Model nematodes as a practical innovation to promote high throughput screening of natural products for anthelmintics discovery in South Asia: Current challenges, proposed practical and conceptual solutions.

With the increasing prevalence of anthelmintic resistance in animals recorded globally, and the threat of resistance in human helminths, the need for novel anthelmintic drugs is greater than ever. Most research aimed at discovering novel anthelmintic leads relies on high throughput screening (HTS) of large libraries of synthetic small molecules in industrial and academic settings in developed countries, even though it is the tropical countries that are most plagued by helminth infections. Tropical countries, however, have the advantage of possessing a rich flora that may yield natural products (NP) with promising anthelmintic activity.

New paradigms in research on Dirofilaria immitis.

Since the advent of ivermectin (along with melarsomine and doxycycline), heartworm has come to be viewed as a solved problem in veterinary medicine, diminishing investment into non-clinical research on Dirofilaria immitis. However, heartworm infections continue to pose problems for practitioners and their patients and seem to be increasing in frequency and geographic distribution. Resistance to preventative therapies (macrocyclic lactones) complicates the picture.

Sugar Coating: Utilisation of Host Serum Sialoglycoproteins by as a Potential Immune Evasion Mechanism.

Parasitic helminths resort to various mechanisms to evade and modulate their host's immune response, several of which have been described for . We recently reported the presence of sialic acid residues on the surface of adult extracellular vesicles (EVs). We now report that these sialylated molecules are mammalian serum proteins.

Analysis of Extracellular Vesicles Surface Glycans Reveals Potential Immune Evasion Mechanism and New Insights on Their Origins of Biogenesis.

Parasitic helminths are master manipulators of host immunity. Their strategy is complex and involves the release of excreted/secreted products, including extracellular vesicles (EVs). The protein and miRNA contents of EVs have been characterised for many parasitic helminths but, despite reports suggesting the importance of EV surface carbohydrate structures (glycans) in the interactions with target cells and thus subsequent effector functions, little is known about parasite EV glycomics.

Structural mechanism underlying the differential effects of ivermectin and moxidectin on the C. elegans glutamate-gated chloride channel GLC-2.

Background And Purpose: Nematode glutamate-gated chloride channels (GluCls) are targets of ivermectin (IVM) and moxidectin (MOX), structurally dissimilar macrocyclic lactone (ML) anthelmintics. IVM and MOX possess different pharmacokinetics and efficacy profiles but are thought to have the same binding site, through which they allosterically activate GluCls, apart from the GLC-2 receptor, which is antagonized by IVM. Our goal was to determine GLC-2 sensitivity to MOX, investigate residues involved in antagonism of GLC-2, and to identify differences in receptor-level pharmacology between IVM and MOX.

Mining nematode protein secretomes to explain lifestyle and host specificity.

Parasitic nematodes are highly successful pathogens, inflicting disease on humans, animals and plants. Despite great differences in their life cycles, host preference and transmission modes, these parasites share a common capacity to manipulate their host's immune system. This is at least partly achieved through the release of excretory/secretory proteins, the most well-characterized component of nematode secretomes, that are comprised of functionally diverse molecules.

When Secretomes Meet Anthelmintics: Lessons for Therapeutic Interventions.

Helminth secretomes comprise many potential immunomodulators. The molecular and functional diversity of these entities and their importance at the host-parasite interface have been increasingly recognized. It is now common to hypothesize that parasite-derived molecules (PDMs) are essential mediators used by parasites to establish and remain in their hosts.

A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors From and .

Effective control of hookworm infections in humans and animals relies on using a small group of anthelmintics. Many of these drugs target cholinergic ligand-gated ion channels, yet the direct activity of anthelmintics has only been studied in a subset of these receptors, primarily in the non-parasitic nematode, . Here we report the characterization of a homopentameric ionotropic acetylcholine receptor (AChR), ACR-16, from and , the first known characterization of human hookworm ion channels.

Contribution of Special Structural Features to High Thermal Stability of a Cold-Active Transglutaminase.

A cold-active transglutaminase (TGase, EC 2.3.2.

Identification of annotated bioactive molecules that impair motility of the blood fluke Schistosoma mansoni.

