Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance.
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.
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Catherine
C
Bourguinat
College of Veterinary Medicine, Cornell University, 602 Tower Rd, Ithaca, NY 14853, USA.
Alice C Y
AC
Lee
Novartis Animal Health, Route de la Petite Glâne, St-Aubin 1566, Switzerland.
Regina
R
Lizundia
College of Veterinary Medicine, Auburn University, 1500 Wire Road, Auburn, AL 36849, USA.
Byron L
BL
Blagburn
College of Veterinary Medicine, Cornell University, 602 Tower Rd, Ithaca, NY 14853, USA.
Janice L
JL
Liotta
College of Veterinary Medicine, Cornell University, 602 Tower Rd, Ithaca, NY 14853, USA.
Marc S
MS
Kraus
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Kathy
K
Keller
Novartis Animal Health, Route de la Petite Glâne, St-Aubin 1566, Switzerland.
Christian
C
Epe
McGill University and Génome Québec Innovation Centre, 740, Dr. Penfield Avenue, QC H3A 0G1, Canada.
Louis
L
Letourneau
Lady Davis Institute for Medical Research and Department of Human Genetics, McGill University, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC H3 T 1E2, Canada.
Claudia L
CL
Kleinman
School of Veterinary Medicine, St. George's University, True Blue, St. George's, Grenada.
Tara
T
Paterson
Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Calle Juan de Quesada, 30, 35001 Las Palmas de Gran Canaria, Spain.
Elena Carreton
EC
Gomez
Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Calle Juan de Quesada, 30, 35001 Las Palmas de Gran Canaria, Spain.
José Alberto
JA
Montoya-Alonso
Haywood Animal Hospital, 2538 N Washington Avenue, Brownsville, TN 38012, USA.
Hubert
H
Smith
Main West Animal Hospital, 1 Broadway, Welland, ON L3 C 5L2, Canada.
Aron
A
Bhan
Ontario Veterinary College, University of Guelph, Gordon Street, Guelph, ON N1G 2W1, Canada.
Andrew S
AS
Peregrine
Novartis Animal Health, 3200 Northline Avenue, Greensboro, NC 27408, USA.
James
J
Carmichael
Novartis Animal Health, 3200 Northline Avenue, Greensboro, NC 27408, USA.
Jason
J
Drake
Novartis Animal Health, Route de la Petite Glâne, St-Aubin 1566, Switzerland.
Rudolf
R
Schenker
Novartis Animal Health, Route de la Petite Glâne, St-Aubin 1566, Switzerland.
Ronald
R
Kaminsky
College of Veterinary Medicine, Cornell University, 602 Tower Rd, Ithaca, NY 14853, USA.
Dwight D
DD
Bowman
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Timothy G
TG
Geary
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada. Electronic address: roger.prichard@mcgill.ca.
Roger K
RK
Prichard
D000818:Animals; D018890:Chemoprevention / Q000662:veterinary; D004183:Dirofilaria immitis / Q000187:drug effects / Q000235:genetics*; D004184:Dirofilariasis / Q000469:parasitology*; D004283:Dog Diseases / Q000469:parasitology*; D004285:Dogs; D004351:Drug Resistance; D005260:Female; D005369:Filaricides / Q000494:pharmacology*; D005819:Genetic Markers / Q000235:genetics; D007559:Ivermectin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008842:Microfilariae; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D005369:Filaricides; D005819:Genetic Markers; D007783:Lactones; D018942:Macrolides; D007559:Ivermectin; C027837:moxidectin
Dirofilaria immitis; Genetic markers; Ivermectin; Macrocyclic lactones; Moxidectin; Resistance