22nd Drug Design & Development Seminar (DDDS) 2022

On the occasion of the 22nd DDDS conference you are cordially invited to participate and to present your research in an oral presentation (15 minutes) or as poster. An abstract is requested for both talks and posters (abstract guidelines below). The scientific board will select the topics for oral presentations or posters depending on the abstracts. Renowned international keynote speakers will provide a high-quality scientific framework. The seminar will be opened with a welcome reception on Wednesday evening and conclude Friday at noon.

Fatal avian malaria in captive Atlantic puffins (Fratercula arctica) in Switzerland

Avian malaria was diagnosed in cases of sudden death in captive Atlantic puffins (Fratercula arctica) at Berne Animal Park by histopathological examination, one-step multiplex PCR and by nested PCR. Plasmodium relictum lineage SGS1 and P. matutinum lineage LINN1 were identified as the involved etiologic agents.

Congratulations Dr. Winzer

We congratulate our PhD student Pablo Winzer to successfully defending his thesis "Molecular changes of Neospora caninum treated with the calcium dependent protein kinase 1 inhibitor BKI-1294 and implications on the immune response"!

Anti-protozoal structure-activity relationships of synthetic leucinostatin-derivatives and elucidation of their mode of action

Leucinostatins are fascinating natural antimicrobial peptides, with high potency against many pathogens, but their acute toxicity has prevented therapeutic use. This work demonstrated how these could be converted into synthetically more accessible and more selective anti-protozoal agents with broad efficacy and undetectable resistance. This study has not only led to therapeutically applicable agents against a wide range of parasites but also shows how peptides can be made clinically useful by targeted synthetic transformations.

One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexan diseases

This review reports on the the development of bumped-kinase inhibitors (BKIs) for the therapy of toxplasmosis, neosporosis and cryptosporidiosis. Proof-of-concept for BKI therapy has been demonstrated in livestock models of cryptosporidiosis (newborn calves infected with Cryptosporidium parvum), toxoplasmosis (pregnant sheep infected with Toxoplasma gondii), and neosporosis (pregnant sheep infected with Neospora caninum). The potential uses of BKIs for the treatment of diseases caused by apicomplexan parasites in animals and humans are discussed, as well as the pitfalls in the development, and the improvements that need to be made.

Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents

This paper originates from a Sinergia project that aims to develop novel ruthenium based organometallic compounds as anti-parasitic drugs. Synthesis, characterization, and in vitro anti-Toxoplasma and anti-cancer activity evaluation of a series of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Overall, compound flexibility and size impacted on the anti-Toxoplasma and anti-cancer cell activities. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates were more cytotoxic against cancer cells than amide analogues. Thus, polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

Description of Intraproboscis sanghae, a new genus and species of Acanthocephala, causing intestinal perforation and secondary peritonitis in a black-bellied pangolin (Phataginus tetradactyla)

A new genus and species of archiacanthocephalan, Intraproboscis sanghae, is described infecting the African black-bellied pangolin Phataginus tetradactyla in the Central African Republic and causing intestinal perforation and peritonitis. In addition, the parasite fauna of this endangered animal species was reviewed.

Sarcocystis infection in red deer (Cervus elaphus) with eosinophilic myositis/fasciitis in Switzerland and involvement of red foxes (Vulpes vulpes) and hunting dogs in the transmission

A cooperation with the Institute of Parasitology in Zurich identified the Sarcocystis species infecting red deer showing greenish carcass discoloration due to eosinophilic myositis/fasciitis from the canton of Grisons. Red foxes and hunting dogs from the region were shown to be definitive hosts of some of these species, and also of other species infecting domestic ruminants and swine. Although Sarcocystis species infecting red deer are not regarded as zoonotic, the affected carcasses can be declared as unfit for human consumption due to the extensive pathological changes.

Toxoplasma gondii and Neospora caninum infections in South American camelids in Switzerland and assessment of serological tests for diagnosis

A nationwide cross-sectional study demonstrated for the first time the presence of antibodies against the protozoan parasites Toxoplasma gondii and Neospora caninum in Swiss llamas and alpacas, highlighting a high seroprevalence for T. gondii and a low prevalence for N. caninum, and allowed the identification of risk factors, which may favour T. gondii infection. The study also presented the evaluation and optimization of different serological tests to be used for diagnosis in these animal species.

Annual meeting of the Swiss Society of Tropical Medicine and Parasitology

02 September

Young Investigator Award to Dr. Reto Rufener

Dr. Reto Rufener received the Young Investigator Award of the Swiss Society of Tropical Medicine and Parasitology (SSTMP) for his PhD thesis. Congratulations!

