Transcriptional Profiling of the Rabbit Liver Infected With Eimeria stiedae Reveals Dynamic Host Cell Responses During the Induction and Resolution of Cholangitis

Abstract

Eimeria stiedae is one of the few eukaryotic pathogens that exclusively infect the liver and serves as a good model to study the host–pathogen interactions in this vital organ. In this study, we show that rabbits infected with E. stiedae develop severe but self-healing cholangitis. RNA-seq analysis of the liver gene expression landscapes over the long course of E. stiedae infection identified 912 differentially expressed genes (DEGs) in the prepatent period (794 up- and 118 downregulated genes), 2889 DEGs in the early oocyst shedding period (1870 up- and 1019 downregulated genes), 2859 DEGs in the peak oocyst shedding period (1923 up- and 936 downregulated genes), and 327 DEGs in the recovery period (164 up- and 163 downregulated genes). Combined with pathological observations, we identified dynamic changes in host–parasite interactions involving multiple pathways. They showed that E. stiedae infection induced full-blown inflammatory, Th1 and Th17 immune responses at all time points. This was associated with the strong innate immune responses during the prepatent period, including increased Toll-like and NOD-like receptor signaling. Despite mounting several damage control and repair responses, such as PI3K-Akt signaling, Ras signaling, and extracellular matrix-receptor interactions, the liver underwent severe metabolic dysfunction, oxidative damage, and coagulopathy after patency and at peak infection, possibly as a result of suppressed peroxisome activities and downregulated PPAR signaling. These responses largely disappeared during late infection, suggesting that the liver self-heals after severe cholangitis. These data provide new insights into host–pathogen interactions during Eimeria infection and improve our understanding of the pathogenesis of parasitic cholangitis.