Co-infection withToxoplasma gondiileads to a loss of resistance inHeligmosomoides bakeritrickle-infected mice due to ineffective granulomas

ABSTRACT The intestinal roundworm Heligmosomoides bakeri causes chronic infection in susceptible (C57Bl/6) mice; however, repeat (trickle) infection confers immunity and facilitates worm clearance. We previously showed that this acquired immunity is associated with a strong Th2 response, notably the enhanced production of intestinal granulomas. Here we demonstrate that elevated proportions of IgG 1 -bound eosinophils and macrophages are observed around the developing tissue worms of trickle-infected female C57Bl/6 mice compared to bolus infected animals. Levels of IgG 2c , IgA or IgE were not detected in the granulomas. Increased proportions of SiglecF + and CD206 + cells, but not Ly6G + and/or NK1.1 + cells, were also found in the granulomas of trickle-infected mice. However, in the natural world rather than the laboratory setting, immune environments are more nuanced. We examined the impact of a mixed immune environment on trickle infection-induced immunity, using a pre-infection with Toxoplasma gondii . The mixed immune environment resulted in fewer and smaller granulomas with a lack of IgG -bound cells as well as reduced proportions of SiglecF + and CD206 + cells, measured by immunofluorescence and flow cytometry. This was associated with a higher worm burden in the co-infected animals. Our data confirm the importance of intestinal granulomas and parasite-specific antibody for parasite clearance. They highlight why it may be more difficult to clear worms in the field than in the laboratory. AUTHOR’S SUMMARY Despite decades of research on intestinal parasitic worms, we are still unable to clearly point to why so many people (approximately 1.8 billion) and most livestock/wild animals are infected with these parasites. We have made progress in understanding how the immune system responds to parasitic worms, and how these parasites manipulate our immune system. However, identifying effective clearance mechanisms is complex and context dependent. We have used models of trickle infection (multiple low doses of parasites) and co-infection (two intestinal parasites) to simulate how people/animals get infected in the real world. Using these models, we have confirmed the host/parasite interface (the granuloma) within the intestinal tissue to be key in determining the host’s ability to clear worms. The lack of specific immune cells and antibodies within the granuloma was associated with chronic infection. Our results help explain why intestinal parasitic worms are so prevalent and why it may be difficult to clear worms in natural settings.