Insights into Echinococcus multilocuaris infection in domestic pigs

Minimal prevalence of E. multilocularis infection in Swiss domestic pigs as well as risk factors for infection were established in this recently published study that reached about 85% of the pigs produced annually in Switzerland. The parasite is widespread, but risk of infection in pigs can be mitigated by relatively simple measures such as increased hygiene.

SNSF Spirit Grant to Prof. Hemphill and collaborators

Mosquitoes of the genus Aedes transmit the viruses responsible for yellow fever, Dengue, Zika and Chikungunya. A surprising recent finding is that Aedes mosquitoes in Sri Lanka have adapted to breed in brackish water as well, thereby extending the area where transmission of viruses can occur. The aim of this collaborative grant (University of Bern and University of Jaffna, Sri Lanka) is to elucidate the physiological and molecular basis of adaptation using next generation sequencing (RNA-seq) and immuno-electron microscopy, to hold a bioinformatics workshop for students in Sri Lanka, and enable 2-3-month stays in the Swiss laboratories for Sri Lankan PhD students to learn recombinant protein technology and electron microscopy.

Incorporation of the Tat cell‐penetrating peptide into nanofibers improves the respective immune response

A major challenge for the development of anti-cancer vaccines is the induction of a safe and effective immune response, particularly mediated by CD8+ T lymphocytes, in an adjuvant‐free manner. A simple strategy is presented to improve the specific CD8+ T cell responses using KFE8 nanofibers bearing a Class I (Kb)‐restricted peptide epitope (called E.nanofibers) without the use of adjuvant. Incorporation of Tat, a cell‐penetrating peptide (CPP) of the
HIV transactivator protein, into E. nanofibers remarkably enhanced tumor‐specific CD8+ T cell responses. This approach could potentially also be applicable for parasitic infections.

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

In this invited review article we summarize our most recent findings in the search for novel chemotherapies against alveolar echinococcosis. In particular, we focus on the anti-malarial mefloquine, which showed promising activities in vitro and in different mouse models of the disease.

Caroline Frey vice president of ESCCAP Switzerland

Caroline Frey is the new vice president of ESCCAP Switzerland. Congratulations!

Congratulations Dr. Ritler

We congratulate our PhD student Dominic Ritler to successfully defending his thesis "New ways to target the deadly parasite Echinococcus multilocularis"!

Isolation of Human Small Extracellular Vesicles and Tracking of Their Uptake by Retinal Pigment Epithelial Cells In Vitro

Small extracellular vesicles (EVs) play major roles in intercellular communication by delivering various cargo molecules to target cells. They could potentially represent an alternative delivery strategy to treat ocular toxoplasmosis, a parasitosis affecting the retinal pigment epithelium (RPE). This study, reports on the intracellular uptake of fluorescently labelled human urine and fibroblast-derived small EVs by human RPE cells. BODIPY-labelled small EVs were found in close vicinity to Toxoplasma gondii. Additionally, an ultrastructural method was enabled to distinguish between labelled exogenous and endogenous small EVs within target cells. Cooperation between IPA and Veterinary Anatomy Division, Vetsuisse Bern.

PhD half-time Nicoleta Anghel

We congratulate Nicoleta Anghel to her successful PhD half-time presentation with the title “Studies on activity and safety of novel compounds against apicomplexan parasites”

Neospora caninum: Differential Proteome of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294

Using shotgun mass spectrometry, we compared the proteomes of tachyzoites to BKI-1294 induced MNCs. More than half of the identified proteins are downregulated in MNCs as compared to tachyzoites. Only 12 proteins are upregulated, the majority of them containing SAG1 related sequence (SRS) domains, and some also known to be expressed in bradyzoites. Thus, MNCs share some bradyzoite-like features, but may constitute a third stage, which remains viable and ensures survival under adverse conditions such as drug pressure. We propose the term “baryzoites” for this stage (from Greek βαρυσ = massive, bulky, heavy, inert).

Regulation of hepatic microRNAs in response to early stage Echinococcus multilocularis egg infection in C57BL/6 mice

We present a comprehensive analysis of the hepatic microRNAs (miRNAs) transcriptome at early stage of experimental primary alveolar echinococcosis. Expression of miRNAs was significantly altered in infected livers; miRNAs were mainly down regulated. Target genes of the most extensively down-regulated miRNAs were involved in angiogenesis and fatty acid synthesis. Furthermore, expression of key angiogenic and lipogenic genes was higher in infected livers. Some precursor miRNAs exhibited different arm selection preferences in normal versus infected liver tissues. Further research on how E. multilocularis contribute to the regulation of the hepatic miRNA transcriptome is needed.

