Our microbiome influences how our immune system functions. Our microbiome has changed as a result of living in highly hygienic industrialized countries. A major change in our microbiome is loss of exposure to helminths (parasitic worms). Prior to the 1940's, helminth colonization was nearly universal and there is strong evidence that this exposure helped to shape our genome. Loss of these previously ubiquitous members of our paleobiome, can have far ranging immunologic effect. Inflammatory bowel disease (IBD) currently afflicts more than one million Americans and many thousands of veterans. The incidence of IBD and other immune-mediated diseases increased dramatically after the 1940's in North America and Europe. These diseases are rare in less developed tropical countries. Veterans that served in Vietnam or were prisoners of war are at lower risk of developing IBD than are other veterans. Moreover, as countries develop economically the incidence of IBD and other immune-mediated diseases increase. Now, IBD is a globally emerging disorder. Although specific genes predispose to IBD, there is strong evidence that a change in environment concurrent with socioeconomic improvement confers risk for developing the disorder. We propose that a change from our historic paleobiome, i.e. the lack of helminth exposure, in developed countries is an important risk factor for developing IBD and other immune-mediated diseases. We and others have shown that colonization with helminths protects mice from immune-mediated colitis, encephalitis, diabetes, and airway disease. These are models of diseases that have emerged within highly industrialized countries. Understanding how helminth exposure decreases immune mediated diseases will guide development of targeted therapy to prevent or treat those diseases. Th17 cells control pro-inflammatory pathological responses, like that of IBD. Recently it has become clear that Th17 cells are heterogeneous. In addition to making IL17, highly pro-inflammatory Th17 cells make IFN?. Other Th17 cells with a regulatory phenotype express FoxP3 or make IL10. Immune mediated disease likely results from dysregulated Th17 plasticity. We discovered that mucosal IL17 production is inhibited by exposure to helminths and that this exposure decreases Th17IFN?+ and increases Th17IL10+ percentages in lamina propria and mesenteric lymph node cell populations. Moreover, we find that helminth exposure alters Treg plasticity and in the absence of T cell Stat6-signaling massively induces a novel Foxp3+IFN?+ population. Our hypothesis is that helminth exposure protects against colitis by altering Th17 and Treg heterogeneity/plasticity. This project will test this hypothesis with 3 specific aims.
Our first aim will explore the mechanisms enabled by helminth exposure that alter Th17 plasticity.
Our second aim will explore the mechanisms enabled by helminth exposure that augment Treg plasticity and the role of newly discovered musculin and TIGIT circuity in helminth-associated Treg function.
Our third aim will explore how helminth-induced changes in Th circuitry increases intestinal epithelial cell resistance to targeted injury. Our research is unique in that we are exploring possible root causes for the emergence of autoimmune and immune-mediated inflammatory disease in modern civilizations. In addition, these studies will provide insight into how helminth-exposed individuals that live or served in less developed countries may respond to immunologic challenges. Furthermore, we are examining in vivo how intestinal organisms alter immune pathways to influence chronic inflammatory diseases like those that afflict veterans.
Inflammatory Bowel Diseases (IBD, including Crohn's disease and ulcerative colitis) are chronic debilitating illnesses. IBD and other immune-mediated diseases emerged as countries industrialized and now afflict over 10% of the population. Many thousands of veterans have IBD. Immune-mediated diseases are rare in less developed countries where parasitic worm (helminth) infection is common. Veterans that were sent to areas with helminths (like Vietnam) have a lower risk for IBD. Data suggest that helminths alter immune responses and inhibit IBD. Helminths were part of our ancient microbiome (paleobiome) and our bodies evolved to expect helminth infection. Loss of that exposure, increases the risk for immune-mediated disease. We propose to study how helminths alter immune responses to inhibit IBD. These mechanistic, hypothesis-driven studies will provide important insight into the circuits exploited by helminths that augment immune regulation, and direction for new therapies that can mimic helminth exposure to treat IBD and other immune-mediated diseases.
| Li, Yue; Guan, Xiaoqun; Liu, Weiren et al. (2018) Helminth-Induced Production of TGF-? and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells. J Immunol 201:2910-2922 |
| Li, Yue; Liu, Weiren; Guan, Xiaqun et al. (2018) STAT6 and Furin Are Successive Triggers for the Production of TGF-? by T Cells. J Immunol 201:2612-2623 |
| Elliott, D E; Weinstock, J V (2017) Nematodes and human therapeutic trials for inflammatory disease. Parasite Immunol 39: |
| Li, Yue; Chen, Hung-Lin; Bannick, Nadine et al. (2015) Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice. J Immunol 194:1011-20 |
| Weinstock, Joel V; Elliott, David E (2014) Helminth infections decrease host susceptibility to immune-mediated diseases. J Immunol 193:3239-47 |
