# Protection from malaria infection using liver-targeted siRNA

## TL;DR

Scientists used RNAi to target CD81 in the liver, preventing malaria parasites from infecting the liver and thus stopping the disease before it reaches the blood.

## Contribution

A liver-targeted siRNA approach is introduced to block CD81 and prevent malaria infection in both mouse and human liver models.

## Key findings

- CD81-targeted siRNA efficiently silenced CD81 in mouse and human liver cells in vivo.
- Liver CD81 knockdown blocked malaria parasite infection and prevented blood stage disease in mice.
- The approach reduced P. falciparum infection in human liver-chimeric mice.

## Abstract

Malaria-causing Plasmodium parasites infect the liver and undergo obligate and asymptomatic replication in hepatocytes prior to infection of the blood. As such, preventing liver infection will prevent blood infection, thereby prevent malaria disease, and the spread of parasites by mosquitoes. The tetraspanin CD81 is expressed on the hepatocyte plasma membrane and is a critical entry receptor for sporozoites of the major human parasite Plasmodium falciparum. Yet, the importance of this molecule has not been effectively exploited for malaria prevention. RNA interference (RNAi) is a clinically proven technology for the silencing of human disease-related genes and may thus represent a promising avenue for malaria prevention. Here, we report the application of CD81-targeted, N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) to efficiently silence both mouse and human hepatic CD81 in vivo. Using a mouse model of malaria, we show that CD81 GalNAc-siRNA blocked parasite liver infection in a dose-dependent manner and prevented the onset of blood stage infection. We further provide evidence that this approach reduced P. falciparum infection using human liver-chimeric mice. The data suggest siRNA as a promising host-based approach to prevent malaria infection.

Malaria parasites first infect the liver and then infect red blood cells, which causes disease. Kappe and colleagues use an RNAi approach to target the hepatocyte entry receptor CD81. They show that in vivo liver knockdown of CD81 blocks parasite liver infection, preventing the occurrence of symptomatic blood stage infection.