Targeted disruption of influenza A virus hemagglutinin in genetically modified mice reduces viral replication and improves disease outcome.

Song Wang,Zhou Yang,Jing Zhang,Ji-Long Chen,Xiaojuan Chi,Chao Chen

doi:10.1038/srep23746

Abstract

Influenza A virus can cause acute respiratory infection in animals and humans around the globe, and is still a major threat to animal husbandry and public health. Due to antigenic drift and antigenic shift of the virus, development of novel anti-influenza strategies has become an urgent task. Here we generated transgenic (TG) mice stably expressing a short-hairpin RNA specifically targeting hemagglutinin (HA) of influenza A virus, and investigated the susceptibility of the mice to influenza virus infection. We found that HA expression was dramatically disrupted in TG mice infected with WSN or PR8 virus. Importantly, the animals showed reduced virus production in lungs, slower weight loss, attenuated acute organ injury and consequently increased survival rates as compared to wild type (WT) mice after the viral infection. Moreover, TG mice exhibited a normal level of white blood cells following the virus infection, whereas the number of these cells was significantly decreased in WT mice with same challenge. Together, these experiments demonstrate that the TG mice are less permissive for influenza virus replication, and suggest that shRNA-based efficient disruption of viral gene expression in animals may be a useful strategy for prevention and control of a viral zoonosis.

Highlights

Influenza viruses are negative-sense, single-stranded, segmented RNA viruses, and can be categorized into three types: A, B, and C1
We found that viral NP expression was clearly reduced in A549 cells expressing HA-specific short hairpin RNA (shRNA) when they were infected with low multiplicity of infection (MOI) of the virus, while NP levels were only slightly decreased when infected with high virus MOI (Fig. S1 and Fig. 1a)
Previous studies have shown that shRNA expressed in transgenic chickens can function as a decoy, inhibit influenza virus polymerase and interfere with virus propagation[38]

Summary

Introduction

Influenza viruses are negative-sense, single-stranded, segmented RNA viruses, and can be categorized into three types: A, B, and C1. Antibodies produced to influenza A virus as a result of infection or vaccination with earlier strains may not be protective against viruses circulating in later years. These necessitate frequent updating of influenza vaccine components to ensure that the vaccine is matched to circulating viruses. There is compelling evidence indicating that RNAi is critical in curtailing influenza virus infection, which implies a promising approach to treat infection by influenza A virus[28,29] This approach has currently limited applications because it can not create a long-term silence of viral genes in vivo[30]

Methods

Results

Conclusion