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Soil-transmitted helminths affect approximately 1.5 billion people worldwide. However, as no vaccine is currently available for humans, the current strategy for elimination as a public health problem relies on preventive chemotherapy. Despite more than 20 years of intense research effort, the development of human helminth vaccines (HHVs) has not yet come to fruition. Current vaccine development focuses on peptide antigens that trigger strong humoral immunity, with the goal of generating neutralizing antibodies against key parasite molecules. Notably, this approach aims to reduce the pathology of infection, not worm burden, with only partial protection observed in laboratory models. In addition to the typical translational hurdles that vaccines struggle to overcome, HHVs face several challenges (1): helminth infections have been associated with poor vaccine responses in endemic countries, probably due to the strong immunomodulation caused by these parasites, and (2) the target population displays pre-existing type 2 immune responses to helminth products, increasing the likelihood of adverse events such as allergy or anaphylaxis. We argue that such traditional vaccines are unlikely to be successful on their own and that, based on laboratory models, mucosal and cellular-based vaccines could be a way to move forward in the fight against helminth infection. Here, we review the evidence for the role of innate immune cells, specifically the myeloid compartment, in controlling helminth infections. We explore how the parasite may reprogram myeloid cells to avoid killing, notably using excretory/secretory (ES) proteins and extracellular vesicles (EVs). Finally, learning from the field of tuberculosis, we will discuss how anti-helminth innate memory could be harnessed in a mucosal-trained immunity-based vaccine.

Background Nippostrongylus brasiliensis —a nematode of rodents—is commonly used as a model to study the immunobiology of parasitic nematodes. It is a member of the Strongylida—a large order of socioeconomically important parasitic nematodes of animals. Lipids are known to play essential roles in nematode biology, influencing cellular membranes, energy storage and/or signalling. Methods The present investigation provides a comprehensive, untargeted lipidomic analysis of four developmental stages/sexes (i.e. egg, L3, adult female and adult male stages) of N. brasiliensis utilising liquid chromatography coupled to mass spectrometry. Results We identified 464 lipid species representing 18 lipid classes and revealed distinct stage-specific changes in lipid composition throughout nematode development. Triacylglycerols (TGs) dominated the lipid profile in the egg stage, suggesting a key role for them in energy storage at this early developmental stage. As N. brasiliensis develops, there was a conspicuous transition toward membrane-associated lipids, including glycerophospholipids (e.g. PE and PC) and ether-linked lipids, particularly in adult stages, indicating a shift toward host adaptation and membrane stabilisation. Conclusions We provide a comprehensive insight into the lipid composition and abundance of key free-living and parasitic stages of N. brasiliensis . This study provides lipidomic resources to underpin the detailed exploration of lipid biology in this model parasitic nematode. Graphical Abstract

Hookworm infections cause a neglected tropical disease (NTD) affecting ~740 million people worldwide, principally those living in disadvantaged communities. Infections can cause high morbidity due to their impact on nutrient uptake and their need to feed on host blood, resulting in a loss of iron and protein, which can lead to severe anaemia and impaired cognitive development in children. Currently, only one drug, albendazole is efficient to treat hookworm infection and the scientific community fears the rise of resistant strains. As part of on-going efforts to control hookworm infections and its associated morbidities, new drugs are urgently needed. We focused on targeting the blood-feeding pathway, which is essential to the parasite survival and reproduction, using the laboratory hookworm model Nippostrongylus brasiliensis (a nematode of rodents with a similar life cycle to hookworms). We established an in vitro-drug screening assay based on a fluorescent-based measurement of parasite viability during blood-feeding to identify novel therapeutic targets. A first screen of a library of 2654 natural compounds identified four that caused decreased worm viability in a blood-feeding-dependent manner. This new screening assay has significant potential to accelerate the discovery of new drugs against hookworms.

Soil-transmitted helminth (STH) infections such as Necator americanus infect millions globally, and are a major cause of anemia and developmental stunting in low and middle income countries. Blood-feeding hookworms in particular rely on the digestion of host erythrocytes for nutrition and therefore detoxify heme as a byproduct of their parasitism. This dependency on blood feeding and subsequent detoxification renders this pathway as a vulnerable target for therapeutic intervention, particularly as it is the cause of morbidity in those infected. Here we described the continued development and application of a high-throughput in vitro assay using the so-called rodent hookworm Nippostrongylus brasiliensis, a model that shares key traits with N. americanus including blood feeding and hemozoin-like pigment formation. We optimized a fluorescence-based screening cascade to utilise GelGreen as a cost-effective viability stain and screened 400 compounds from the MMV Pathogen Box. Multiple compounds displayed enhanced activity in the presence of blood, suggesting interference with blood-feeding or blood-feeding-induced development. Five hits were selected for further validation, and as proof-of-principle of this screening cascade, all five were well tolerated in vivo at low doses in a murine model. This study therefore demonstrates this method can be used as a tractable and biologically relevant screening approach to identify compounds active against blood-feeding nematodes. Future work can further develop such compounds into lead drug candidates, and be leveraged for comparative parasitology approaches to identify pan-anthelmintic drugs.

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