Impairment of anti-Plasmodium T cell memory by type I Interferon Signaling

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PROJECT SUMMARY AND ABSTRACT Annually, liver disease accounts for nearly 2 million deaths worldwide. Immune responses in the liver must balance elimination of local infection with non-reactivity to benign gut-derived dietary and microbial antigens. Excessive/dysregulated immune activation in the absence of infection promotes liver tissue damage while insufficient immunity facilitates the development of chronic infection and hepatocellular carcinoma. Thus, there is an urgent need to pinpoint immunological pathways that can be modified to control hepatic maladies without compromising liver function. Our proposal will utilize malaria liver stage infection as a model system to identify factors that dictate the quality of hepatic CD8 T cell responses. Plasmodium malaria parasites initially infect the liver and replicate as liver stages within hepatocytes to generate exoerythrocytic merozoites that are released to infect red blood cells. Liver stages are essential to establish infection but are clinically silent and were only recently shown to induce a significant innate immune response. We previously demonstrated that Plasmodium infection induced IFN-I signaling weakens anti-Plasmodium adaptive immunity by promoting the development of dysfunctional hepatic CD8 T cells. This dysfunctional signature bears striking similarity to the T cell exhaustion program induced by chronic infection and tumors. Yet, how does a transient, non-chronic infection that is limited to hepatocytes induce such profound T cell dysfunction? We now report that IFN-I signaling solely in hepatocytes is a major contributor to the induction of hepatic CD8 T cell dysfunction suggesting that hepatocytes are central immune platforms that determine the quality of adaptive immunity in the liver. From functional assays and gene expression analyses of hepatocytes enriched from mice infected with rodent malaria parasites or human-liver chimeric mice infected with Plasmodium falciparum, we show that this IFN-I response is initiated by hepatocyte expression of the IRF3 transcription factor. Moreover, we establish that concurrent with IFN-I induction, LS infection profoundly reshapes the hepatocyte transcriptome and metabolome likely inducing an immunosuppressive microenvironment around the infected hepatocyte, which we predict impairs an ensuing hepatic T cell response. In Aim 1, we will use cutting-edge single cell multi-omic studies and functional analyses to identify hallmark features of Plasmodium infection induced CD8 T cell dysfunction to determine whether it is distinct from bonafide T cell exhaustion. In Aim 2, we will focus on hepatocytes to characterize how parasite- induced IFN-I signaling remodels intrahepatocyte transcriptomes and metabolomes to impair hepatic CD8 T cell responses. In Aim 3, we will generate novel transgenic parasites that deliver viral antagonists of IRF3 into the infected hepatocyte to compromise Plasmodium-induced IFN-I signaling solely within the infected hepatocyte and improve anti-Plasmodium adaptive immunity. These aims will broaden and deepen our understanding of the immune responses to a complex eukaryotic pathogen to improve liver-directed anti-malaria vaccines.