Nuclear import of malaria RNA rewires splicing in host immune cells

Abstract

Eukaryotic pathogens deploy diverse strategies to manipulate host immunity, yet RNA-based virulence mechanisms remain poorly understood. We describe a mechanism by which the malaria parasite Plasmodiumfalciparum governs host immune responses through direct interference with host nuclear RNA processing. Malaria-encoded mRNAs of the early transcribed membrane protein family, exported from infected red blood cells, evade cytoplasmic degradation within host immune cells and are imported into their highly secured nuclei. Inside the nucleus, parasite transcripts bind the host RNA-binding proteins ACIN1 and PNN, key components of the splicing machinery that associate with the exon junction complex. This interaction disrupts host splicing regulation, leading to widespread misprocessing of transcripts and altered expression of proteins involved in immune function. Our findings uncover an RNA-based strategy by which pathogen-derived transcripts exploit the host splicing machinery, reshaping transcript isoform landscapes and immune signaling.

Keywords: ACIN1; CP: microbiology; CP: molecular biology; PNN; cell-cell communication; extracellular RNA; extracellular vesicles; host-pathogen interaction; malaria; splicing; splicing dysregulation.