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Resistance to the anthelmintic macrocyclic lactone ivermectin (IVM) has a great impact on the control of parasitic nematodes. The mechanisms by which nematodes adapt to IVM remain to be deciphered. We have identified NHR-8, a nuclear hormone receptor involved in the xenobiotic response in Caenorhabditis elegans, as a new regulator of tolerance to IVM. Loss-of-function nhr-8(ok186) C. elegans mutants subjected to larval development assays and electropharyngeogram measurements, displayed hypersensitivity to IVM, and silencing of nhr-8 in IVM-resistant worms increased IVM efficacy. In addition, compared to wild-type worms, nhr-8 mutants under IVM selection pressure failed to acquire tolerance to the drug. In addition, IVM-hypersensitive nhr-8(ok186) worms displayed low transcript levels of several genes from the xenobiotic detoxification network and a concomitant low Pgp-mediated drug efflux activity. Interestingly, some pgp and cyp genes known to impact IVM tolerance in many nematode species, were down regulated in nhr-8 mutants and inversely upregulated in IVM-resistant worms. Moreover, pgp-6 overexpression in nhr-8(ok186) C. elegans increased tolerance to IVM. Importantly, NHR-8 function was rescued in nhr-8(ok186) C. elegans with the homolog of the parasitic nematode Haemonchus contortus, and silencing of Hco-nhr-8 by RNAi on L2 H. contortus larvae increased IVM susceptibility in both susceptible and resistant H. contortus isolates. Thus, our data show that NHR-8 controls the tolerance and development of resistance to IVM in C. elegans and the molecular basis for this relates to the NHR-8-mediated upregulation of IVM detoxification genes. Since our results show that Hco-nhr-8 functions similarly to Cel-nhr-8, this study helps to better understand mechanisms underlying failure in drug efficacy and open perspectives in finding new compounds with NHR-8 antagonist activity to potentiate IVM efficacy.

Background Gastrointestinal nematode (GIN) infections are common in domestic sheep and impact directly and indirectly on the health of infected animals as well as on the associated economic production. In this study, we aim at summarizing the current knowledge on the influence of GIN infections on sheep production by conducting a systematic review. A subsequent meta-analysis of relevant studies was performed to provide an estimate of the effect of GIN infections on weight gain, wool production and milk yield. Methods A literature search was performed on the CAB, Pubmed and Web of Science database for the period 1960–2012. Inclusion criteria were: 1) Measurement of at least one production parameter. 2) Comparison between groups of sheep with different nematode burdens. 3) Same conditions regarding all aspects except parasite burden between groups. 4) Quantitative measurements of one or more production traits. Results Altogether, 88 studies describing 218 trials were included in this review. The majority of studies (86 %) reported that GIN infections had a negative effect on production but this was reported to be statistically significant in only 43 % of the studies. Meta-analysis indicated that performances of sheep infected with nematodes was 85, 90 and 78 % of the performance in uninfected individuals for weight gain, wool production and milk yield respectively. Our results suggest a possible reporting bias or small study effect for the estimation of the impact of GIN infections on weight gain. Finally, a general linear model provided an estimate for the decrease in weight gain in relation to the increase in faecal egg count of nematodes. Conclusion This study underlines the importance of GIN infections for sheep production and highlights the need to improve parasite management in sheep, in particular in face of challenges such as anthelmintic resistance.

