Recent Results
Update: 31.08.2021

2020 - 2021


Riehl, J., Rijal, R., Nitz, L., Clemen, C.S., Hofmann, A., Eichinger, L. (2021) Frontiers Cell Develop. Biol., in press
Abstract
The abundant homohexameric AAA+ ATPase p97 (also known as valosin-containing protein, VCP) is highly conserved from Dictyostelium discoideum to human and a pivotal factor of cellular protein homeostasis as it catalyses the unfolding of proteins. Owing to its fundamental function in protein quality control pathways, it is regulated by more than 30 cofactors, including the UBXD protein family, whose members all carry an Ubiquitin Regulatory X (UBX) domain that enables binding to p97. One member of this latter protein family is the largely uncharacterised UBXD9 protein.
Here, we analysed protein-protein interactions of D. discoideum UBXD9 with p97 using a series of N- and C-terminal truncation constructs and probed the UBXD9 interactome in D. discoideum.
Pull-down assays revealed that the UBX domain (amino acids 384–466) is necessary and sufficient for p97 interactions and that the N-terminal extension of the UBX domain, which folds into a β0–α1–α0 lariat structure, is required for the dissociation of p97 hexamers. Functionally, this finding is reflected by strongly reduced ATPase activity of p97 upon addition of full length UBXD9 or UBXD9261–573. Results from Blue Native PAGE as well as structural model prediction suggest that hexamers of UBXD9 or UBXD9261–573 interact with p97 hexamers and disrupt the p97 subunit interactions via insertion of a helical lariat structure, presumably by destabilising the p97 D1:D1' intermolecular interface. It is thus proposed that UBXD9 regulates p97 activity in vivo by shifting the quaternary structure equilibrium from hexamers to monomers.
Using three independent approaches, we further identified novel interaction partners of UBXD9, including glutamine synthetase type III as well as several actin-binding proteins. These findings suggest a role of UBXD9 in the organisation of the actin cytoskeleton, and are in line with the hypothesised oligomerisation-dependent mechanism of p97 regulation.
DOI

Clemen, C.S., Schmidt, A., Winter, L., Canneva, F., Wittig, I., Becker, L., Coras, R., Berwanger, C., The German Mouse Clinic Consortium, Hofmann, A., Eggers, B., Marcus, K., Gailus-Durner, V., Fuchs, H., Hrabe de Angelis, M., Krüger, M., von Hörsten, S., Eichinger, L., Schröder, R. (2021) Neuropath. Appl. Neuro., in press
Abstract
Aims: We investigated N471D WASH complex subunit strumpellin knock-in and WASH complex subunit strumpellin knock-out mice as models for hereditary spastic paraplegia type 8.
Methods: We generated heterozygous and homozygous N471D WASH complex subunit strumpellin knock-in mice, which underwent a comprehensive clinical, morphological, and laboratory parameter screen and gait analysis. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous WASH complex subunit strumpellin knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting.
Results: Homozygous N471D WASH complex subunit strumpellin knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline phosphatase and potassium levels, and increased white blood cell counts. Gait analysis revealed multiple aberrations indicative of locomotor instability. Similarly, the clinical chemistry, hematology, and gait parameters of heterozygous animals also deviated from the values expected for healthy individuals, albeit to a lesser extent. Proteomic analysis of brain tissue depicted consistent upregulation of BPTF and downregulation of KLHL11 in heterozygous and homozygous knock-in mice. WASH complex subunit strumpellin-related protein interaction partners and complexes showed no change in abundancies. Heterozygous knock-out mice showing normal WASH complex subunit strumpellin levels could not be bred to homozygosity.
Conclusions: While biallelic ablation of WASH complex subunit strumpellin was prenatally lethal, expression of N471D mutated WASH complex subunit strumpellin led to several mild clinical and laboratory parameter abnormalities, but not to a SPG8 phenotype. The consistent upregulation of BPTF and downregulation of KLHL11 in the brain of knock-in animals suggest mechanistic links for hereditary spastic paraplegia type 8 through their roles in neurodegeneration and protein quality control, respectively.
DOI

