Polymorphism in ion channel genes of Dirofilaria immitis: Relevant knowledge for future anthelmintic drug design.
Dirofilaria immitis, a filarial parasite, causes cardiopulmonary dirofilariasis in dogs, cats and wild canids. The macrocyclic lactone (ML) class of drugs has been used to prevent heartworm infection. There is confirmed ML resistance in D. immitis and thus there is an urgent need to find new anthelmintics that could prevent and/or control the disease. Targeting ion channels of D. immitis for drug design has obvious advantages. These channels, present in the nematode nervous system, control movement, feeding, mating and respond to environmental cues which are necessary for survival of the parasite. Any new drug that targets these ion channels is likely to have a motility phenotype and should act to clear the worms from the host. Many of the successful anthelmintics in the past have targeted these ion channels and receptors. Knowledge about genetic variability of the ion channel and receptor genes should be useful information for drug design as receptor polymorphism may affect responses to a drug. Such information may also be useful for anticipation of possible resistance development. A total of 224 ion channel genes/subunits have been identified in the genome of D. immitis. Whole genome sequencing data of parasites from eight different geographical locations, four from ML-susceptible populations and the other four from ML-loss of efficacy (LOE) populations, were used for polymorphism analysis. We identified 1762 single nucleotide polymorphic (SNP) sites (1508 intronic and 126 exonic) in these 224 ion channel genes/subunits with an overall polymorphic rate of 0.18%. Of the SNPs found in the exon regions, 129 of them caused a non-synonymous type of polymorphism. Fourteen of the exonic SNPs caused a change in predicted secondary structure. A few of the SNPs identified may have an effect on gene expression, function of the protein and resistance selection processes.
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Thangadurai
T
Mani
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Catherine
C
Bourguinat
Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
Kathy
K
Keller
Research Institute of Biomedical and Health Sciences (IUIBS), Faculty of Veterinary, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
Elena
E
Carreton
Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.
Andrew
A
Peregrine
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; D000871:Anthelmintics / Q000302:isolation & purification* / Q000494:pharmacology*; D004183:Dirofilaria immitis / Q000201:enzymology* / Q000235:genetics*; D015195:Drug Design; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation
D000871:Anthelmintics; D007473:Ion Channels
Dirofilaria immitis; Drug targets; Ion channels; Loss of efficacy; Macrocyclic lactones; Neuromuscular system; Single nucleotide polymorphism
Int J Parasitol. 2007 Mar;37(3-4):435-47
17234192
Int J Parasitol Drugs Drug Resist. 2011 Nov 07;2:58-75
24533264
Br J Pharmacol. 1989 Nov;98(3):841-50
2556203
IUBMB Life. 2007 Mar;59(3):151-62
17487686
Br J Pharmacol. 1985 Feb;84(2):445-61
2579701
Nat Rev Drug Discov. 2002 Jun;1(6):427-36
12119744
PLoS One. 2007 Nov 14;2(11):e1189
18000556
PLoS Negl Trop Dis. 2013;7(2):e2084
23469307
Parasitol Int. 2013 Dec;62(6):599-605
23602737
Nat Rev Cancer. 2014 Jan;14(1):39-48
24336491
Trends Parasitol. 2001 Sep;17(9):445-53
11530357
J Parasitol. 2015 Apr;101(2):125-33
25584662
Nat Neurosci. 1999 Sep;2(9):791-7
10461217
WormBook. 2013 Aug 13;:1-106
24081909
J Parasitol. 2007 Jun;93(3):704-8
17626368
Adv Exp Med Biol. 2011;704:359-71
21290306
Genetics. 2013 Aug;194(4):885-901
23695300
PLoS Negl Trop Dis. 2014 Apr 24;8(4):e2824
24762816
Physiol Rev. 2004 Oct;84(4):1097-153
15383649
Curr Biol. 2008 Jul 8;18(13):1010-5
18583134
PLoS Pathog. 2009 Jul;5(7):e1000517
19609360
J Neurosci. 2004 Sep 15;24(37):8135-40
15371514
J Neurosci. 2005 Jul 20;25(29):6745-54
