Host-Pathogen Interactions in thePlasmodium-Infected Mouse Liver at Spatial and Single-Cell Resolution

Abstract

Upon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The spatial coordination of factors regulating immune responses and metabolic zonation during malaria infection, in the true tissue context, remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA-sequencing (snRNA-seq) over multiple time points during liver infection to delineate transcriptional programs of host-pathogen interactions acrossP. berghei-infected liver tissues. Our data suggest changes in gene expression related to lipid metabolism in response toPlasmodiuminfection in the proximity of infected hepatocytes, such as the modulation of the expression of genes involved in peroxisome proliferator-activated receptor pathway signaling. The data further indicate the presence of inflammatory hotspots with distinct cell type compositions and differential liver inflammation programs along the lobular axis in the malaria-infected tissues. Furthermore, a significant upregulation of genes involved in inflammation is observed in liver tissues of control mice injected with mosquito salivary gland components, which is considerably delayed compared toP. bergheiinfected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regardingin vivostudy design linked to infection, and provides a useful tool for the discovery and validation ofde novointervention strategies aimed at malaria liver stage infection.