Amani, P., Habibpour, R., Karami, L., Hofmann, A. (2021) ACS Chem. Neurosci. 12, 2218-2232
Abstract
Chemoinformatics appraisal and molecular docking were employed to investigate 225 complexes of 75 schizophrenia antipsychotics with the dopamine receptor subtypes D2R, D3R, and D4R. Considering the effective noncovalent interactions in the subtype-D2 receptor selectivity of antipsychotics, this study evaluated the possible physicochemical properties of ligands underlying the design of safer and more effective antipsychotics. The pan-assay interference compounds (PAINs) include about 25% of typical antipsychotics and 5% of atypicals. Popular antipsychotics like haloperidol, clozapine, risperidone, and aripiprazole are not PAINs. They have stronger interactions with D2R and D4R, but their interactions with D3R are slightly weaker, which is similar to the behavior of dopamine. In contrast to typical antipsychotics, atypical antipsychotics exhibit more noncovalent interactions with D4R than with D2R. These results suggest that selectivity to D2R and D4R comes from the synergy between hydrophobic and hydrogen-bonding interactions through their concomitant occurrence in the form of a hydrogen-bonding site adorned with hydrophobic contacts in antipsychotic–receptor complexes. All the antipsychotics had more synergic interactions with D2R and D4R in comparison with D3R. The atypical antipsychotics made a good distinction between the subtype D2 receptors with high selectivity to D4R. Among the popular antipsychotics, haloperidol, clozapine, and risperidone have hydrophobic–hydrogen-bonding synergy with D4R, while aripiprazole profits with D2R. The most important residue participating in the synergic interactions was threonine for D2R and cysteine for D4R. This work could be useful in informing and guiding future drug discovery and development studies aimed at receptor-specific antipsychotics.
PubMed | DOI

Kim, J-H, Hofmann, A, Kim, J-S (2021) Proteins 89, 1030-1038
Abstract
Carbohydrates play a major role in infection strategies of various enteric pathogens. In Campylobacter jejuni, the most common cause of gastroenteritis, uniquely modified heptoses found in surface carbohydrates are synthesized by specific pathways. Owing to the importance of such pathways for the infectious potential of pathogens and/or their virulence, these biosynthesis pathways present potential targets for therapeutic intervention. Here, we determined the crystal structure of GDP-6-OMe-4-keto–L-xylo-heptose reductase (MlghC), an enzyme within the L-gluco-heptose synthesis pathway of C. jejuni strain NCTC 11168. This enzyme lacks the canonical tyrosine residue of the conserved catalytic Ser-Lys-Tyr triad commonly found among functionally related reductases. Despite adopting the overall two-domain fold shared with other short-chain dehydrogenase/reductase family members, subtle structural differences in the interface between the cofactor- and substrate-binding domains explain the absence of epimerase activity and different substrate specificity of this reductase. Modeling of the product-bound complex based on the crystal structure presented here suggests that a tyrosine residue unique to MlghC replaces the missing canonical residue of the catalytic triad.
PubMed | DOI

Liu, G.-H., Korhonen, P.K., Young, N.D., Lu, J., Wang, T., Fu, Y.-T., Koehler, A.V., Hofmann, A., Chang, B.C.H., Wang, S., Li, N., Lin, C.-Y., Zhang, H., Xiangli, L., Lin, L., Liu, W.-M., Li, H.-W., Gasser, R.B., Zhu, X.-Q. (2021) Genomics 113, 1272-1280
Abstract
Here, we present a draft genome of the tapeworm Dipylidium caninum (family Dipylidiidae) and compare it with other cestode genomes. This draft genome of D. caninum is 110 Mb in size, has a repeat content of approximately 13.4% and is predicted to encode ~10,000 protein-coding genes. We inferred excretory/secretory molecules (representing the secretome), other key groups of proteins (including peptidases, kinases, phosphatases, GTPases, receptors, transporters and ion-channels) and predicted potential intervention targets for future evaluation. Using 144 shared single-copy orthologous sequences, we investigated the genetic relationships of cestodes for which nuclear genomes are available. This study provides first insights into the molecular genetics and biology of D. caninum and a new resource for molecular ecological studies and future comparative molecular-genetic and genomic explorations of this and other flatworms.
PubMed | DOI

