Insights into inflammatory bowel disease using Toxoplasma gondii as an infectious trigger

Abstract

Oral infection of certain inbred mouse strains with the protozoan Toxoplasma gondii triggers inflammatory pathology resembling lesions seen during human inflammatory bowel disease, in particular Crohn's disease (CD). Damage triggered by the parasite is largely localized to the distal portion of the small intestine, and as such is one of only a few models for ileal inflammation. This is important because ileal involvement is a characteristic of CD in over two-thirds of patients. The disease induced by Toxoplasma is mediated by Th1 cells and the cytokines tumor necrosis factor-α and interferon-γ. Inflammation is dependent upon IL-23, also identified by genome-wide association studies as a risk factor in CD. Development of lesions is concomitant with emergence of E. coli that display enhanced adhesion to the intestinal epithelium and subepithelial translocation. Furthermore, depletion of gut flora renders mice resistant to Toxoplasma-triggered ileitis. Recent findings suggest complex CCR2-dependent interactions between lamina propria T cells and intraepithelial lymphocytes in fueling proinflammatory pathology in the intestine. The advantage of the Toxoplasma model is that disease develops rapidly (within 7-10 days of infection) and can be induced in immunodeficient mice by adoptive transfer of mucosal T cells from infected donors. We propose that Toxoplasma acts as a trigger setting into motion a series of events culminating in loss of tolerance in the intestine and emergence of pathogenic T cell effectors. The Toxoplasma trigger model is providing new leaps in our understanding of immunity in the intestine.

Figure 1

Toxoplasma-induced immunopathology in the C57BL/6 ileum. (a), Non-infected mouse, showing normal architecture of the intestinal mucosa. (b) Typical ileal lesions occurring 8 days following oral infection of C57BL/6 mice (100 cysts; ME49 parasite strain). Damage is characterized histopathologically by transmural inflammation, sloughing of epithelial tips, fusion of villi and increased necrosis.

Figure 2

Bacteria and Toxoplasma are present in the lamina propria. C57BL/6 strain mice were orally infected and the lamina propria compartment was isolated 8 days later. Neutrophil-like cells containing intracellular bacteria (a) and Toxoplasma tachyzoites (b) are readily identified. Panel c shows a cell containing an intracellular parasite (arrow) and intracellular bacteria (arrowhead).

Figure 3

Model for emergence of intestinal pathology during Toxoplasma infection. (a) At 24–48hr after cyst ingestion invasive parasites cross the small intestinal epithelium to initiate infection in cells such as macrophages and dendritic cells. (b) Dendritic cells recognize and initiate immunity to Toxoplasma. They also respond to intestinal bacteria, possibly as a result of translocation occurring as parasites cross the epithelial barrier. (c) Early inflammation results in recruitment of CD8⁺ T cells into the intraepithelial lymphocyte compartment, detectable 4–5 days after infection. (d) In turn, IEL are involved in recruiting lamina propria CD4⁺ T cells into the intraepithelial compartment. (e) This results in damage to the intestine and bacterial translocation with fulminant Th1-type immunopathology that peaks around 7–9 days post-infection. In ways that are not clear, concurrent with emergence of disease, the intestinal microbiota increases in number and shifts from a predominantly gram-positive population (f) to a gram-negative population with increased adherence characteristics (g).