Genomics of Loa loa, a Wolbachia-free filarial parasite of humans.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.65). 03/2013; DOI: 10.1038/ng.2585
Source: PubMed

ABSTRACT Loa loa, the African eyeworm, is a major filarial pathogen of humans. Unlike most filariae, L. loa does not contain the obligate intracellular Wolbachia endosymbiont. We describe the 91.4-Mb genome of L. loa and that of the related filarial parasite Wuchereria bancrofti and predict 14,907 L. loa genes on the basis of microfilarial RNA sequencing. By comparing these genomes to that of another filarial parasite, Brugia malayi, and to those of several other nematodes, we demonstrate synteny among filariae but not with nonparasitic nematodes. The L. loa genome encodes many immunologically relevant genes, as well as protein kinases targeted by drugs currently approved for use in humans. Despite lacking Wolbachia, L. loa shows no new metabolic synthesis or transport capabilities compared to other filariae. These results suggest that the role of Wolbachia in filarial biology is more subtle than previously thought and reveal marked differences between parasitic and nonparasitic nematodes.

Download full-text


Available from: Jennifer Russo Wortman, Apr 02, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite RIO kinases being essential for life, their functions, substrates and cellular pathways remain enigmatic. In the present study, gene structures were characterised for 26 RIO kinase from draft genomes of parasitic and free-living nematodes. RNA-seq transcription profiles of RIO kinase genes were investigated for selected parasitic nematodes and showed that these kinases are transcribed in developmental stages that infect their mammalian host. Three-dimensional structural models of Caenorhabditis elegans RIO kinases were predicted, and elucidated functional domains and conserved regions in nematode homologs. These findings provide prospects for functional studies of RIO kinase genes in C. elegans and an opportunity for the design and validation of nematode-specific inhibitors of these enzymes in socioeconomic parasitic worms.
    International Journal for Parasitology 07/2014; 44(11). DOI:10.1016/j.ijpara.2014.06.005 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although helminth infections are characteristically associated with Th2-mediated responses that include the production of the prototypical cytokines IL-4, IL-5, and IL-13 by CD4+ cells, the production of IgE, peripheral blood eosinophilia and mucus production in localized sites, these responses are largely attenuated when helminth infections become less acute. This modulation of the immune response that occurs with chronic helminth infection is often induced by molecules secreted by helminth parasites, by non-Th2 regulatory CD4+ cells, and by non-classical B cells, macrophages and dendritic cells. This review will focus on those parasite- and host-mediated mechanisms underlying the modulated T cell response that occurs as the default in chronic helminth infections. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Parasite Immunology 04/2015; 37(6). DOI:10.1111/pim.12194 · 1.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. Copyright © 2015 Elsevier B.V. All rights reserved.
    Veterinary Parasitology 04/2015; 210(3-4). DOI:10.1016/j.vetpar.2015.04.002 · 2.55 Impact Factor