Title : Long term infection with Toxoplasma activates monocytes leading to enhanced susceptibility to colitis
Abstract:
Previous studies have shown that acute Toxoplasma gondii (T. gondii) infection in mice causes microbial dysbiosis and ileitis both of which return to normal condition during chronic infection. There are studies in the field that suggest latent toxoplasmosis play role in the pathogenesis of other diseases characterized by excessive inflammation. However, whether prior toxoplasma infection leaves a lasting effect on mucosal responses or not remained an open question in the field. Using chemically induced colitis model, we found that chronically infected mice showed greater damage in the colon following treatment with DSS. Infected mice also showed blunted wound healing response in the colonic mucosa due to defect in stem cell regeneration. Given that acute T. gondii infection results in microbial dysbiosis in the gut, we investigated whether changes in the microbiota also occur during chronic infection and following DSS treatment. Our data suggest that differences in the microbiota composition do not play a major role in the increased severity of DSS treatment in chronically T. gondii–infected mice. Enhanced susceptibility to DSS was also not related to changes in regulatory T cells that were unaltered in chronically infected mice. Rather, chronically infected mice showed persistently higher levels of IFN-γ in CD4+ and CD8+ T cells and systemic activation of inflammatory monocytes that migrate to the site of the infection and produce inflammatory cytokines. We found that enhanced tissue damage was attributable to pathogenic inflammatory monocytes that emerge from bone marrow in pre-activated form and release inflammatory mediators like nitric oxide upon reaching the inflamed tissue sites. We further observed that blocking recruitment of monocyte or using Nos2-/- mice which lack inducible nitric oxide synthase, protected chronically infected mice from DSS associated intestinal damage. Although heightened innate immunity provides protection to the host, but our study demonstrate that such immune responses are not always beneficial and may have detrimental effect as in our study we found pre-activated monocytes to be responsible for increased tissue damage in response to DSS. Together, our work uncovers the pathogenic role for inflammatory monocytes in an acute experimental colitis model that is further exacerbated in chronically T. gondii–infected mice that may increase the risk of severe outcome to environmental irritants, underlying genetic susceptibilities, or other enteric infections that are implicated in intestinal diseases such as sepsis, celiac disease, and autoimmunity.
What will audience learn from your presentation?
- The audience will learn the disadvantage associated with enhanced trained immunity.
- Our study can be used further in other infectious model to study the consequence of prior chronic infection to secondary insult.
