TLR2-FADS1-cPLA2-arachidonic acid axis drives necroptosis to restrict zoonotic Cryptosporidium parvum infection and mitigate intestinal injury
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Cryptosporidiosis is a globally prevalent diarrheal disease caused by Cryptosporidium parvum (C. parvum), yet effective therapies remain lacking. Here, we uncover a host-protective mechanism wherein C. parvum infection activated necroptosis via the TLR2-FADS1-cPLA2-arachidonic acid axis to limit parasitic proliferation and intestinal pathology. Through integrated transcriptomic and metabolomic analyses of infected suckling mouse ileum, we demonstrated that C. parvum induced necroptosis and disrupted AA metabolism. Mechanistically, TLR2 sensing of C. parvum drived FADS1/cPLA2-dependent AA release, which amplified necroptosis. Pharmacological or genetic inhibition of necroptosis (Nec-1, MLKL-/- mice) exacerbated infection burden and tissue damage, while AA supplementation intensified anti-parasitic necroptosis. Strikingly, P-MLKL translocated to C. parvum parasitophorous vacuoles (CpPVM), suggesting direct targeting of the pathogen. Necroptosis not only restricted parasite load but also orchestrated macrophage recruitment and pro-inflammatory cytokines production to bolster mucosal defense. Our findings identified AA metabolism as a druggable hub governing infection-triggered necroptosis, offering novel therapeutic strategies against cryptosporidiosis.
