Pyroptosis Drives the Impairment of Colonic Barrier Integrity During Toxoplasma Gondii Chronic Infection.

Abstract

Toxoplasma gondii (T. gondii) impairs gut barrier integrity in hosts, which helps the establishment of long-term infection and is closely associated with disease progression. However, the precise mechanisms remain largely unclear. This study investigated whether pyroptosis, a form of inflammatory programmed cell death, contributes to the impairment of colonic barrier integrity induced by T. gondii chronic infection in mice. We found that the infection resulted in pronounced pathological damage in the colon, characterised by reduced colon length, decreased expression of tight junction proteins, and elevated serum LPS levels. Interestingly, the infection activated the pyroptosis pathway, supported by the higher expression of NLRP3 (NOD-like receptor thermal protein domain associated protein 3), Caspase-1, gasdermin D (GSDMD), GSDMD-N, as well as IL-1β and IL-18. In addition, dimethyl fumarate, an anti-pyroptogenic drug, significantly attenuated the infection-induced pyroptosis and colonic pathology. Notably, macrophages exhibited pyroptosis post T. gondii infection, which was attenuated by DMF treatment. Overall, our results uncover that pyroptosis is vital for the impairments of gut barrier integrity post T. gondii chronic infection.