A secreted fatty acid- and retinol- binding protein from Heligmosomoides polygyrus suppresses host macrophage polarization

Abstract

Parasitic nematodes are major pathogens of humans, animals, and plants, contributing to global health challenges and substantial agricultural losses. Fatty acid- and retinol-binding proteins (FARs), secreted by parasitic nematodes, are believed to play key roles in host-pathogen interactions, including immune modulation and nutrient acquisition. In this study, we characterize a FAR protein from the gastrointestinal nematode Heligmosomoides polygyrus, Hp-FAR-2. Unlike FARs from Caenorhabditis elegans, Steinernema carpocapsae, and Ancylostoma ceylanicum, Hp-FAR-2 did not influence immunity or survival in a Drosophila melanogaster infection model, suggesting functional divergence within the FAR family. Competitive lipid-binding assays revealed a preference for omega-3 and omega-6 polyunsaturated fatty acids, indicating selective binding to bioactive lipids that may modulate immunity. Using RAW 264.7 macrophages, we found that Hp-FAR-2 suppresses the expression of both M1-associated (TNF-, IL-6) and M2-associated (Chil3) markers during polarization, implicating it as a broad immunomodulator that may inhibit inflammatory responses and tissue repair mechanisms to promote chronic infection. Our findings support a model in which Hp-FAR-2 disrupts host lipid signaling and immune function to favor parasite persistence, suggesting its potential role in the excretory/secretory products of H. polygyrus. Together, these data enhance our understanding of FAR-mediated host manipulation and may inform the development of novel anthelmintic or immunoregulatory therapies.