Type I Interferon remodels intrahepatocytic signaling to promote T cell dysfunction during liver stage Plasmodium infection

Abstract

Abstract Malaria is caused by Plasmodium parasites and accounted for 627,000 deaths in 2021. Upon deposition into the dermis, Plasmodium parasites traffic to, infect, and develop within hepatocytes before egressing to cause symptomatic erythrocytic infection. We recently reported that liver stage Plasmodium replication induces type I Interferon (IFN-I) signaling that compromises anti-malaria T cells. We now show that this IFN-I-mediated, inferior T cell response is mostly limited to hepatic CD8 T cells and is characterized by diminished cytokine production, impaired homeostatic CD8 T cell survival, and the expression of receptors and transcription factors associated with T cell exhaustion. We set out to identify the cells and molecular events involved in the induction of T cell exhaustion during the transient and non-persistent liver stage Plasmodium infection and observed that infected mice lacking IFNAR expression solely on hepatocytes do not generate significant frequencies of exhausted T cells. Furthermore, transcriptomic analyses of hepatocytes isolated during infection indicate that IFN-I signaling coincides with a remodeling of the hepatocyte transcriptome such that antigen processing and presentation, chemokine transcripts and immunoregulatory receptors and soluble factors are upregulated. We hypothesize that IFN-I signaling reshapes the hepatocyte transcriptome to promote an immunosuppressive liver microenvironment that impairs anti-malaria T cells. Together, our studies represent the first description of a negative role for liver stage IFN-I signaling on anti-malaria adaptive immunity and may necessitate a paradigm shift in the rational design of efficacious anti-malaria whole parasite vaccines. Supported by 1U01AI42001