to their outstanding effects, the continuous use of the MLs against parasitic nematodes, including H. contortus, has led to drug resistance, and now limits their use. In H. contortus, one of the resistance mechanisms involved could be the over expression of P- glycoproteins (PGPs) and possibly other nematode transporters, homologs of multidrug resistance (MDR) pumps in mammals which belong to the ATP-Binding- Cassette (ABC) transporter protein family. The activity of the ABC transporters is based on the hydrolysis of ATP coupling to the extrusion of many unrelated compounds across the membrane. In the host, these plasma membrane proteins are expressed in different organs and tissues such as intestine, liver, blood-brain- barreer (BBB) and kidney, influencing the bioavailability and pharmacokinetics of different substrates including the ML drugs. In H. contortus, some ABC transporter sequences have been described to be homologs of the free-living nematode 1 Caenorhabditis elegans ABC transporters. This protein family has shown a consistent link with ML resistance. In addition, studies characterizing the interaction between mammalian ABC transporters with ML such as avermectins, have established a strong interaction between these compounds and P-glycoprotein pumps. PGPs may be transporting these drugs in different compartments and contributing to their elimination. The goal of this project was the characterization of some H. contortus P- glycoproteins (Hco-PGP-2, Hco-PGP-9.1 and Hco-PGP-16) and their interaction with MLs such as avermectins and moxidectin in order to elucidate if these transporters could interact with the MLs and possibly play a role in a mechanism of resistance in this parasite. These H. contortus transporters were expressed in a mammalian cell heterologous expression system, and their functional activity characterized. The localization of two of the transporters inside the worm was also determined. In the transfected mammalian cells, these nematode transporters were localized in the plasma membrane. After expression was confirmed, fluorophore probes were used to test the activity of the H. contortus PGPs. Once the functionality of the transporters was confirmed, the interaction with different MLs was studied. There was a strong inhibition of transport with the avermectins (abamectin (ABA), ivermectin (IVM) and ivermectin aglycone (IVM-agly) with the three H. contortus PGPs, whereas inhibition by moxidectin (MOX) was markedly different, suggesting a weaker interaction of these nematode transporters with MOX. Additionally, the expression of two H. contortus PGPs was localized 2 in adult worms. Hco-PGP-2 was expressed in the head region, particularly in the pharynx, nerve chords around the pharynx, in the deirids and in the first portion of the intestine. On the other hand, Hco-PGP-9.1 was localized in the female reproductive system at the level of the uterus. These results indicate firstly, that the expression and characterization of these nematode transporters is possible using a host system such as mammalian cell cultures. Also, these H. contortus PGPs may interact with, and possibly efflux, the avermectins such as IVM and ABA, but less with MOX. The location of these transporters in the adult parasite may suggest a role as efflux pumps for the avermectins in key tissues where the glutamate-gated chloride channels, ML target receptors, are expressed and thus these PGPs may contribute to the elimination of the avermectins in resistant H. contortus parasites. This work provides new information on the interaction and potential involvement of nematode transporters with ML anthelmintics. This knowledge may be useful in planning how to modulate their function in order to improve ML anthelmintic chemotherapy. 