Neglected tropical diseases are of growing worldwide concern and schistosomiasis, caused by parasitic flatworms, continues to be a major threat with more than 200 million people requiring preventive treatment. As praziquantel (PZQ) remains the treatment of choice, an urgent need for alternative treatments motivates research to identify new lead compounds that would complement PZQ by filling the therapeutic gaps associated with this treatment. Because impairing parasite neurotransmission remains a core strategy for control of parasitic helminths, we screened a library of 708 compounds with validated biological activity in humans on the blood fluke Schistosoma mansoni, measuring their effect on the motility on schistosomulae and adult worms.

FDA-Approved Antiparasitic Drugs in the 21st Century: A Success for Helminthiasis?

Diseases caused by helminth infections affect more than a quarter of the population of the world, but the therapeutic arsenal is limited. The approval of moxidectin in 2018 and triclabendazole in 2019 by the FDA marked an important moment in the fight against diseases of poverty, such as helminthiases.

Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance.

Macrocyclic lactone (ML) anthelmintics are the most important class of anthelmintics because of our high dependence on them for the control of nematode parasites and some ectoparasites in livestock, companion animals and in humans. However, resistance to MLs is of increasing concern. Resistance is commonplace throughout the world in nematode parasites of small ruminants and is of increasing concern in horses, cattle, dogs and other animals.

A protocol to count Cryptosporidium oocysts by flow cytometry without antibody staining.

Cryptosporidiosis caused by the protozoan parasites Cryptosporidium hominis and C. parvum, threatens the lives of young children in developing countries. In veterinary medicine, C.

Flubendazole as a macrofilaricide: History and background.

Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lead to high macrofilaricidal efficacy in a variety of preclinical models and in humans.

Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties.

Parasitic worms have a remarkable ability to modulate host immune responses through several mechanisms including excreted/secreted proteins (ESP), yet the exact nature of these proteins and their targets often remains elusive. Here, we performed mass spectrometry analyses of ESP (TsESP) from larval and adult stages of the pig whipworm Trichuris suis (Ts) and identified ~350 proteins. Transcriptomic analyses revealed large subsets of differentially expressed genes in the various life cycle stages of the parasite.

Helminth extracellular vesicles in host-parasite interactions.

Extracellular vesicles (EVs) have been characterized from many species of parasitic helminths, and recent experimental evidence supports important functions for their cargo in host-parasite relationships as immunomodulatory mediators. Here we summarize available data on the effects of parasite-derived EVs, including their protein and/or small RNA contents, on their hosts.

Further Characterization of Molecular Markers in Canine Dirofilaria immitis Infection.

Dirofilaria immitis is a common filarial parasite found in dogs and cats in the Americas, with the pathophysiological consequences of the infection differing somewhat between these 2 host species. Recent research efforts have been focused on determining if the microRNAs (miRNAs) released from adult Dirofilariae have a role as markers for distinguishing the intensity of adult worm infection, as well as determining the presence of new infections. This study expands previous work on 2 nematode miRNAs, miR34 and miR-71, by addressing their ability to discriminate between low and high D.

Chloroquine exposure triggers distinct cellular responses in sensitive versus resistant Plasmodium falciparum parasites.

Chloroquine (CQ) treatment failure in Plasmodium falciparum parasites has been documented for decades, but the pharmacological explanation of this phenotype is not fully understood. Current concepts attribute CQ resistance to reduced accumulation of the drug at a given external CQ concentration ([CQ]) in resistant compared to sensitive parasites. The implication of this explanation is that the mechanisms of CQ-induced toxicity in resistant and sensitive strains are similar once lethal internal concentrations have been reached.

Clinical validation of molecular markers of macrocyclic lactone resistance in Dirofilaria immitis.

Prophylaxis with macrocyclic lactone (ML) endectocides is the primary strategy for heartworm control. Recent evidence has confirmed that ML-resistant Dirofilaria immitis isolates have evolved. Comparison of genomes of ML-resistant isolates show they are genetically distinct from wild-type populations.

Characterization of Divalent Metal Transporter 1 (DMT1) in Brugia malayi suggests an intestinal-associated pathway for iron absorption.

Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication.

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections.

Background: Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L.

Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity.

Flubendazole (FLBZ) is a potent and efficacious macrofilaricide after parenteral administration. Studies in animal models and one trial in patients infected with revealed that FLBZ elicits minimal effects on microfilariae (mf). Severe complications after ivermectin (IVM) treatment of patients with high microfilaraemia are of great concern.