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The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets.

Godel C, Kumar S, Koutsovoulos G, Ludin P, Nilsson D, Comandatore F, Wrobel N, Thompson M, Schmid CD, Goto S, Bringaud F, Wolstenholme A, Bandi C, Epe C, Kaminsky R, Blaxter M, Mäser P - FASEB J. (2012)

Bottom Line: The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States.Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates.This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.

ABSTRACT
The heartworm Dirofilaria immitis is an important parasite of dogs. Transmitted by mosquitoes in warmer climatic zones, it is spreading across southern Europe and the Americas at an alarming pace. There is no vaccine, and chemotherapy is prone to complications. To learn more about this parasite, we have sequenced the genomes of D. immitis and its endosymbiont Wolbachia. We predict 10,179 protein coding genes in the 84.2 Mb of the nuclear genome, and 823 genes in the 0.9-Mb Wolbachia genome. The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States. The differential presence of anabolic pathways such as heme and nucleotide biosynthesis hints at the intricate metabolic interrelationship between the heartworm and Wolbachia. Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates. This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.

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Anabolic pathways in Wolbachia and Dirofilaria. Selected pathways were identified by screening the predicted proteomes with HMM profiles representing each enzyme in the pathway using HMMer (29). The proteomes were hierarchically clustered (77) based on city block distance between the vectors consisting of the best scores (represented as a heat plot) obtained against each profile. A complete prediction of D. immitis metabolic pathways is available online at the Draft Genomes page of the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/catalog/org_list1.html).
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Figure 2: Anabolic pathways in Wolbachia and Dirofilaria. Selected pathways were identified by screening the predicted proteomes with HMM profiles representing each enzyme in the pathway using HMMer (29). The proteomes were hierarchically clustered (77) based on city block distance between the vectors consisting of the best scores (represented as a heat plot) obtained against each profile. A complete prediction of D. immitis metabolic pathways is available online at the Draft Genomes page of the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/catalog/org_list1.html).

Mentions: The relationship between filarial nematodes and their Wolbachia endosymbionts is thought to be a mutualistic symbiosis (62), because extended treatment of infected mammals with tetracycline and other antibiotics results in clearance of the nematodes. The bases of this symbiosis remain unclear. It has been proposed that wBm provides B. malayi with additional sources of critical metabolites such as heme and riboflavin (63). We interrogated the wDi genome to examine the symbiont's biochemical capabilities. C. elegans and other nematodes (including B. malayi, and, on the basis of the genome sequence presented here, D. immitis) are deficient in heme synthesis but wBm has an intact heme pathway (Fig. 2) and a CcmB heme exporter, suggesting that it may support its host by providing heme. wBm has a complete pathway from succinyl-CoA to heme (one apparently missing component, HemG, may be substituted by a functional HemY). wDi lacks both HemY and HemG (and the recently described HemJ that can perform the same transformation). This step in the heme pathway is apparently absent in other bacteria, and so this may not indicate a nonfunctional heme synthesis pathway. Further anabolic pathways absent in D. immitis but present in wDi are purine and pyrimidine de novo synthesis (Fig. 2).


The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets.

Godel C, Kumar S, Koutsovoulos G, Ludin P, Nilsson D, Comandatore F, Wrobel N, Thompson M, Schmid CD, Goto S, Bringaud F, Wolstenholme A, Bandi C, Epe C, Kaminsky R, Blaxter M, Mäser P - FASEB J. (2012)

Anabolic pathways in Wolbachia and Dirofilaria. Selected pathways were identified by screening the predicted proteomes with HMM profiles representing each enzyme in the pathway using HMMer (29). The proteomes were hierarchically clustered (77) based on city block distance between the vectors consisting of the best scores (represented as a heat plot) obtained against each profile. A complete prediction of D. immitis metabolic pathways is available online at the Draft Genomes page of the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/catalog/org_list1.html).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475251&req=5

Figure 2: Anabolic pathways in Wolbachia and Dirofilaria. Selected pathways were identified by screening the predicted proteomes with HMM profiles representing each enzyme in the pathway using HMMer (29). The proteomes were hierarchically clustered (77) based on city block distance between the vectors consisting of the best scores (represented as a heat plot) obtained against each profile. A complete prediction of D. immitis metabolic pathways is available online at the Draft Genomes page of the Kyoto Encyclopedia of Genes and Genomes (http://www.genome.jp/kegg/catalog/org_list1.html).
Mentions: The relationship between filarial nematodes and their Wolbachia endosymbionts is thought to be a mutualistic symbiosis (62), because extended treatment of infected mammals with tetracycline and other antibiotics results in clearance of the nematodes. The bases of this symbiosis remain unclear. It has been proposed that wBm provides B. malayi with additional sources of critical metabolites such as heme and riboflavin (63). We interrogated the wDi genome to examine the symbiont's biochemical capabilities. C. elegans and other nematodes (including B. malayi, and, on the basis of the genome sequence presented here, D. immitis) are deficient in heme synthesis but wBm has an intact heme pathway (Fig. 2) and a CcmB heme exporter, suggesting that it may support its host by providing heme. wBm has a complete pathway from succinyl-CoA to heme (one apparently missing component, HemG, may be substituted by a functional HemY). wDi lacks both HemY and HemG (and the recently described HemJ that can perform the same transformation). This step in the heme pathway is apparently absent in other bacteria, and so this may not indicate a nonfunctional heme synthesis pathway. Further anabolic pathways absent in D. immitis but present in wDi are purine and pyrimidine de novo synthesis (Fig. 2).

Bottom Line: The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States.Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates.This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland.

ABSTRACT
The heartworm Dirofilaria immitis is an important parasite of dogs. Transmitted by mosquitoes in warmer climatic zones, it is spreading across southern Europe and the Americas at an alarming pace. There is no vaccine, and chemotherapy is prone to complications. To learn more about this parasite, we have sequenced the genomes of D. immitis and its endosymbiont Wolbachia. We predict 10,179 protein coding genes in the 84.2 Mb of the nuclear genome, and 823 genes in the 0.9-Mb Wolbachia genome. The D. immitis genome harbors neither DNA transposons nor active retrotransposons, and there is very little genetic variation between two sequenced isolates from Europe and the United States. The differential presence of anabolic pathways such as heme and nucleotide biosynthesis hints at the intricate metabolic interrelationship between the heartworm and Wolbachia. Comparing the proteome of D. immitis with other nematodes and with mammalian hosts, we identify families of potential drug targets, immune modulators, and vaccine candidates. This genome sequence will support the development of new tools against dirofilariasis and aid efforts to combat related human pathogens, the causative agents of lymphatic filariasis and river blindness.

Show MeSH
Related in: MedlinePlus