16033884
J Cell Biol. 1996 Aug;134(4):885-93
8769414
Nature. 2008 Mar 13;452(7184):176-80
18337814
Vet Parasitol. 2012 Apr 30;185(2-4):201-9
22075040
PLoS Pathog. 2014 Jan 30;10(1):e1003870
24497826
PLoS One. 2011;6(7):e22390
21818319
Development. 1998 Jan;125(2):249-58
9486798
J Neurosci. 1999 Jul 1;19(13):5348-59
10377345
Bioinformatics. 2011 Dec 15;27(24):3435-6
22025480
Philos Trans R Soc Lond B Biol Sci. 1986 Nov 12;314(1165):1-340
22462104
Curr Biol. 2007 Sep 18;17 (18):1595-600
17825559
Science. 2006 Dec 22;314(5807):1930-3
17185601
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W465-7
15980513
Gene. 1997 Nov 12;201(1-2):119-25
9409779
Future Med Chem. 2011 May;3(7):887-96
21644834
J Neurobiol. 1992 Nov;23(9):1327-51
1469391
FASEB J. 2012 Nov;26(11):4650-61
22889830
PLoS Negl Trop Dis. 2012;6(4):e1582
22545164
BMC Bioinformatics. 2004 May 14;5:59
15144565
J Comp Neurol. 2003 Jul 21;462(2):213-22
12794744
Nature. 1994 Feb 3;367(6462):470-3
8107806
PLoS Pathog. 2014 Jun 12;10(6):e1004181
24945827
Bioessays. 2004 Jan;26(1):39-49
14696039
Invert Neurosci. 2012 Jun;12(1):3-12
22430311
Lancet. 2007 Jun 16;369(9578):2021-9
17574093
Expert Opin Drug Discov. 2007 Oct;2(s1):S25-33
23489029
J Neurochem. 2004 Jun;89(5):1137-47
15147506
Neurotherapeutics. 2007 Apr;4(2):184-98
17395128
PLoS Negl Trop Dis. 2010 Jul 27;4(7):e779
20668545
J Parasitol. 2011 Aug;97(4):602-9
21506823
Pharmacogenomics J. 2011 Aug;11(4):274-86
20386561
Vet Parasitol. 2011 Mar 22;176(4):374-81
21300438
J Biol Chem. 1999 Nov 26;274(48):34238-44
10567397
Mol Biochem Parasitol. 2006 May;147(1):118-25
16527366
Nat Rev Genet. 2002 Apr;3(4):285-98
11967553
Neuron. 1996 Oct;17(4):707-18
8893027
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2674-9
10716995
Parasitol Int. 2009 Mar;58(1):6-11
18952001
Vet Parasitol. 2011 Mar 22;176(4):368-73
21310534
Int J Parasitol Drugs Drug Resist. 2012 Apr 14;2:134-53
24533275
Trends Parasitol. 2004 Oct;20(10):456-61
15363438
Mol Biochem Parasitol. 2012 Sep;185(1):10-8
22677339
Curr Biol. 2007 Apr 3;17(7):624-9
17350263
Mol Biochem Parasitol. 2006 Nov;150(1):46-55
16872692
Vet Clin North Am Small Anim Pract. 2009 Nov;39(6):1127-58, vii
19932367
Science. 2007 Jan 26;315(5811):525-8
17185560
Int J Parasitol. 2014 Mar;44(3-4):235-41
24503202
Neuron. 1996 Oct;17(4):695-706
8893026
Trends Parasitol. 2005 Nov;21(11):530-2
16126457
Aging Cell. 2009 Jun;8(3):258-69
19627265
Int J Parasitol Drugs Drug Resist. 2011 Oct 14;1(1):2-13
24533259
Vet Parasitol. 2015 Jun 15;210(3-4):167-78
25936435
PLoS Negl Trop Dis. 2011 Mar 29;5(3):e998
21468315
Int J Parasitol Drugs Drug Resist. 2014 Aug 13;4(3):164-84
25516826
Invert Neurosci. 2008 Sep;8(3):107-19
18696132
Top Companion Anim Med. 2011 Nov;26(4):186-92
22152606
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R243-9
16244322
Vet Parasitol. 2005 Oct 24;133(2-3):191-5
16099105
Int J Parasitol Drugs Drug Resist. 2016 Aug;6(2):116-24
27164440
Vet Parasitol. 2011 Sep 27;181(2-4):388-92
21570194
Int J Parasitol. 2004 Aug;34(9):1075-81
15313134
J Neurochem. 2002 Nov;83(4):870-8
12421359
J Helminthol. 2010 Sep;84(3):276-83
19889245
Science. 2009 Jul 3;325(5936):96-100
19574391
J Clin Invest. 2008 Apr;118(4):1311-21
18382743
Parasit Vectors. 2014 Nov 07;7:494
25376278
Curr Biol. 2005 Jun 7;15(11):1045-50
15936276
Trends Parasitol. 2014 Jul;30(7):361-7
24888669
Curr Clin Microbiol Rep. 2014 Dec;1(3-4):51-60
25554739
PLoS One. 2013 Sep 10;8(9):e75869
24040423
J R Soc Interface. 2012 Jul 7;9(72):1409-37
22552919
Parasitology. 2015 Sep;142(10):1249-59
26040450
Int J Parasitol. 2010 Aug 15;40(10):1177-81
20430031
Physiol Rev. 2002 Jul;82(3):769-824
12087135
N Engl J Med. 2007 Sep 6;357(10):1018-27
17804846
Hum Mutat. 2011 Jul;32(7):773-82
21412952
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
9254694
Mol Biochem Parasitol. 1999 Oct 15;103(2):129-40
10551358
Int J Antimicrob Agents. 2008 Feb;31(2):91-8
18037274
Nature. 2003 Jan 16;421(6920):231-7
12529635