Helminths stage a powerful infection that allows the parasite to damage host tissue through migration and feeding while simultaneously evading the host immune system. This feat is accomplished in part through the release of a diverse set of molecules that contribute to pathogenicity and immune suppression. Many of these molecules have been characterized in terms of their ability to influence the infectious capabilities of helminths across the tree of life. These include nematodes that infect insects, known as entomopathogenic nematodes (EPN) and plants with applications in agriculture and medicine. In this review we will first discuss the nematode virulence factors, which aid parasite colonization or tissue invasion, and cause many of the negative symptoms associated with infection. These include enzymes involved in detoxification, factors essential for parasite development and growth, and highly immunogenic ES proteins. We also explore how these parasites use several classes of molecules (proteins, carbohydrates, and nucleic acids) to evade the host’s immune defenses. For example, helminths release immunomodulatory molecules in extracellular vesicles that may be protective in allergy and inflammatory disease. Collectively, these nematode-derived molecules allow parasites to persist for months or even years in a host, avoiding being killed or expelled by the immune system. Here, we evaluate these molecules, for their individual and combined potential as vaccine candidates, targets for anthelminthic drugs, and therapeutics for allergy and inflammatory disease. Last, we evaluate shared virulence and immunomodulatory mechanisms between mammalian and non-mammalian plant parasitic nematodes and EPNs, and discuss the utility of EPNs as a cost-effective model for studying nematode-derived molecules. Better knowledge of the virulence and immunomodulatory molecules from both entomopathogenic nematodes and soil-based helminths will allow for their use as beneficial agents in fighting disease and pests, divorced from their pathogenic consequences.

Macrophages are a heterogeneous population of innate immune cells that are often divided into two major subsets: classically activated, typically pro-inflammatory (M1) macrophages that mediate host defense, and alternatively activated, tolerance-inducing (M2) macrophages that exert homeostatic and tissue-regenerative functions. Disturbed macrophage function/differentiation results either in inadequate, excessive immune activation or in a failure to induce efficient protective immune responses against pathogens. Loss-of-function variants in protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with chronic inflammatory disorders, but the effect of macrophage-intrinsic PTPN2 loss is still poorly understood. Here we report that PTPN2-deficient macrophages fail to acquire an alternatively activated/M2 phenotype. This was the consequence of reduced IL-6 receptor expression and a failure to induce IL-4 receptor in response to IL-6, resulting in an inability to respond to the key M2-inducing cytokine IL-4. Ultimately, failure to adequately respond to IL-6 and IL-4 resulted in increased levels of M1 macrophage marker expression in vitro and exacerbated lung inflammation upon infection with Nippostrongylus brasiliensis in vivo. These results demonstrate that PTPN2 loss interferes with the ability of macrophages to adequately respond to inflammatory stimuli and might explain the increased susceptibility of PTPN2 loss-of-function carriers to developing inflammatory diseases.

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More than 2 billion humans carry infectious parasites leading to chronic co-morbidities and growth retardation in children. Parasitic infections induce a T helper type 2 (Th2) immune response in the host to promote clearance which can lead to fibrosis if chronic. We recently showed that infection with the soil-transmitted nematode Nippostrongylus brasiliensis (Nb) induces overproduction of endocannabinoids (eCBs) in the host. Endocannabinoids are endogenous cannabis-like molecules that influence the development of obesity and are anti-inflammatory, however their function in infection is largely unknown. The overproduction of eCBs in Nb-infected mice was observed throughout infection in the infected lung and intestine. Pharmacological inhibition of cannabinoid receptor subtype 1 (CB-1R) with AM6545 (10 mg/Kg/2mL), a peripherally-restricted CB1R neutral antagonist, throughout Nb infection exacerbated weight loss of mice without altering food or water intake. This inhibition of CB1Rs led to a prolonged presence of eosinophils and neutrophils in the broncho-alveolar fluid and an accumulation of lymphocytes in the spleen. Furthermore, CB1R inhibition caused an increase in the expression of the mannose receptor on alveolar macrophages at day 8 post infection, indicating a sustained need for inflammatory resolution. Strikingly, we also found that Nb produces its own eCBs which vary in concentration based on stage of development, and that the eCB system is present in many parasitic nematodes including those that infect humans. These findings suggest that the eCB system is active in several hookworm species, and that host and helminth eCBs may influence immune and anti-inflammatory functions.