Granuloma formation is a key host immune response generated to confine invading pathogens and limit extensive host damage. It consists of an accumulation of host immune cells around a pathogen. This host response has been extensively studied in the context of inflammatory diseases. However, there is much less known about Th2-type granulomas generated in response to parasitic worms. Based onin vitrodata, innate immune cells within the granuloma are thought to immobilize and kill parasites but also act to repair damaged tissue. Understanding this dual function is key. The two billion people and many livestock/wild animals infected with helminths demonstrate that granulomas are not effective at clearing infection. However, the lack of high mortality highlights their importance in ensuring that parasite migration/tissue damage is restricted and wound healing is effective. In this review, we define two key cellular players (macrophages and eosinophils) and their associated molecular players involved in Th2 granuloma function. To date, the underlying mechanisms remain poorly understood, which is in part due to a lack of conclusive studies. Most have been performedin vitrorather thanin vivo, using cells that have not been obtained from granulomas. Experiments using genetically modified mouse strains and/or antibody/chemical-mediated cell depletion have also generated conflicting results depending on the model. We discuss the caveats of previous studies and the new tools available that will help fill the gaps in our knowledge and allow a better understanding of the balance between immune killing and healing.

IntroductionIntestinal roundworms cause chronic debilitating disease in animals, including humans. Traditional experimental models of these types of infection use a large single-dose infection. However, in natural settings, hosts are exposed to parasites on a regular basis and when mice are exposed to frequent, smaller doses of Heligmosomoides polygyrus, the parasites are cleared more quickly. Whether this more effective host response has any negative consequences for the host is not known.ResultsUsing a trickle model of infection, we found that worm clearance was associated with known resistance-related host responses: increased granuloma and tuft cell numbers, increased levels of granuloma IgG and decreased intestinal transit time, as well as higher serum IgE levels. However, we found that the improved worm clearance was also associated with an inflammatory phenotype in and around the granuloma, increased smooth muscle hypertrophy/hyperplasia, and elevated levels of Adamts gene expression.DiscussionTo our knowledge, we are the first to identify the involvement of this protein family of matrix metalloproteinases (MMPs) in host responses to helminth infections. Our results highlight the delicate balance between parasite clearance and host tissue damage, which both contribute to host pathology. When continually exposed to parasitic worms, improved clearance comes at a cost.

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Disrupting or harnessing immune suppression is leading to new therapeutic avenues in a number of immune‐related diseases. Understanding the suppressive functions of regulatory T cells (Tregs) in different environments is therefore key. Parasitic worms are strong inducers of Tregs and previous research has suggested that parasite‐induced Tregs are stronger suppressors than naïve Tregs. In strains susceptible to the intestinal worm Heligmosomoides polygyrus, like C57BL/6 mice, it has been hypothesized that increased Treg suppression downregulates both Th1 and Th2 responses, leading to chronic infections and high worm burden. Here, we show that the suppressive capacity of Tregs is no different between cells from infected and/or naive animals. In vitro suppression induced by CD4+CD25+Tregs (Peyers’ Patches or the mesenteric lymph nodes), isolated early (day 7, tissue dwelling phase) or late (day 21, luminal phase) during infection was similar to that induced by cells from naïve animals. Suppression was CTLA‐4 dependent in Tregs from acute but not chronic infection or in Tregs from naïve animals. This highlights the versatility of Tregs and the importance of extensive Treg characterization prior to potential in vivo manipulation of this cell type.

Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Despite this, it is key to develop models that will provide better translatability to real world situations. Heligmosomoides polygyrus (parasitic roundworm) and Toxoplasma gondii (protozoan parasite) are well studied organisms that stimulate a characteristic Th2 and Th1 response respectively. IFNγ-producing T cells, NK and γδ T cells contribute to early protective immunity during T. gondii infection. To minimise immunopathology, IL-10 is also key to a successful response. Previous research has found H. polygyrus to improve survival during co-infection with both parasites. IFNγ-producing CD4+ and CD8+ T cells were implicated in this protection. Using a similar approach, we have found the opposite. Our co-infected animals displayed greater mortality and intestinal pathology than either single infection. This was associated with an early increase in Th2 cytokines in the Peyers patches, mesenteric lymph nodes and spleen. Co-infected animals also had reduced IFNγ producing cells at day 5 post T. gondii infection in the Peyers patches (CD8 T cells only) and in the MLN (NK, NKT, γδ T, CD4+ T and CD8+ T cells). This correlated with increased parasite loads in the MLN at 10 days post T. gondii infection. Our results demonstrate that co-infection dynamics can vary dramatically and that careful consideration needs to be taken when interpreting data in each situation.

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.

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