Seo, P-W., Park, S.-Y., Hofmann, A., Kim, J.-S. (2021) Acta Crystallogr. D 77, 618–627
Abstract
Peptidoglycan comprises repeating units of N-acetylmuramic acid (NAM), N-acetylglucosamine (NAG), and short cross-linking peptides. After conversion of UDP-N-acetylglucosamine (UNAG) into UDP-N-acetylmuramic acid (UNAM) by the MurA and MurB enzymes, an amino acid is added to UNAM by the UDP-N-acetylmuramic acid L-alanine ligase (MurC). As peptidoglycan is an essential component of the bacterial cell wall, the enzymes involved in its biosynthesis represent promising targets for the development of novel antibacterial drugs. Here, we report the crystal structure of Mycobacterium bovis MurC (MbMurC) which exhibits a three-domain architecture for binding of UNAM, ATP, and an amino acid as substrates with a nickel ion at the domain interface. The ATP-binding loop adopts a conformation not seen in other MurCs. In the UNAG-bound structure of MbMurC, the substrate mimic interacts with the UDP-binding domain of MbMurC, which does not invoke rearrangement of three domains. Interestingly, the glycine-rich loop of the UDP-binding domain of MbMurC interacts through hydrogen bonds with the glucose moiety, but not with the ligand’s pyrophosphate moiety. These findings suggest that UNAG analogs might serve as potential candidates for neutralizing the catalytic activity of bacterial MurC.
PubMed | DOI

Herath, H.M.P.D., Taki, A.C., Sleebs, B.E., Hofmann, A., Nguyen, N., Preston, S., Davis, R.A., Jabbar, A., Gasser, R.B. (2021) Adv. Parasitol. vol. 111, 203-251
Abstract
Widespread resistance to currently-used anthelmintics represents a major obstacle to controlling parasitic nematodes of livestock animals. Given the reliance on anthelmintics in many control regimens, there is a need for the continued discovery and development of new nematocides. Enabling such a focus are: (i) the major chemical diversity of natural products; (ii) the availability of curated, drug-like extract-, fraction- and/or compound-libraries from natural sources; (iii) the utility and practicality of well-established whole-worm bioassays for Haemonchus contortus – an important parasitic nematodes of livestock – to screen natural product libraries; and (iv) the availability of advanced chromatographic (HPLC), spectroscopic (NMR) and spectrometric (MS) techniques for bioassay-guided fractionation and structural elucidation. This context provides a sound basis for the identification and characterisation of anthelmintic candidates from natural sources. This chapter provides a background on the importance and impact of helminth infections/diseases, parasite control and aspects of drug discovery, and reviews recent work focused on (i) screening well-defined compound libraries to establish the methods needed for large-scale screening of natural extract libraries; (ii) discovering plant and marine extracts with nematocidal or nematostatic activity, and purifying bioactive compounds and assessing their potential for further development; and (iii) synthesising analogues of selected purified natural compounds for the identification of possible ‘lead’ candidates. The chapter describes some lessons learned from this work and proposes future areas of focus for drug discovery. Collectively, the findings from this recent work show potential for selected natural product scaffolds as candidates for future development. Developing such candidates via future chemical optimisation, efficacy and safety evaluations, broad spectrum activity assessments, and target identification represents an exciting prospect and, if successful, could pave the way to subsequent pre-clinical and clinical evaluations.
PubMed | DOI

Kim, J.-H., Kim, J.-W., Joa, J., Straub, J.H., Cross, M., Hofmann, A., Kim, J.-S. (2021) Biochim. Biophys. Acta - Prot. Proteom. 1869, 140564
Abstract
The trehalose biosynthesis pathway has recently received attention for therapeutic intervention combating infectious diseases caused by bacteria, helminths or fungi. Trehalose‐6‐phosphate phosphatase (TPP) is a key enzyme of the most common trehalose biosynthesis pathway and a particularly attractive target owing to the toxicity of accumulated trehalose‐6‐phosphate in pathogens.
Here, we characterised TPP-like proteins from bacterial pathogens implicated in nosocomial infections in terms of their steady-state kinetics as well as pH- and metal-dependency of their enzymatic activity. Analysis of the steady-state kinetics of recombinantly expressed enzymes from Acinetobacter baumannii, Corynebacterium diphtheriae and Pseudomonas stutzeri yielded similar kinetic parameters as those of other reported bacterial TPPs. The pH optimum curves of the enzymatic activity of TPP-like proteins from C. diphtheriae, P. stutzeri and Stenotrophomonas maltophilia agree with a mechanism involving two ionisable residues and allowed estimation of their pKa values. In contrast to nematode TPPs, the divalent metal ion appears to be bound only weakly in the active site of bacterial TPPs, allowing the exchange of the resident magnesium ion with other metal ions. Enzymatic activity comparable to the wild-type enzyme was observed for the TPP from P. stutzeri with manganese, cobalt and nickel. Analysis of the enzymatic activity of S. maltophilia TPP active site mutants provides evidence for the involvement of four canonical aspartate residues as well as a strictly conserved histidine residue of TPP-like proteins from bacteria in the enzyme mechanism. That histidine residue is a member of an interconnected network of five conserved residues in the active site of bacterial TPPs which likely constitute one or more functional units, directly or indirectly cooperating to enhance different aspects of the catalytic activity.
PubMed | DOI