Neospora caninum: Structure and Fate of Multinucleated Complexes Induced by the Bumped Kinase Inhibitor BKI-1294

BKI-1294 exposure of N. caninum results in the formation of multinucleated complexes (MNCs), which remain viable in vitro under constant drug pressure. We investigated the formation of BKI-1294 induced MNCs by TEM and SEM, the re-emergence of viable tachyzoites following drug removal by immunofluorescence microscopy using various antibodies against surface antigens and secretory proteins, and studied the localization of CDPK1, the molecular target of BKIs by immunogold-TEM.

Whole genome sequencing of bovine, feline and porcine Tritrichomonas foetus strains

Tritrichomonas foetus is a protozoan parasite that colonizes the reproductive tract of cattle, the gastrointestinal tract of cats, or the nasal cavity of pigs. We generated whole genome sequencing data from bovine, feline and porcine T. foetus strains. These data clearly indicated a close phylogenetic relationship between bovine and porcine T. foetus but a remarkable genetic distinctness of these two strains from the feline strain. Our comparative genome sequencing approach granted deep insights into the genetic diversity of T. foetus in relation to the different host origins of the parasite. Furthermore, our study identified a large number of SNP- and indel-containing sequences that may be useful molecular markers for future epidemiological studies aimed at the elucidation of the transmission patterns of T. foetus within different host species.

Review: Bumped kinase inhibitors as therapy for apicomplexan parasitic diseases: lessons learned

BKIs that target CDPK1 in apicomplexan parasites with a glycine gatekeeper are promising new therapeutics. Numerous challenges have shaped the selection of pre-clinical BKI candidates. These include chirality, hERG, teratogenicity, cardiovascular, GI, and toxicity issues, and poor efficacy due to PK/PD. The BKI-consortium is comprised of many laboratories worldwide (US, Spain, including the IPA).

Coumarin-Tagged Dinuclear Trithiolato-Bridged Ruthenium(II)⋅Arene Complexes: Photophysical Properties and Antiparasitic Activity

The synthesis, characterization, photophysical and biological properties of 13 new conjugate coumarin‐diruthenium(II)⋅arene complexes against Toxoplasma gondii were studied. An almost complete loss of fluorescence efficacy was observed. The in vitro activity against T. gondii depends on the various chemical properties of the conjugates and ranges from 105 to 735 nM. Nine compounds displayed lower IC50 than the standard drug pyrimethamine. TEM showed that treatment predominantly affected the parasite mitochondrion. Cooperation between IPA and Department of Chemistry, University of Bern (Sinergia).

Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole.

A series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ were synthesized and were assessed for their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The derivatives show a species-specific in vitro activity and the choice of the organometallic moieties attached to the organic drug plays a very important role. This study confirms the potential of organometallic complexes against parasites of medical and veterinary importance. Carried out within a consortium comprised of several laboratories (France, Switzerland, Australia, including the IPA (protozoans)).

Congratulations Dr. Rufener

We congratulate our PhD student Reto Rufener to successfully defending his thesis "New drugs against Echinococcus multilocularis - targeting the energy metabolism"!

In vitro efficacy and ultrastructural effects induced by MMV Malaria Box compounds against Neospora caninum.

390 compounds of the MMV Malaria Box were screened against Neospora caninum tachyzoites Five compounds exhibited promising IC50 values ranging from 25-200 nM. By TEM, aberrant structural changes were first detected in the parasite mitochondrion, and subsequently alterations progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies.

Activities of Endochin-Like Quinolones (ELQs) against in vitro cultured Besnoitia besnoiti tachyzoites

ELQs target the cytochrome b and interfere with oxidative phosphorylation and pyrimidine biosynthesis in many apicomplexans. 14 different ELQs were assessed against B. besnoiti by quantitative real time PCR and TEM. The IC50s on B. besnoiti were higher than previously observed for P. falciparum and T. gondii. However, the cytochrome b sequence and the predicted Qo and Qi ELQ-binding sites are virtually identical. TEM demonstrated alterations in the mitochondrion and the nuclear membrane, as well as increased vacuolization within the tachyzoite cytoplasm. Long-term treatments did not act parasiticidal. Cooperation with groups in the US and Portugal.

