# Nuclear import of malaria RNA rewires splicing in host immune cells

## TL;DR

The malaria parasite uses its RNA to enter host immune cells' nuclei and disrupt RNA splicing, altering immune responses.

## Contribution

Discovery of an RNA-based mechanism by malaria parasites to interfere with host splicing machinery and immune signaling.

## Key findings

- Malaria mRNAs are imported into host nuclei and bind to splicing proteins ACIN1 and PNN.
- This binding disrupts host RNA splicing, leading to altered immune protein expression.
- The mechanism reveals a novel strategy for pathogen manipulation of host immunity.

## 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.

•Plasmodium falciparum delivers three parasitic ETRAMP mRNAs into host monocytes via EVs•Delivered RNAs evade degradation, enter the protected host nucleus, and bind ACIN1/PNN•Host splicing dysregulation causes transcript misprocessing and altered immune response•An extracellular RNA-based mechanism shows how malaria reshapes host immune signaling

Plasmodium falciparum delivers three parasitic ETRAMP mRNAs into host monocytes via EVs

Delivered RNAs evade degradation, enter the protected host nucleus, and bind ACIN1/PNN

Host splicing dysregulation causes transcript misprocessing and altered immune response

An extracellular RNA-based mechanism shows how malaria reshapes host immune signaling

Abou Karam et al. identify a cell communication mechanism used by the malaria parasite Plasmodium falciparum. The parasite delivers its mRNAs into monocytes and imports them into their protected nuclei, where they perturb the splicing. This extracellular RNA-based strategy disrupts host transcript processing and immune signaling, revealing another layer of host interference.