Intense Focus of Alveolar Echinococcosis, South Kyrgyzstan

Bebezov, B. Kh.; Mamashev, N. D.; Umetaliev, T. M.; Ziadinov, Iskender; Craig, Philip S.; Joekel, Deborah E.; Deplazes, Peter; Grimm, Felix; Torgerson, Paul R.

doi:10.3201/eid2406.161641

Cited by 23 publications

(33 citation statements)

References 13 publications

(17 reference statements)

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“…E. multilocularis is endemic to the Northern hemisphere including areas in Europe, Asia, and North America 2 . Over the recent years, E. multilocularis has been emerging in Europe, North America and Asia 3–5 . The life cycle of E. multilocularis includes canids as definitive hosts, and voles as intermediate hosts.…”

Section: Introductionmentioning

confidence: 99%

In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

Ritler

Rufener

et al. 2019

Sci Rep

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Alveolar echinococcosis (AE) is a zoonotic disease that is deadly if left untreated. AE is caused by the larval metacestode stage of the cestode Echinococcus multilocularis. Better knowledge on the host-parasite interface could yield novel targets for improvement of the treatment against AE. We analyzed culture media incubated with in vitro grown E. multilocularis metacestodes by 1H nuclear magnetic resonance spectroscopy to identify the unknown metabolic footprint of the parasite. Moreover, we quantitatively analyzed all amino acids, acetate, glucose, lactate, and succinate in time-course experiments using liquid chromatography and enzymatic assays. The E. multilocularis metacestodes consumed glucose and, surprisingly, threonine and produced succinate, acetate, and alanine as major fermentation products. The metabolic composition of vesicle fluid (VF) from in vitro grown E. multilocularis metacestodes was different from parasite-incubated culture medium with respect to the abundance, but not the spectrum, of metabolites, and some metabolites, in particular amino acids, accumulated in the VF. Overall, this study presents the first characterization of the in vitro metabolic footprint of E. multilocularis metacestodes and VF composition, and it provides the basis for analyses of potentially targetable pathways for future drug development.

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Section: Introductionmentioning

confidence: 99%

In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

Ritler

Rufener

et al. 2019

Sci Rep

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“…AE is the highest ranked foodborne parasitic disease in Europe and is classified third on a global level ( Bouwknegt et al, 2018 ), despite relatively low case numbers in comparison to other parasitic diseases. In 2010, 18′451 new human cases of AE were estimated ( Torgerson et al, 2015 ), with the highest prevalences in Asia with up to 9.43% in Qinghai, China, and 6.4% in Kyrgyz Alay district, Kyrgyzstan ( Baumann et al, 2019 ; Bebezov et al, 2018 ). In Western-Central Europe, the annual infection rate is comparably low with 0.3–3 per 1′000′000 inhabitants ( Gottstein et al, 2015a ).…”

Section: Introduction – Alveolar Echinococcosis (Ae)mentioning

confidence: 99%

“…However, due to the severity and fatality of the disease, human AE has an annual global impact of more than 687′823 disability adjusted life years (DALYs) ( Torgerson et al, 2015 ), which poses an uncontrolled health problem especially in developing and resource-poor regions ( Kern et al, 2017 ). Furthermore, AE is recognized as an emerging disease in Europe, North America and Asia ( Gottstein et al, 2015a ; Thompson, 2017 ; Trotz-Williams et al, 2017 ; Bebezov et al, 2018 ; Robertson, 2018 ; Polish et al, 2020 ), and curative drug treatments are still lacking ( Lundström-Stadelmann et al, 2019 ).…”

