Advances in the treatment, diagnosis, control and scientific understanding of taeniid cestode parasite infections over the past 50 years

Lightowlers, Marshall W.; Gasser, Robin B.; Hemphill, Andrew; Römig, Thomas; Tamarozzi, Francesca; Deplazes, Peter; Torgerson, Paul R.; Garcı́a, Héctor H.; Kern, Peter

doi:10.1016/j.ijpara.2021.10.003

“…Pathogens 2022, 11, 239 2 of 13 Over the last decades, substantial progress has been made in the prevention, diagnosis, and management of cestode infections, including human echinococcosis [6,7]. To date, primary diagnosis of the disease is mainly based on imaging procedures and immunological testing for the confirmation of suspect imaging results, i.e., in particular, serological antibody detection in patient sera or immunohistochemistry from tissue samples.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Serological Markers in Alveolar Echinococcosis Emphasizing the Correlation of PET-CTI Tracer Uptake with RecEm18 and Echinococcus-Specific IgG

Hotz

¹

,

Peters

²

,

Kapp-Schwörer

³

et al. 2022

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Human alveolar echinococcosis (AE), which is caused by the cestode Echinococcus (E.) multilocularis, is an epidemiologically relevant issue in modern medicine and still poses a diagnostic and therapeutic challenge. Since diagnosis mainly relies on imaging procedures and serological testing, we retrospectively and comparatively analyzed the performance of an Echinococcus IgG screening ELISA, whole serum IgE, and two specific confirmatory ELISA platforms using the defined E. multilocularis antigens Em2-Em18 (Em2+) and recombinant Em18 (recEm18). With special emphasis on the clinical usefulness of recEm18, we correlated the laboratory results with clinical characteristics and imaging findings in a large and well-characterized cohort of N = 124 AE patients, who were followed over several years after either surgical plus subsequent pharmacological treatment or pharmacotherapy alone. All patients had routinely received PET-CTI every two years. Our data reveal strong correlations for both Echinococcus IgG and recEm18 with tracer uptake in PET-CTI and parasitic lesion size and number, suggesting additional clinical usefulness of recEm18 for certain constellations only, while IgG and Em2+ still appear reasonable and sensitive screening methods for initial diagnosis of AE. With this study, we aim to contribute to further optimizing medical care of AE patients. For instance, it might be reasonable to consider the replacement of some PET-CTI follow-ups by imaging procedures with less radiation exposure or serological means alone. Further studies that clarify the correlation of serological markers with ultrasound criteria might be particularly useful, and further retrospective as well as prospective investigations are justified in this context.

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“…Surgical removal of parasite tissue is, however, only possible in around 20% of cases, leaving BZ chemotherapy as the only remaining treatment option for non-operable patients [ 3 ]. Although the prognosis of such patients has significantly improved after the introduction of BZ chemotherapy around 40 years ago, adverse side effects are frequently observed [ 6 ]. Furthermore, albendazole and mebendazole appear to be effective against the parasite in only one third of cases [ 7 ], whereas they are parasitostatic only in the majority of patients and must, therefore, be applied for years to decades, sometimes even life-long [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy

Koike

¹

,

Becker²,

Sennhenn³

et al. 2022

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Background The potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed. Methodology/principal findings By applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPim, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with E. multilocularis CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells. Conclusions/significance Repurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.

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“…Although the prognosis of such patients has significantly improved after the introduction of BZ chemotherapy around 40 years ago, adverse side effects are frequently observed [6]. Furthermore, BZ are parasitostatic only and must be applied for years to decades, sometimes even life-long [7].…”

Section: Introductionmentioning

confidence: 99%

“…Surgical removal of parasite tissue is, however, only possible in around 20% of cases, leaving BZ chemotherapy as the only remaining treatment option for non-operable patients [3]. Although the prognosis of such patients has significantly improved after the introduction of BZ chemotherapy around 40 years ago, adverse side effects are frequently observed [6]. Furthermore, BZ are parasitostatic only and must be applied for years to decades, sometimes even life-long [7].…”

Section: Introductionmentioning

confidence: 99%

TargetingEchinococcus multilocularisPIM kinase for improving anti-parasitic chemotherapy

Koike

¹

,

Becker²,

Sennhenn³

et al. 2022

Preprint

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BackgroundThe potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed.Methodology/Principal findingsBy applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPIM, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPIM with E. multilocularis CDC25, indicating an involvement of EmPIM in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPIM, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258, but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells.Conclusions/SignificanceRepurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPIM as a promising target for respective approaches towards AE treatment.Author summaryThe larva of the tapeworm E. multilocularis grows tumor-like within the host liver, thus causing the lethal disease alveolar echinococcosis (AE). Anti-parasitic treatment relies on chemotherapy with benzimidazoles, which do not kill the parasite and must be applied for years. As druggable enzymes with key functions in growth control, protein kinases are promising drug targets and many kinase inhibitors have been identified during cancer research. Optimized for binding to human kinases, however, repurposing of such drugs for parasitic disease treatment is associated with adverse side effects. Herein, the authors applied an in silico approach to identify small molecule compounds that show higher specificity for a parasite kinase, EmPIM, over its mammalian homologs. The authors demonstrate expression of EmPIM in Echinococcus stem cells, which are the drivers of parasite growth, and show that mammalian PIM kinase inhibitors SGI-1776 and CX-6258 also affect parasite development in vitro. Finally, they show that one of the in silico screened compounds is equally effective against the parasite as SGI-1776 and CX-6258, but significantly less toxic to human cells. These results demonstrate the utility of in silico approaches to identify parasite-specific kinase inhibitors.

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Advances in the treatment, diagnosis, control and scientific understanding of taeniid cestode parasite infections over the past 50 years

Cited by 35 publications

References 273 publications

Evaluation of Serological Markers in Alveolar Echinococcosis Emphasizing the Correlation of PET-CTI Tracer Uptake with RecEm18 and Echinococcus-Specific IgG

Evaluation of Serological Markers in Alveolar Echinococcosis Emphasizing the Correlation of PET-CTI Tracer Uptake with RecEm18 and Echinococcus-Specific IgG

Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy

TargetingEchinococcus multilocularisPIM kinase for improving anti-parasitic chemotherapy

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