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

Abstract

Intestinal roundworms cause chronic debilitating disease in animals, including humans. A lack of effective vaccines and the emergence of widespread drug resistance only increase the need to better understand parasite clearance mechanisms within the host. Heligmosomoides polygyrus larvae induce a strong intestinal granuloma response within their murine host, which has been associated with resistance. Immune cells, mostly alternatively activated macrophages and eosinophils, accumulate around the tissue encysted parasites to immobilize and damage/kill developing worms. In a one dose (bolus) experimental infection, infected C57Bl/6 mice are unable to clear parasites which results in chronic infection with high worm burdens. However, using a frequent dose trickle model of infection, we, like others, have found that C57Bl/6 mice can clear infection. We found that the clearance is associated with higher granuloma numbers, but no changes in systemic/intestinal Th2 responses. Within the granulomas, we found that myeloid cells had a different transcriptional profile in each of the infected groups, and that high IgG1, but not IgG2c, IgA or IgE, levels were observed around the larvae of only trickle-infected mice. Our results highlight the importance of the granuloma in the host’s ability to clear H. polygyrus and emphasise the need to study this key tissue in more depth, rather than using correlates such as general intestinal or systemic responses.AUTHOR’S SUMMARYDespite 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 a model of trickle infection (multiple low doses of parasites) to simulate how people/animals get infected in the real world. Using this model, we have identified the host/parasite interface (the granuloma) within the intestinal tissue to be key in determining the host’s ability to clear worms. Specific gene expression signatures in granuloma immune cells and the presence/absence of antibodies within the granuloma are key factors associated with parasite clearance. Surprisingly, more common identifiers of parasitic worm infections (increased serum antibody levels and/or generalized immune markers) did not associate with protection. These novel findings contribute to a better understanding of the mechanisms underlying effective parasitic worm clearance.