Bourguinat Catherine, Lee Alice C Y, Lizundia Regina, Blagburn Byron L, Liotta Janice L, Kraus Marc S, Keller Kathy, Epe Christian, Letourneau Louis, Kleinman Claudia L, Paterson Tara, Gomez Elena Carreton, Montoya-Alonso José Alberto, Smith Hubert, Bhan Aron, Peregrine Andrew S, Carmichael James, Drake Jason, Schenker Rudolf, Kaminsky Ronald, Bowman Dwight D, Geary Timothy G, Prichard Roger K
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
College of Veterinary Medicine, Cornell University, 602 Tower Rd, Ithaca, NY 14853, USA.
Vet Parasitol. 2015 Jun 15;210(3-4):167-78. doi: 10.1016/j.vetpar.2015.04.002. Epub 2015 Apr 13.
Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom(®) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms.
大环内酯类体内外寄生虫杀虫剂被用作犬猫预防心丝虫感染（犬恶丝虫）的化学预防药物。在美国的一些地区，关于大环内酯类心丝虫预防药物效力丧失（LOE）的说法已很常见。我们直接测试了犬恶丝虫效力丧失分离株中是否存在对大环内酯类药物的抗性，并确定了与大环内酯类抗性相关、因此可预测该抗性的遗传标记。大环内酯类对照研究表明，尽管使用口服伊维菌素或注射用莫西菌素进行化学预防，犬恶丝虫的效力丧失株仍能在犬体内建立感染。采用全基因组方法来寻找与抗性表型相关的基因座。许多基因座在敏感和效力丧失的犬恶丝虫群体之间显示出高度显著差异。基于186个潜在标记基因座，对663个个体寄生虫（成虫和微丝蚴）进行了Sequenom（®）单核苷酸多态性频率分析，这些寄生虫在表型上被表征为敏感（SUS）、经确认的大环内酯类治疗存活者/抗性（RES）或疑似抗性/效力丧失（LOE）寄生虫。有一个单核苷酸多态性基因座子集似乎是预测大环内酯类抗性的有前景的标记，包括一些在其他寄生虫中与大环内酯类抗性相关的基因中的单核苷酸多态性。这些数据提供了犬恶丝虫对大环内酯类药物抗性的确凿证据，并确定了可用于监测心丝虫对大环内酯类药物抗性的遗传标记。
