RNAFLU

EFFECT OF NATURAL VIRAL RNA SEQUENCE VARIATION ON INFLUENZA VIRUS RNA FUNCTION

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 Obiettivo del progetto (Objective)

'Influenza A virus has an amazing ability to rapidly change its properties. We believe that pathogenic properties of an influenza virus could be determined also by differences in influenza virus RNA sequence that do not affect the protein sequence of the virus genome. In other words, sequences that affect structure and/or function of the viral RNA, could themselves contribute to the pathogenic properties of the influenza A virus, as well as its ability to adopt to a new host. All RNAs in a cell are associated with proteins and RNAs are dependent on these interactions to function efficiently. Interactions of RNA with proteins depend on the RNA sequence and secondary structure. The exact RNA sequence is therefore of paramount importance since it affects secondary structure and function and utilisation efficiencies of the viral RNAs. RNA sequence has a direct effect on mRNA splicing, mRNA stability and translation. The exact sequence of the influenza virus RNA should therefore affect the replication efficiency of each virus strain. It is reasonable to speculate that RNA sequence variation itself can affect virus pathogenic properties. The immediate goal of this short, 2-year project is therefore to investigate if naturally occurring RNA sequence variations in various influenza virus isolates with different pathogenic properties affect influenza virus RNA structure and function. The long-term goal with this project, which reaches past this 2-year period applied for here, is to determine if the influenza virus RNA sequence itself, independently of effects on viral protein sequence, affects viral pathogenesis and tropism.'

Introduzione (Teaser)

The influenza virus has an amazing inherent ability to mutate, thereby changing its properties and its pathogenicity. European researchers have discovered that sequence variations in the virus genome alter virus pathogenicity by affecting the function of the virus genome itself.

Descrizione progetto (Article)

Given the ability to cross species barriers, new influenza virus types with different pathogenic properties might arise quickly. It is of paramount importance to quickly identify influenza viruses that are highly pathogenic or are efficiently transmitted between humans in the early stages of an epidemic.

The aim of the EU-funded project 'Effect of natural viral RNA sequence variation on influenza virus RNA function' (RNAFLU) was to investigate if mutations introduced in the influenza virus genome could affect the function of the viral RNA itself, regardless of the effect on the viral proteins. The working hypothesis was that such mutations might indirectly affect the ability of the virus to replicate in human cells, thereby affecting the pathogenic properties of the influenza virus or its ability to adapt to new host species.

In this context, researchers decided to investigate if naturally occurring mutations affected important properties and functions of the viral RNA, such as microRNA (mRNA) structure, splicing, binding to cellular mRNAs and mRNA translation. They found that RNA molecules derived from influenza viruses with different pathogenic properties or with different species tropism had different properties and secondary structure.

Additionally, well conserved binding sites for cellular mRNAs were identified in the influenza virus mRNAs that inhibited virus expression. Processing of the influenza viral mRNAs revealed substantial differences in splicing efficiencies, which might affect the ratio between proteins implicated in virus pathogenicity.

Collectively, RNAFLU results challenge the current perception that variation in influenza virus RNA sequence primarily affects viral proteins. The finding that differences in influenza RNA sequence affected the function of the RNA itself and impacted virus pathogenicity provides novel insight into the mechanisms of influenza virus pathogenicity. This knowledge could be employed for disease transmission control, minimising the chances of a flu pandemic.