Campos, T.L., Korhonen, P.K., Hofmann, A., Gasser, R.B., Young, N.D. (2020) NAR Genomics Bioinf. 2, lqaa051
Abstract
Characterizing genes that are critical for the survival of an organism (i.e. essential) is important to gain a deep understanding of the fundamental cellular and molecular mechanisms that sustain life. Functional genomic investigations of the vinegar fly, Drosophila melanogaster, have unravelled the functions of numerous genes of this model species, but results from phenomic experiments can sometimes be ambiguous. Moreover, the features underlying gene essentiality are poorly understood, posing challenges for computational prediction. Here, we harnessed comprehensive genomic-phenomic datasets publicly available for D. melanogaster and a machine-learning-based workflow to predict essential genes of this fly. We discovered strong predictors of suchgenes, paving the way for computational predictions of essentiality in less-studied arthropod pests and vectors of infectious diseases.
PubMed | DOI

Taki, A.C., Brkljača, R., Wang, T., Koehler, A.V., Ma, G., Danne, J., Ellis, S., Hofmann, A., Chang, B.C.H., Jabbar, A., Urban, S., Gasser, R.B. (2020) Pathogens 9, 550
Abstract
Eight secondary metabolites were isolated from a marine sponge, a marine alga and three terrestrial plants collected in Australia and subsequently chemically characterised. Here, these natural product-derived compounds were screened for in vitro-anthelmintic activity against the larvae and adult stages of Haemonchus contortus (barber’s pole worm) – a highly pathogenic parasitic nematode of ruminants. Using an optimised, whole-organism screening system, compounds were tested on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s). Anthelmintic activity was initially evaluated on these stages based on the inhibition of motility, development and/or changes in morphology (phenotype). We identified two compounds, 6-undecylsalicylic acid (3) and 6-tridecylsalicylic acid (4) isolated from the marine brown alga, Caulocystis cephalornithos, with inhibitory effects on xL3 and L4 motility and larval development, and the induction of a “skinny-straight” phenotype. Subsequent testing showed that these two compounds had an acute nematocidal effect (within 1–12 h) on adult males and females of H. contortus. Ultrastructural analysis of adult worms treated with compound 4 revealed significant damage to subcuticular musculature and associated tissues and cellular organelles including mitochondria. In conclusion, the present study has discovered that two algal compounds possessing acute anthelmintic effects and with potential for hit-to-lead progression. Future work should focus on undertaking a SAR study and on elucidating the mode(s) of action of optimised compounds.
PubMed | DOI

Rostami, A., Riahi, S.M., Omrani, V.F., Wang, T., Hofmann, A., Mirzapour, A., Foroutan, M., Fakhri, Y., Macpherson, C.N.L., Gasser, R.B. (2020) Pathogens 9, 503
Abstract
Toxascaris leonina is an ascaridoid nematode of dogs and cats; this parasite affects the health of these animals. This study estimated the global prevalence of Ta. leonina infection in dogs and cats using random effects meta-analysis as well as subgroup, meta-regression and heterogeneity analyses. The data were stratified according to geographical region, the type of dogs and cats, and environmental variables. A quantitative analysis of 135 published studies, involving 119,317 dogs and 25,364 cats, estimated prevalence rates of Ta. leonina in dogs and cats at 2.9% and 3.4%, respectively. Prevalences were highest in the Eastern Mediterranean region (7.2% for dogs and 10.0% for cats), and were significantly higher in stray dogs (7.0% vs. 1.5%) and stray cats (7.5% vs. 1.8%) than in pets. The findings indicate that, worldwide, ~ 26 million dogs and 23 million cats are infected with Ta. leonina; these animals would shed substantial numbers of Ta. leonina eggs into the environment each year, and might represent reservoirs of infection to other accidental or paratenic hosts. It is important that populations of dogs and cats as well as other canids and felids be monitored, and dewormed for Ta. leonina and (other) zoonotic helminths.
PubMed | DOI