Section: Introduction – Alveolar Echinococcosis (Ae)mentioning

confidence: 99%

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Lundström‐Stadelmann

Rufener

Hemphill

2020

International Journal for Parasitology: Drugs and Drug Resistan

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The current chemotherapeutical treatment against alveolar echinococcosis relies exclusively on benzimidazoles, which are not parasiticidal and can induce severe toxicity. There are no alternative treatment options. To identify novel drugs with activity against Echinococcus multilocularis metacestodes, researchers have studied potentially interesting drug targets (e.g. the parasite's energy metabolism), and/or adopted drug repurposing approaches by undertaking whole organism screenings. We here focus on drug screening approaches, which utilize an in vitro screening cascade that includes assessment of the drug-induced physical damage of metacestodes, the impact on metacestode viability and the viability of isolated parasite stem cells, structure-activity relationship (SAR) analysis of compound derivatives, and the mode of action. Finally, once in vitro data are indicative for a therapeutic window, the efficacy of selected compounds is assessed in experimentally infected mice. Using this screening cascade, we found that the anti-malarial mefloquine was active against E. multilocularis metacestodes in vitro and in vivo . To shed more light into the mode of action of mefloquine, SAR analysis on mefloquine analogues was performed. E. multilocularis ferritin was identified as a mefloquine-binding protein, but its precise role as a drug target remains to be elucidated. In mice that were infected either intraperitoneally with metacestodes or orally with eggs, oral treatment with mefloquine led to a significant reduction of parasite growth compared to the standard treatment with albendazole. However, mefloquine was not acting parasiticidally. Assessment of mefloquine plasma concentrations in treated mice showed that levels were reached which are close to serum concentrations that are achieved in humans during long-term malaria prophylaxis. Mefloquine might be applied in human AE patients as a salvage treatment. Future studies should focus on other repurposed anti-infective compounds (MMV665807, niclosamide, atovaquone), which showed stronger in vitro activity against E. multilocularis than mefloquine.

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“…While CE has a worldwide distribution, AE is confined to the northern hemisphere; thus, in some countries, both parasites co-exist as is the case of Kyrgyzstan [2]. AE has become an increasing public health problem in Kyrgyzstan, as in other Asian countries [1,3,4,5], with a rise in the hospital incidence from 0-2 cases/year in the early 1990s to 148 cases reported in 2013 (2.6 cases per 10 5 inhabitants/year) with some districts in Kyrgyzstan reporting up to 58 cases per 10 5 inhabitants/year [6,7]. A recent detailed account of surgical incidence for AE shows values as high as 11.77/10 5 in Naryn and 7.94/10 5 in Osh [8].…”

Section: Introductionmentioning

confidence: 99%

Genetic diversity of Echinococcus multilocularis and Echinococcus granulosus sensu lato in Kyrgyzstan: The A2 haplotype of E. multilocularis is the predominant variant infecting humans

et al. 2020

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Alveolar and cystic echinococcosis (AE, CE) caused by E. multilocularis and E. granulosus s.l., respectively, are considered emerging zoonotic diseases in Kyrgyzstan with some of the world highest regional incidences. Little is known regarding the molecular variability of both species in Kyrgyzstan. In this study we provide molecular data from a total of 72 parasite isolates derived from humans (52 AE and 20 CE patients) and 43 samples from dogs (23 infected with E. multilocularis and 20 with E. granulosus s.l.).Genetic variability in E. multilocularis was studied using the concatenated complete sequences of the cob, nad2 and cox1 mitochondrial genes adding a total of 3,558bp per isolate. The cob/nad2/cox1 A2 haplotype was identified in 63.4% of the human and in 65.2% of the dog samples. This haplotype was originally described in samples from Kazakhstan and St. Lawrence Island (Alaska, USA). We also describe here 16 non-previously defined variants of E. multilocularis (called A11-A26). All haplotypes cluster together within the Asian group in the haplotype network. Based on Fst values, low level of genetic differentiation was found between the populations of E. multilocularis isolated from different regions within the country. However, high degree of differentiation was found when all the concatenated sequences from Kyrgyzstan are considered as a single population and compared with the population of the parasite from the neighbouring country China. In the case of E. granulosus s.l. the analysis was based in 1,609bp of the cox1 gene. One isolate from a dog was identified as E. equinus, while all the other sequences were identified belonging to E. granulosus s.s. In total, 24 cox1 haplotypes of E. granulosus s.s. were identified including the already described variants: Eg01 (in 6 samples), Eg33 (in 4 samples), EgCl04 (in 2 samples), Eg03 (in 1 sample) and Eg32 (in 1 sample). From the twenty-five other isolates of E. granulosus s.s. a total of 19 non-PLOS NEGLECTED TROPICAL DISEASES

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Intense Focus of Alveolar Echinococcosis, South Kyrgyzstan

Cited by 23 publications

References 13 publications

In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

Drug repurposing applied: Activity of the anti-malarial mefloquine against Echinococcus multilocularis

Genetic diversity of Echinococcus multilocularis and Echinococcus granulosus sensu lato in Kyrgyzstan: The A2 haplotype of E. multilocularis is the predominant variant infecting humans

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