Background Cyathostomins are the most important and common parasitic nematodes of horses, with > 50 species known to occur worldwide. The frequent and indiscriminate use of anthelmintics has resulted in the development of anthelmintic resistance (AR) in horse nematodes. In this study we assessed the efficacy of commonly used anthelmintics against cyathostomins in Australian thoroughbred horses. Methods Two drug efficacy trials per farm were conducted on two thoroughbred horse farms in the state of Victoria, Australia. In the first trial, the horses on Farm A were treated with single and combinations of anthelmintics, including oxfendazole (OFZ), abamectin (ABM), abamectin and morantel (ABM + MOR), moxidectin (MOX) and oxfendazole and pyrantel (OFZ + PYR), at the recommended doses, whereas the horses on Farm B only received MOX, at the recommended dose. The faecal egg count reduction test (FECRT) was used to determine the efficacy and egg reappearance period (ERP) of anthelmintics. Based on the results of the first trial, the efficacies of MOX and a combination of ABM + MOR were reassessed to confirm their activities against cyathostomins. Results Of the five anthelmintic products tested on Farm A, resistance against OFZ, ABM and OFZ + PYR was found, with efficacies of − 41% (− 195% lower confidence limit [LCL]), 73% (60% LCL) and 82% (66% LCL) at 2 weeks post-treatment, respectively. The FECRT showed high efficacies of MOX and ABM + MOR (100%) at 2 week post-treatment and shortened ERPs for these anthelmintics (ABM + MOR: 4 weeks; MOX: 5 weeks). Resistance to MOX was found on Farm B, with a reduced efficacy of 90% (70% LCL) and 89% (82% LCL) at 2 weeks post-treatment in trials one and two, respectively. Conclusions This study provides the first evidence of MOX- and multidrug-resistant (ABM and combinations of anthelmintics) cyathostomins in Australia and indicates the need for continuous surveillance of the efficacy of currently effective anthelmintics and large-scale investigations to assess the ERP for various anthelmintics. Graphical Abstract

Parasitic nematodes (roundworms) of small ruminants and other livestock have major economic impacts worldwide. Despite the impact of the diseases caused by these nematodes and the discovery of new therapeutic agents (anthelmintics), there has been relatively limited progress in the development of practical molecular tools to study the epidemiology of these nematodes. Specific diagnosis underpins parasite control, and the detection and monitoring of anthelmintic resistance in livestock parasites, presently a major concern around the world. The purpose of the present article is to provide a concise account of the biology and knowledge of the epidemiology of the gastrointestinal nematodes (order Strongylida), from an Australian perspective, and to emphasize the importance of utilizing advanced molecular tools for the specific diagnosis of nematode infections for refined investigations of parasite epidemiology and drug resistance detection in combination with conventional methods. It also gives a perspective on the possibility of harnessing genetic, genomic and bioinformatic technologies to better understand parasites and control parasitic diseases.

Treatment of parasitic nematode infections in humans and livestock relies on a limited arsenal of anthelmintic drugs that have historically reduced parasite burdens. However, anthelmintic resistance (AR) is increasing, and little is known about the molecular and genetic causes of resistance for most drugs. The free-living roundworm Caenorhabditis elegans has proven to be a tractable model to understand AR, where studies have led to the identification of molecular targets of all major anthelmintic drug classes. Here, we used genetically diverse C . elegans strains to perform dose-response analyses across 26 anthelmintic drugs that represent the three major anthelmintic drug classes (benzimidazoles, macrocyclic lactones, and nicotinic acetylcholine receptor agonists) in addition to seven other anthelmintic classes. First, we found that C . elegans strains displayed similar anthelmintic responses within drug classes and significant variation across drug classes. Next, we compared the effective concentration estimates to induce a 10% maximal response (EC 10 ) and slope estimates of each dose-response curve of each strain to the laboratory reference strain, which enabled the identification of anthelmintics with population-wide differences to understand how genetics contribute to AR. Because genetically diverse strains displayed differential susceptibilities within and across anthelmintics, we show that C . elegans is a useful model for screening potential nematicides before applications to helminths. Third, we quantified the levels of anthelmintic response variation caused by genetic differences among individuals (heritability) to each drug and observed a significant correlation between exposure closest to the EC 10 and the exposure that exhibited the most heritable responses. These results suggest drugs to prioritize in genome-wide association studies, which will enable the identification of AR genes.