Rostami, A., Kish, M.S., Ma, G., Wang, T., Ebrahimi, M., Fakhri, Y., Mirjalali, H., Hofmann, A., Macpherson, C., Hotez, P.J., Gasser, R.B. (2020) Adv. Parasitol. vol. 109, 615-639
Abstract
Zoonotic parasites of both pet and stray cats, including Toxocara species, are of public health concern. Therefore, reliable prevalence data for cats can assist in the design of strategies for the prevention and control of human toxocariasis. Here, we sought to estimate the prevalence of Toxocara species in cats worldwide, considering geographical location, type of cats, gender and age. This first, systematic review and meta-analysis of cross-sectional studies was conducted to estimate the prevalence of Toxocara infection(s) in cats. We assessed pooled data using a random effects-model as well as several meta-regression and stratified analyses. From a total of 1,733 peer-reviewed articles, 143 unique studies representinged 2,158,069 cats from 51 countries. The global mean (95% CI) prevalence of Toxocara infection in cats was 17.0% (16.1–17.8%), being highest in African countries (43.3%; 28.3–58.4%) and lowest in South American countries (12.6%; 8.2–17.0%). For the other WHO regions, the following prevalences were estimated: Eastern Mediterranean region (mean: 21.6%, range: 15.1–28.1%), North American countries (18.3% 15.4–21.2%), European region (17.8%, 15.9–19.7%), Western Pacific region (17.3%, 14.7-19.9%) and South-East Asian region (14.9%, 9.8-20.1%). The prevalence in pet cats (mean: 11.1%, range: 10.1–-12.0%) was significantly lower than in stray cats (28.6%, 25.0–32.2%). Cats of ≤12 months of age (27.7%; 23.4–32.0%) had a significantly higher prevalence compared with cats of >12 months of age (23.8%; 14.8–32.7%). Moreover, the prevalence was higher in low-income countries, geographical regions at a low longitude/latitude and with a warm and humid climate. In conclusion, we estimated that 118-150 million cats worldwide are shedders of Toxocara eggs. The present findings might encourage medical health policy makers to develop prevention and control strategies for Toxocara/toxocariasis, based on risk level in a particular geographic location, and emphasize a risk of Toxocara infection to cat owners and the public.
PubMed | DOI

Ma, G., Rostami, A., Wang, T., Hofmann, A., Hotez, P.J., Gasser, R.B. (2020) Adv. Parasitol. vol. 109, 275-290
Abstract
Human toxocariasis is a parasitic disease transmitted usually from dogs and/or cats that are infected with Toxocara species, and can be associated with a range of allergic, neurological and/or visual disorders. Recent epidemiological research has estimated that ~1.4 billion people worldwide, particularly in subtropical and tropical regions, are infected with, or exposed to Toxocara species, indicating that human toxocariasis is a neglected tropical disease. Here, we review recent research efforts, consider risk factors, discuss limitations in current seroprevalence estimates, and propose some future research directions toward improved awareness, surveillance, prevention and control of this neglected disease.
PubMed | DOI

Dilrukshi Herath, H.M.P., Taki, A.C., Nguyen, N., Garcia-Bustos, J., Hofmann, A., Wang, T., Ma, G., Chang, B.C.H., Jabbar, A., Sleebs, B.E., Gasser, R.B. (2020) Molecules 25, 2004
Abstract
Kava extract, an aqueous rhizome emulsion of the plant Piper methysticum, has been used for centuries by Pacific islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extracts. In a previous investigation, we had identified three kavalactones that inhibit larval development of Haemonchus contortus in an in vitro-bioassay. In the present study, we synthesised two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy and 4-N-morpholine substitutions had anthelmintic activities (IC50 values in the range of 1.9–8.9 μM) that were greater than either of the parent natural products desmethoxyyangonin (IC50 of 37.1 μM) and yangonin (IC50 of 15.0 μM). The synthesised analogues did not exhibit toxicity on HepG2 human liver hepatoma cells in vitro at concentrations of up to 40 μM. These findings confirm the previously identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent.
PubMed | DOI