Metabolic profiling of Giardia lamblia strains

In Giardia lamblia, enzymes involved in anaerobic nitro reduction have been investigated in detail as potential targets. Their role within the normal metabolic context is, however, not understood. Using 1H HR-MAS NMR spectroscopy, we analyzed the metabolomes of G. lamblia trophozoites overexpressing three nitroreductases (NR1 – NR3) and thioredoxin reductase (TrxR), most likely a scavenger of reactive oxygen species. We compared the patterns to convenient controls and to the situation in the strain nitro drug resistant strain C4 where NR1 is downregulated. Trophozoites overexpressing NR1 presented a distinct pattern of nine metabolites, in particular arginine catabolites, differing from the respective controls. This pattern matched a differential pattern between wildtype and strain C4. This suggests that NR1 interferes with arginine and thus energy metabolism. The exact metabolic function of NR1 (and the other nitroreductases) remains to be elucidated.

In vitro metabolomic footprint of the Echinococcus multilocularis metacestode

We analyzed the unknown metabolic footprint of the parasite E. multilocularis and identified that the metacestode of E. multilocularis consumed glucose, and, surprisingly, threonine, whereas it released succinate, acetate, and alanine as major fermentation end products. This study provides the basis for analyses of potentially targetable pathways for future drug development.

Die Haller Medaille wird an Frau Prof. Dr. Caroline Frey verliehen

Wir gratulieren Prof. Dr. Caroline Frey zur Haller Medaille.

Andrew Hemphill Honorary Professor at National University of La Plata, Argentina

Prof. Dr. Andrew Hemphill received the titel Visiting Professor at the National University La Plata (Argentina). Congratulations Andrew!

Britta Lundström-Stadelmann elected president of Swiss Society of Tropical Medicine and Parasitology

Prof. Dr. Britta Lundström-Stadelmann was elected president of the Swiss Society of Tropical Medicine and Parasitology at the society's general assembly in Lausanne on Sept 19.

Andrew Hemphill Honorary Professor at Complutense University of Madrid

Prof. Dr. Andrew Hemphill received the titel Honorary Professor at the Complutense University of Madrid. Congratulations Andrew!

Development and comparative evaluation of different LAMP and PCR assays for coprological diagnosis of feline tritrichomonosis

The protozoan parasite Tritrichomonas foetus may cause severe diarrhea in cats all over the world. We developed a
loop-mediated isothermal amplification (LAMP) as well as a real-time PCR assay allowing a reliable and direct coprological
diagnosis of T. foetus infections. The LAMP assay may also serve as practical molecular tools to perform epidemiological
studies on feline tritrichomonosis under simple laboratory conditions.

Nitroreductases of bacterial origin in Giardia lamblia: Potential role in detoxification of xenobiotics

The anaerobic parasite Giardia lamblia, causative agent of persistent diarrhea, contains a family of nitroreductases that
may provide at least two evolutionary advantages namely a higher potential to recycle electron acceptors for the
(fermentative) energy and intermediary metabolism, and the possibility to inactivate toxic xenobiotics produced by
microorganisms living in concurrence inside the intestinal habitat.

Emerging issues for zoonotic Echinococcus species – engaging old enemies in a changing environment

In this special issue of the Journal Food and Waterborne Parasitology the guest editors Caroline Frey, Emely Jenkins, and Britta Lundström-Stadelmann present a series of invited papers on echinococcosis covering topics from molecular markers of emergence, diagnostics in both definitive and intermediate hosts, treatment, to control strategies in definitive hosts.

Annual Repot 2018

The Annual Report 2018 of the Institute of Parasitology is available online now.

PhD half-time Dominic Ritler

We congratulate Dominic Ritler to his successful PhD half-time presentation with the title “Bullets against Echinococcus multilocularis: screening-based drug discovery and omics-based target identification”

SNSF Project Grant group Hemphill

Prof. A. Hemphill's project on "Effects of a double-edged sword: exploiting the interaction between immunity and chemotherapy in murine and ovine models of congenital neosporosis and toxoplasmosis" got approved by the Swiss National Science Foundation. Congratulations!

The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis

In this review we give an update on drug development for the treatment of alveolar echinococcosis, the disease caused by the fox tapeworm Echinococcus multilocularis.

Directorship in Jobsharing

Prof. Dr. C. Frey and Prof. Dr. Lundström-Stadelmann elected as extraordinary Professors by the University of Bern and the Vetsuisse-Rat, sharing the directorship of the Institute of Parasitology Bern from August 1 2019 on.