Background Gastrointestinal nematodes pose a significant health risk to grazing livestock and cause economic losses, which are further increased by anthelmintic resistance. This study examined the gastrointestinal parasite fauna of Old World Camels (OWCs) in Germany and evaluated the efficacy of anthelmintic treatment. Methods In total, nine German OWC-keeping farms that dewormed their stock in spring 2023 were examined. The farms with their veterinarians independently selected the drug for treatment. The number of strongyle eggs per gram (EPG) feces was determined in 107 OWCs, Camelus bactrianus (86.0%), Camelus dromedarius (6.5%), and hybrids (7.5%), using the FLOTAC method (multiplication factor = 1) before and 14 days after treatment (paired sample size: 100 OWCs). The fecal egg count reduction (FECR) was calculated using bayescount and eggCounts software. For the identification and relative quantification of strongyle species, deep amplicon sequencing (nemabiome analysis) was used. Results Farms differed widely regarding egg shedding intensities and prevalence. On most farms, the weight of the animals was only estimated. Evaluation of the anthelmintic efficacy revealed FECRs of 26.6–90.8% after treatment with albendazole, fenbendazole, ivermectin, moxidectin, or doramectin, while only on one farm treatment with monepantel resulted in > 99% FECR. The strongyle species diversity, as determined using the nemabiome approach, was low. With Trichostrongylus colubriformis , Haemonchus contortus , Trichostrongylus axei , and Cooperia oncophora abundant strongyles of German domestic ruminants dominated, while Camelostrongylus mentulatus also occurred. After deworming, strongyle communities almost completely consisted of T. colubriformis and H. contortus . In contrast, C. mentulatus and C. oncophora were consistently eliminated by treatments. Conclusions This study shows the insufficient efficacy of standard treatments chosen by farmers/veterinarians for OWCs in Germany. Since treatment eliminated some species but did not eliminate others, not underdosing but resistant nematode species presumably led to treatment failure. However, owing to the small sample size, assessment of animal weight only by visual estimation, and no drugs licensed for OWCs in Europe, the term resistance should be used with care. The species T. colubriformis and H. contortus that survived after anthelmintic treatment are also frequently resistant in ruminants in Germany. Graphical Abstract

Background Eucoleus aerophilus (syn. Capillaria aerophila ) is a nematode with a worldwide geographical distribution. It causes a disease called lung capillariosis by affecting the respiratory tract of wild and domestic animals, and has also occasionally been described in humans. Despite steady increases in knowledge of the morphology of this neglected parasite, many aspects are still poorly understood. Epidemiological data regarding, for example, geographic distribution, range of hosts, clinical relevance and the actual zoonotic potential of this nematode are scarce and incomplete. Methods This article is a systematic review based on the screening of three databases (PubMed, Web of Science and Science Direct) to identify eligible studies published from 1973 to the end of 2022. Results From a total of 606 studies describing the occurrence of E. aerophilus , 141 articles from 38 countries worldwide were included in this meta-analysis, all of which presented results obtained mainly with flotation and necropsy. Due to the occurrence of E. aerophilus in many different species and different matrices (lungs and faeces), we decided to conduct the meta-analysis separately for each species with a given matrix. This systematic review confirmed the status of the Red fox as the main reservoir and main transmitter of E. aerophilus (average prevalence of 43% in faeces and 49% in lungs) and provided evidence of a higher prevalence of E. aerophilus in wild animals in comparison to domestic animals, such as dogs (3% in faeces) and cats (2% in faeces and 8% in lungs). Previous studies have investigated many host-related factors (age, sex, environmental/living conditions) in relation to the prevalence of E. aerophilus , but they show wide variations and no simple relationship has been demonstrates. Furthermore, mixed infections with other pulmonary nematodes, such as Crenosoma vulpis and/or Angiostrongylus vasorum , are reported very frequently, which greatly complicates the diagnosis. Conclusions This systematic review focused on identifying data gaps and promoting future research directions in this area. To the best of our knowledge, this is the first systematic review that evaluates and summarizes existing knowledge on the occurrence and prevalence of E. aerophilus in wild and domestic animals originating from different geographical locations worldwide. Graphical Abstract

