PhD Oral Defense: Macrocyclic lactone interactions with a P-glycoprotein and polymorphism in ABC transporter and ion channel genes in Dirofilaria immitis

PhD Oral Defense of Thangadurai Mani, Institute of Parasitology

Dirofilaria immitis is a filarial nematode that causes dirofilariasis or heartworm in dogs, cats, wild canids and occasionally humans. Effective control and prevention of this veterinary helminth, as well as other helminths, has been primarily by the administration of anthelmintics and it is still the most effective strategy to overcome parasitosis in the veterinary field. One particular class of anthelmintics is the macrocyclic lactones (MLs) and this drug class includes the avermectins and milbemycins. MLs, also referred as endectocides because of their remarkable efficacy against ectoparasites and endoparasites, are fermentation products of different organisms.  For heartworm, MLs are the only class of drugs used as preventives for more than 26 years. The continuous use of the MLs has led to drug resistance in many parasitic nematodes, and in D. immitis, ML resistance has very recently been confirmed. In heartworm, although no gene has been definitely implicated in ML resistance so far, preliminary evidence shows that the presence of two polymorphic loci on D. immitis P-glycoprotein-14 (Dim-Pgp-14) correlated with loss of efficacy of ML anthelmintics, suggesting that this Pgp may be involved in ML resistance. ABC transporters such as Pgps modulate drug concentration at the target site and therefore can contribute to multidrug resistance. In many parasitic nematodes, this protein family has shown a consistent link with ML resistance. The first goal of this project was to characterize interaction of MLs, namely ivermectin (IVM), selamectin (SEL), moxidectin (MOX) and milbemycin oxime (MBO) with the expressed nematode transporter and to possibly understand the mechanism of ML resistance in D. immitis.

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