Jiao, Y., Preston, S., Hofmann, A., Taki, A., Baell, J., Chang, B.C.H., Jabbar, A., Gasser, R.B. (2020) Adv. Parasitol. vol. 108, 1-45
Abstract
Parasitic roundworms (nematodes) cause substantial morbidity and mortality in animals worldwide. Anthelmintic treatment is central to controlling these worms, but widespread resistance to most of the commercially available anthelmintics for veterinary and agricultural use is compromising control, such that there is an urgency to discover new and effective drugs. The purpose of this article is to review information on parasitic nematodes, the treatment and control of parasitic nematode infections and aspects of discovering new anthelmintics in the context of anthelmintic resistance problems, and then to discuss some progress that our group has made in identifying selected compounds with activity against nematodes. The focus of our recent work has been on discovering new chemical entities and known drugs with anthelmintic activities against Haemonchus contortus as well as other socioeconomically important parasitic nematodes for subsequent development. Using whole worm-based phenotypic screening assays, we have been screening compound collections obtained via product-development-partnerships and/or collaborators, and active compounds have been assessed for their potential as anthelmintic candidates. Following the screening of 15,333 chemicals from five distinct compound collections against H. contortus, we have discovered one new chemical entity (designated SN00797439), two human kinase inhibitors (SNS-032 and AG-1295), 14 tetrahydroquinoxaline analogues, one insecticide (tolfenpyrad) and two tolfenpyrad (pyrazole-5-carboxamide) derivatives (a-15 and a-17) with anthelmintic activity in vitro. Some of these 20 'hit' compounds have selectivity against H. contortus in vitro when compared to particular human cell lines. In our opinion, some of these compounds could represent starting points for 'lead' development. Accordingly, the next research steps to be pursued include: (i) chemical optimisation of representative chemicals via structure-activity relationship (SAR) evaluations; (ii) assessment of the breadth of spectrum of anthelmintic activity on a range of other parasitic nematodes, such as strongyloids, ascaridoids, enoplids and filarioids; (iii) detailed investigations of the absorption, distribution, metabolism, excretion and toxicity (ADMET) of optimised chemicals with broad nematocidal or nematostatic activity; and (iv) establishment of the modes of action of lead candidates.
PubMed | DOI

Rostami, A., Riahi, S.M., Hofmann, A., Ma, G., Wang, T., Behniafar, H., Taghipour, A., Fakhri, Y., Spotin, A., Chang, B.C.H., Macpherson, C., Hotez, P.J., Gasser, R.B. (2020) Adv. Parasitol. vol. 109, 561-583
Abstract
Dogs are a key reservoir for Toxocara spp., causative agents of human toxocariasis, one of the most widespread zoonotic helminth infections worldwide. The present study was undertaken to assess the global prevalence of Toxocara infection in dogs. We searched PubMed, Scopus, Web of Science, EMBASE and SciELO to identify relevant prevalence studies. We used a random-effects model to estimate the overall and the subgroup pooled prevalence rates across studies, and heterogeneity was assessed via the I2 test. The data were categorised according to WHO region, different types of dogs, risk factors, and environmental variables. From a total of 4370 peer-reviewed publications, 229 articles that studied 13,010,004 dogs in 60 countries met the final inclusion criteria. The overall prevalence of Toxocara infection in dogs was 11.1% (95% CI, 10.6–11.7%). The estimated prevalence rates in the different WHO regions ranged from 6.4% to 19.2%: Eastern Mediterranean (19.2%; 13.7–25.5%), Africa (18.5%; 13.7–23.9%), South-East Asia (11.9%; 6.8–18.2%), North America (11.1%; 10.6–11.7%), South America (10.9%; 7.6–14.6%), Europe (10.8%; 8.9–12.9%) and Western Pacific (6.4%; 3.3–10.2%). Stray dogs, male dogs, and dogs that were resident in rural areas had a significantly (P < 0.001) higher prevalence of infection than pet dogs, female dogs and dogs in urban areas. Moreover, the prevalence rate was higher in low income countries and regions in a low geographical longitude and close to equator with a warmer climate. From all original studies included, we estimated that at least 100 million dogs are carriers of Toxocara around the world. Our findings highlight the need for an increased focus on implementing deworming programs for all types of dogs to reduce the environmental contamination with Toxocara eggs and to reduce the potential risk of transmission of infection to humans.
PubMed | DOI