BACKGROUND : Veterinary diagnostics aid intervention strategies, track zoonoses, and direct selective breeding programs in livestock. In ruminants, gastrointestinal nematode (GIN) parasites are a major cause of production losses, but morphologically similar species limit our understanding of how specific GIN co-infections impact health in resource-limited settings. To estimate the presence and relative abundance of GINs and other helminths at the species level, we sought to develop a low-cost and low-resource molecular toolkit applied to goats from rural Malawi smallholdings. METHODS : Goats were subjected to health scoring and faecal sampling on smallholdings in Lilongwe district, Malawi. Infection intensities were estimated by faecal nematode egg counts with a faecal subsample desiccated for DNA analysis. Two DNA extraction methods were tested (low-resource magbead kit vs high-resource spin-column kit), with resulting DNA screened by endpoint polymerase chain reaction (PCR), semi-quantitative PCR, quantitative PCR (qPCR), high-resolution melt curve analysis (HRMC), and ‘nemabiome’ internal transcribed spacer 2 (ITS-2) amplicon sequencing. RESULTS : Both DNA isolation methods yielded comparable results despite poorer DNA purity and faecal contaminant carryover from the low-resource magbead method. GINs were detected in 100% of samples regardless of infection intensity. Co-infections with GINs and coccidia (Eimeria spp.) were present in most goats, with GIN populations dominated by Haemonchus contortus, Trichostrongylus colubriformis, Trichostrongylus axei, and Oesophagostomum columbianum. Both multiplex PCR and qPCR were highly predictive of GIN species proportions obtained using nemabiome amplicon sequencing; however, HRMC was less reliable than PCR in predicting the presence of particular species. CONCLUSIONS : These data represent the first ‘nemabiome’ sequencing of GINs from naturally infected smallholder goats in Africa and show the variable nature of GIN co-infections between individual animals. A similar level of granularity was detected by semi-quantitative PCR methods, which provided an accurate summary of species composition. Assessing GIN co-infections is therefore possible using cost-efficient low-resource DNA extraction and PCR approaches that can increase the capacity of molecular resources in areas where sequencing platforms are not available; and also open the door to affordable molecular GIN diagnostics. Given the diverse nature of infections in livestock and wildlife, these approaches have potential for disease surveillance in other areas.

Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type 2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.

Background There is a demand for broad-spectrum products effective against internal and external parasites to simplify dog-owner compliance with veterinary parasiticide treatment recommendations. A field study investigated the safety and efficacy of a broad-spectrum formulation of fluralaner, moxidectin, and pyrantel pamoate compared with a licensed afoxolaner–milbemycin oxime combination product in treating canine intestinal nematode infections in client-owned dogs at multiple sites in Europe. Methods Dogs with positive pre-treatment fecal egg counts (FEC) were randomized to treatment on day 0 with the investigative veterinary product (IVP), at dose rates of: IVP, fluralaner 10–20 mg/kg, moxidectin 0.025–0.050 mg/kg, pyrantel 5–10 mg/kg ( n  = 172); or a control product (CP), afoxolaner 2.5–5.2 mg/kg, milbemycin oxime 0.5–1.0 mg/kg ( n  = 86). On day 14, FEC were completed on all study dogs. Efficacy against any intestinal nematode species was claimed if the FEC reduction in ≥ 10 dogs initially positive for that species was ≥ 90%, and if the geometric mean difference between pre- and post-treatment FEC was statistically significant ( P  ≤ 0.05). Results Study dogs were enrolled at veterinary clinics in Albania ( n  = 60), Bulgaria ( n  = 111), Greece ( n  = 27), and Italy ( n  = 60). Where a sufficient number of infected dogs allowed for statistical comparison, geometric mean FEC reductions on day 14 versus day 0 in the IVP group were significant ( P  < 0.0001) for hookworms, Toxocara canis , Toxascaris leonina, Trichuris vulpis , and capillarid-type eggs. On the basis of geometric mean reductions in FEC relative to day 0, the efficacy of the IVP exceeded 99% against all intestinal nematode parasites, and FEC reductions in the CP exceeded 98%. The percentage of nematode-free dogs in the IVP group was statistically noninferior ( P  < 0.0001) to the CP group and even statistically superior at the α  = 0.025 level of significance (one-sided). There were no treatment-related adverse events. Conclusions In client-owned dogs, the combination of fluralaner–moxidectin–pyrantel is safe and effective for the treatment of intestinal infections with hookworms, ascarids, including T. canis , and whipworms. On the basis of the complete elimination of parasite ova from the feces evaluated in this study, this fluralaner–moxidectin–pyrantel combination demonstrated to be significantly superior ( P  < 0.025) to an afoxolaner–milbemycin combination in the treatment of canine intestinal nematode infections. Graphical Abstract