PhD half-time Pablo Winzer

We congratulate Pablo Winzer to his successful PhD half-time presentation with the title “Molecular changes of Neosporacaninum treated with Calcium dependent protein kinase 1 inhibitor 1294 and implications on the immune response”

Targeting of the mitochondrion by dinuclear thiolato-bridged arene ruthenium complexes in cancer cells and in the apicomplexan parasite Neospora caninum

Ruthenium(II) complexes have attracted attention because of their favorable anti-cancer properties. In this paper, we report on the antiparasitic efficacy of dinuclear-thiolato bridged arene ruthenium complexes against the apicomplexan parasites N. caninum. We show that their activity and uptake can be correlated with their lipophilicity and we demonstrate their ability to selectively target the mitochondria not only in cancer cells, but also in the parasite. In vivo experiments also reveal that the compounds accumulated in liver and kidneys, but were absent from the brain. However, the compounds did not act as parasiticidal.

Karl-Enigk doctoral stipend

Congratulations to Dominic Ritler for the doctoral stipend form the Karl-Enigk-Stiftung for his work on “metabolomics host-pathogen interaction studies of the fox tapeworm Echinococcus multilocularis“.

Strongyloides stercoralis infection in imported and local dogs in Switzerland: from clinics to molecular genetics

This study reports on the diagnosis and genetic characterization of Strongyloides stercoralis infecting imported and locally born dogs in Switzerland. Some of the infected dogs presented severe disease, with diarrhoea, dehydration, vomiting, respiratory and/or neurologic signs, and needed hospitalisation. S. stercoralis isolated from three independent clinical cases exhibited an identical genetic background on the nuclear 18S rDNA (fragment involving hypervariable regions I and IV) and the mitochondrial cytochrome oxidase subunit I (cox1) loci, similar to that of zoonotic isolates from other geographical regions, and not to that of dog-adapted variants. Due to the clinical relevance and zoonotic potential of this parasite, the awareness of both diagnosticians and clinicians is strongly required.

Endochin-like quinolones for treatment of neosporosis

This paper reports that endochin-like quinolones, a group of cytochrome b Qi site inhibitors of the respiratory chain, were identified as highly potent compounds, exhibiting IC50 values against Neospora caninum in the sub-nanomolar range. In vivo, treatment of pregnant mice with ELQ-334, applied as prodrug for the highly active compound ELQ-316, clearly limited vertical transmission of N. caninum, and lead to significantly increased survival of offspring. This renders this compound class highly interesting for further development.

Repurposing of an old drug: activities of Buparvaquone against Echinococcus multilocularis

In this study we screened 400 compounds of the Medicines for Malaria Venture (MMV) pathogen box against the disease-causing metacestode stage of the fox tapeworm Echinococcus multilocularis. One of the most active compounds, buparvaquone, was shown to inhibit the mitochondrial complex III in isolated parasite cells. However, the drug was not active against the parasite in mice.

Recombinant vaccine against neosporosis

This study reports on the application of a polyvalent recombinant vaccine formulation, composed of three Neospora antigens that were physically linked to OprI, a bacterial outer membrane protein that acts as a Toll-like receptor 2 (TLR2) ligand. Conjugation to OprI modulates immunity to elicit a balanced Th1/Th2 response, which is not detrimental to pregnancy outcome, and at the same time mediates protection against clinical signs of neosporosis and vertical transmission in offspring mice.

PD-L1 inhibition against alveolar echinococcosis

In immunology, checkpoints inhibitors have become very atractive immunotherapeutics especially in cancer treatment (see respective Nobel prize award 2018). In parasitic diseases such as alveolar echinococcosis, where Treg-induced anergy is a hallmark of the host-parasite interplay, experimental abrogation of down-regulated immunity may be a way to immunologically treat this disease e.g. as a support of conventional therapy by albendazole medication. In a first respective study, we now elegantly documented how the parasite load could be significantly reduced upon inhibition of the PD-L1 pathway.

Communications Chemistry - Nature

A study published in Communications Chemistry – Nature shows that decoquinate derivatives are highly and selectively active against the causative agents of malaria, tuberculosis, toxoplasmosis and neosporosis. Andrew Hemphill and Joachim Müller from the Institute of Parasitology in Bern contributed to this paper by studying the impact of decoquinate derivatives against the parasites Toxoplasma gondii and Neospora caninum. Congratulations!

PhD half-time Reto Rufener

We congratulate Reto Rufener to his successful PhD half-time presentation with the title “Echinococcus multilocularis: Studies on drugs and metabolism”