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Gulia-Nuss M.,Purdue University | Gulia-Nuss M.,University of Nevada, Reno | Nuss A.B.,Purdue University | Nuss A.B.,University of Nevada, Reno | And 125 more authors.
Nature Communications | Year: 2016

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent. © 2016, Nature Publishing Group. All rights reserved. Source

Sharma P.,Laboratory of Malaria and Vector Research | Wollenberg K.,U.S. National Institutes of Health | Sellers M.,Laboratory of Malaria and Vector Research | Zainabadi K.,Laboratory of Malaria and Vector Research | And 5 more authors.
Journal of Biological Chemistry | Year: 2013

Acquired antimalarial drug resistance produces treatment failures and has led to periods of global disease resurgence. In Plasmodium falciparum, resistance is known to arise through genome-level changes such as mutations and gene duplications. We now report an epigenetic resistance mechanism involving genes responsible for the plasmodial surface anion channel, a nutrient channel that also transports ions and antimalarial compounds at the host erythrocyte membrane. Two blasticidin S-resistant lines exhibited markedly reduced expression of clag genes linked to channel activity, but had no genome-level changes. Silencing aborted production of the channel protein and was directly responsible for reduced uptake. Silencing affected clag paralogs on two chromosomes and was mediated by specific histone modifications, allowing a rapidly reversible drug resistance phenotype advantageous to the parasite. These findings implicate a novel epigenetic resistance mechanism that involves reduced host cell uptake and is a worrisome liability for water-soluble antimalarial drugs. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Eastman R.T.,Columbia University | Eastman R.T.,Laboratory of Malaria and Vector Research | Dharia N.V.,Scripps Research Institute | Winzeler E.A.,Scripps Research Institute | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2011

The combination of piperaquine and dihydroartemisinin has recently become the official first-line therapy in several Southeast Asian countries. The pharmacokinetic mismatching of these drugs, whose plasma halflives are ∼20 days and ∼1 h, respectively, implies that recrudescent or new infections emerging shortly after treatment cessation will encounter piperaquine as a monotherapy agent. This creates substantial selection pressure for the emergence of resistance. To elucidate potential resistance determinants, we subjected cloned Plasmodium falciparum Dd2 parasites to continuous piperaquine pressure in vitro (47 nM; ∼2-fold higher than the Dd2 50% inhibitory concentration [IC 50]). The phenotype of outgrowth parasites was assayed in two clones, revealing an IC 50 against piperaquine of 2.1 μM and 1.7 μM, over 100-fold greater than that of the parent. To identify the genetic determinant of resistance, we employed comparative whole-genome hybridization analysis. Compared to the Dd2 parent, this analysis found (in both resistant clones) a novel single-nucleotide polymorphism in P. falciparum crt (pfcrt), deamplification of an 82-kb region of chromosome 5 (that includes pfmdr1), and amplification of an adjacent 63-kb region of chromosome 5. Continued propagation without piperaquine selection pressure resulted in "revertant" piperaquine-sensitive parasites. These retained the pfcrt polymorphism and further deamplified the chromosome 5 segment that encompasses pfmdr1; however, these two independently generated revertants both lost the neighboring 63-kb amplification. These results suggest that a copy number variation event on chromosome 5 (825600 to 888300) is associated with piperaquine resistance. Transgene expression studies are underway with individual genes in this segment to evaluate their contribution to piperaquine resistance. Copyright © 2011, American Society for Microbiology. All Rights Reserved. Source

Leke R.F.G.,University of Yaounde I | Bioga J.D.,University of Yaounde I | Zhou J.,AZ DataClinic Inc. | Fouda G.G.,Duke University | And 10 more authors.
American Journal of Tropical Medicine and Hygiene | Year: 2010

A prospective longitudinal study of Plasmodium falciparum in pregnant women was conducted in the rural village of Ngali II, where malaria is hyperendemic and individuals receive ∼0.7 infectious mosquito bites/person/day throughout the year. Pregnant women ( N = 60; 19 primigravidae, 41 multigravidae) were enrolled early in pregnancy (median 14 wk) and were followed monthly, with 38 women followed through term (5.7 ± 1.1 prenatal visits and delivery). The total number of times primigravidae were slide-positive during pregnancy was higher than multigravidae (3.3 ± 1.1 versus 1.3 ± 1.3 times; P < 0.001), but no difference in the number of polymerase chain reaction-positive cases (4.6 ± 1.7 and 3.4 ± 1.7 times, P = 0.106) or total genotypes they harbored (8.9 ± 3.2 and 7.0 ± 2.9) was found. Only 7.9% women developed symptomatic infections. All primigravidae and 38% multigravidae were placental malaria-positive at delivery ( P = 0.009). Genotyping showed that 77% of placental parasites were acquired ≥ 30 wks in pregnancy. These results help identify the extent of malaria-associated changes women experience during pregnancy. Copyright © 2010 by The American Society of Tropical Medicine and Hygiene. Source

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