Ma, G., Wang, T., Korhonen, P., Hofmann, A., Sternberg, P.W., Young, N.D., Gasser, R.B. (2020) Adv. Parasitol. vol. 108, 175-229
Abstract
Parasitic worms are important pathogens of humans and animals. In the past two decades, significant progress has been made in the sequencing, assembly, annotation and analyses of genomes and transcriptomes of socioeconomically important parasitic worms. Although this progress has improved our knowledge somewhat of these pathogens at the molecular level, there are still major gaps in understanding the biology of parasitic nematodes. Recent progress has been made using genomic, transcriptomic or proteomic studies. The improved genome and well-established in vitro larval culture system for selected nematode provide unprecedented opportunities for comprehensive transcriptomics (mRNA and miRNA), proteomics (somatic, excretory/secretory and phosphorylated proteins) and metabolomics (e.g., polar and neutral lipids). Here, we review the background on the development of nematodes; critically appraise the current state of knowledge of the developmental biology of parasitic nematodes and identify key knowledge gaps; discuss salient aspects of Haemonchus contortus (one of most important parasitic nematodes of ruminant livestock animals), with a focus on the recent advances in genomics, transcriptomic, proteomics and lipidomics as well as in vitro culturing systems; contextualise the use of an integrative multiomics approach, and discuss the implications of such an approach for detailed explorations of signalling molecules, molecular processes and pathways likely associated with nematode development, adaptation and parasitism, and for the identification of novel intervention targets against these pathogens. A multiomics approach will be broadly applicable to exploring a range of interesting and socioeconomically significant parasites and to elucidating host-parasite interactions and disease processes.
PubMed | DOI

Ruan, B., Zhang, Y., Tadesse, S., Preston, S., Taki, A.C., Jabbar, A., Hofmann, A., Jiao, Y., Garcia-Bustos, J., Harjani, J., Le, T.G., Varghese, S., Teguh, S., Xie, Y., Odiba, J., Hu, M., Gasser, R.B., Baell, J. (2020) Eur. J. Med. Chem. 190, 112100
Abstract
Parasitic roundworms (nematodes) are significant pathogens of humans and animals and cause substantive socioeconomic losses due to the diseases that they cause. The control of nematodes in livestock animals relies heavily on the use of anthelmintic drugs. However, their extensive use has led to a widespread problem of drug resistance in these worms. Thus, the discovery and development of novel chemical entities for the treatment of parasitic worms of humans and animals is needed. Herein, we describe our medicinal chemistry optimization efforts of a phenotypic hit against Haemonchus contortus based on a pyrrolidine-oxadiazole scaffold. This led to the identification of compounds with potent inhibitory activities (IC50 = 0.78–22.4 μM) on the motility and development of parasitic stages of H. contortus, and which were found to be highly selective in a mammalian cell counter-screen. These compounds could be used as suitable chemical tools for drug target identification or as lead compounds for further optimization.
PubMed | DOI

Wang, T., Ma, G., Ang, C.-S., Korhonen, P.K., Ströhlein, A., Young, N.D., Hofmanna, A., Chang, B.C.H., Williamson, N.A., Gasser, R.B. (2020) J. Proteomics 213, 103615
Abstract
Protein phosphorylation plays essential roles in many cellular processes. Despite recent progress in the genomics, transcriptomics and proteomics of socioeconomically important parasitic nematodes, there is scant phosphoproteomic data to underpin molecular biological discovery. Here, using the phosphopeptide enrichment-based LC-MS/MS and data-independent acquisition (DIA) quantitation, we characterised the first developmental phosphoproteome of the parasitic nematode Haemonchus contortus – one of the most pathogenic parasites of ruminant livestock. Totally, 1804 phosphorylated proteins with 4406 phosphorylation sites (“phosphosites”) from different developmental stages/sexes were identified. Bioinformatic analyses of quantified “phosphosites” exhibited distinctive stage- and sex-specific patterns during development, and identified a subset of phosphoproteins proposed to play crucial roles in processes such as spindle positioning, signal transduction and kinase activity. A sequence-based comparison of the phosphoproteome of H. contortus with those of two free-living nematode species (Caenorhabditis elegans and Pristionchus pacificus) suggested a limited number of common protein phosphorylation events among these species. Our findings infer active roles for protein phosphorylation in the adaptation of a parasitic nematode to a constantly changing external environment. The phosphoproteomic data set for H. contortus provides a basis to better understand phosphorylation and associated biological processes (e.g., regulation of signal transduction), and might enable the discovery of novel anthelmintic targets.
PubMed | DOI