Immunity to Helminths in Complex Environments: Co-Infection Disrupts Effective Granuloma Formation and Parasite Clearance

Abstract Introduction The intestinal roundworm Heligmosomoides bakeri establishes chronic infections in susceptible C57Bl/6 mice, yet repeated (“trickle”) infections confer immunity and promote worm clearance. We previously linked this acquired immunity to enhanced intestinal granuloma formation. Here, we focused on effector molecules (antibodies) and cells (eosinophils and macrophages) known to immobilise and damage developing parasites. Methods and Results We used flow cytometry and immunofluorescence to show that granulomas in trickle-infected female mice contain elevated levels of IgG1, SiglecF+ eosinophils and CD206+ macrophages compared to bolus-infected animals, while IgG2c, IgA, and IgE were undetectable and levels of Ly6G+ neutrophils or NK1.1+ NK cells were unchanged. To mimic natural complexity, we introduced a mixed immune environment via prior Toxoplasma gondii infection which induces IFNγ production in the small intestine. Co-infected mice exhibited fewer and smaller granulomas, which lacked IgG1, SiglecF+ eosinophils and CD206+ macrophages, correlating with higher worm burdens. Conclusion Together, these findings highlight the importance of local immune responses to tissue-invading worms and help explain why helminth elimination is frequently more difficult in the complex immune environments found in field settings compared to laboratory conditions.