3 Abrégé Haemonchus contortus est un nématode parasite distribués partout dans le monde où des ruminants broutent et il provoque des baisses graves dans la production de petites ruminants. Afin de contrôler ces helminthes vétérinaires ainsi que pour d'autres, l'administration de médicaments chimiothérapeutiques anthelminthiques reste la principale stratégie utilisée pour surmonter les parasitoses en médecine vétérinaire. Une classe d’anthelminthiques particulier sont les lactones macrocycliques (LM), qui depuis leur lancement plus de trente ans ont montré il ya une remarquable efficacité contre les endo et ectoparasites, atteindre du succès contre les agents pathogènes parasitaires résistantes aux médicaments plus anciens antiparasitaires. Actuellement, ils représentent la pierre angulaire de la chimiothérapie antiparasitaire en santé animale et sont également importants chez les humains. Malheureusement, en raison de leur effet exceptionnelle, l'utilisation continue des LM contre les nématodes parasitaires, y compris H. contortus, a conduit à la résistance vers leur utilisation. En H. contortus, l'un des mécanismes de résistance impliqués pourrait être la surexpression de P-glycoprotéines (PGPs) et éventuellement d'autres transporteurs de nématodes, des homologues de pompes multirésistance (MDR) chez les mammifères qui appartiennent à la famille de protéines des transporteurs ABC (ATP-Binding Cassette). L'activité des transporteurs ABC est basé sur le couplage hydrolyse de l'ATP à l'extrusion de nombreux composés non apparentés à travers la membrane. Dans l'hôte, ces protéines de la membrane plasmique sont exprimés dans différents organes et 4 tissus, tels que l'intestin, le foie, la barrièr hémato-encéphalique (BHE) et les reins qui influencent la biodisponibilité et la pharmacocinétique de différents substrats, y compris les LM. En H. contortus certaines séquences de transporteurs ABC ont été décrits comme des homologues des transporteurs ABC du nématode de vie libre Caenorhabditis elegans. Cette famille de protéines ont montré un lien cohérent avec la résistance vers les LM. En outre, des études caractérisant l'interaction entre les transporteurs ABC mammifères avec LM tels que avermectines, ont établi une forte interaction entre ces composés et les pompes P-glycoprotéine. Les PGP peuvent effectuer le transport de ces médicaments dans les différents compartiments et de contribuer à leur élimination. Le but de ce projet était la caractérisation de certains P-glycoprotéines d’H. contortus (Hco-PGP-2, Hco-PGP-9.1 et la Hco-PGP-16) et leur interaction avec les LM tels que les avermectines et la moxidectine, afin d'élucider si ces transporteurs pourraient interagir avec les LM et d’établir si ells jouent un rôle dans un mécanisme de résistance à ce parasite. Ces transporteurs de H. contortus, ont été exprimés dans des cellules mammifères en tant que système d'expression hétérologue et leur activité de fonction a été caractérisé, suivi par la localisation de la Hco-PGP à l'intérieur des vers a été déterminée dans certains cas. Dans les cellules hôtes de mammifères, ces transporteurs de nématodes ont été localisés dans la membrane plasmique. Après l’expression a été confirmée, des études ont été effectuées, en utilisant des sondes fluorophores pour tester l'activité de ces PGPs d’H. contortus. Une fois que la fonctionnalité des transporteurs a été confirmée, 5 l'interaction avec les différents LM a été étudiée. Il y avait une forte interaction des avermectines (l’abamectine (ABA), l'ivermectine (IVM) et l'ivermectine aglycone (IVM-agly) avec les trois PGPs d’H. contortus qui ont été caractérisées, tandis que l'interaction avec la moxidectine (MOX) était sensiblement différente, suggérant une interaction plus faible de ces transporteurs de nématodes avec la MOX. En outre, l'expression des deux PGPs d’H. contortus a été localisé en vers adultes. Hco- PGP-2 a été exprimé dans la région de tête, en particulier dans le pharynx, cordes nerveuses dans le pharynx, dans les deirids et dans la première partie de l'intestin. D'autre part, pour Hco-PGP-9,1 a été localisé dans le système reproducteur femelle, au niveau de l'utérus. Ces résultats montrent, d'une part que l'expression et la caractérisation de ces transporteurs de nématodes sont possibles en utilisant comme système hôte tel que des cultures de cellules mammifères. Également, ces PGPs d’H. contortus pourraient interagir avec, et peut-être efflux, des avermectines telles que l'IVM et l’ABA, mais moins avec la MOX. La localisation de ces transporteurs chez le parasite adulte peut suggérer un rôle de pompes d'efflux pour les avermectines
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