ABSTRACT: Intracellular parasites reprogram the host functions for their survival and reproduction. Conversely, the infected host attempts to defend the microbial insult. The extent and relevance of parasite-mediated host response in vivo remains poorly studied. We utilized Eimeria falciformis, an obligate intracellular parasite completing its entire life cycle in the mouse intestinal epithelium, to identify and validate the host determinants of the parasite infection. The most prominent mouse genes induced during the onset of asexual (24 hrs) and sexual (144 hrs) parasite cycle include IFNg-regulated factors, e.g., immunity-related GTPases IRGA6/B6/D/M2/M3, guanylate-binding proteins GBP2/3/5/8, chemokines CxCL9-11 and several enzymes of the kynurenine pathway including indoleamine 2,3-dioxygenase 1 (IDO1). These results indicated a multifarious innate defense (tryptophan catabolism, IRG, GBP, chemokines signaling) mounted by epithelial cells, and a consequential adaptive immune response (chemokines-cytokines signaling, lymphocyte recruitment). A notable increase in the inflammation- and immunity-associated transcripts correlated with the severity of infection and influx of B-cells, T-cells and macrophages to the parasitized tissue. Indeed, parasite growth was enhanced in the animals inhibited for CxCr3, a major chemokine receptor on immune cells. Interestingly, despite a prominent induction, the mouse IRGB6 failed to recognize and disrupt the parasitophorous vacuole in the parasite cultures, implying an immune evasion by E. falciformis. Likewise, the oocyst output was impaired in IFNg-R-/- and IDO1-/- mice, which signifies a subversion of IFNg-signaling by the parasite to promote its growth. In brief, the Eimeria-rodent model shows contrasting roles of IFNg-signaling for parasite development, identifies a retinue of potential host determinants, and epitomizes its efficacy for in vivo parasite-host interaction studies.
