The Central Role of Non-Structural Protein 1 (NS1) in Influenza Biology and Infection

Abstract

Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae family and have a negative sense eight-segment single-stranded RNA genome that encodes 11 different proteins. The only control over influenza seasonal epidemic outbreaks around the world are vaccines, annually updated according to viral strains in circulation, but, because of high rates of mutation and recurrent genetic assortment, new viral strains of influenza are constantly emerging, increasing the likelihood of pandemics. Vaccination effectiveness is limited, calling for new preventive and therapeutic approaches and a better understanding of the virus–host interactions. In particular, grasping the role of influenza non-structural protein 1 (NS1) and related known interactions in the host cell is pivotal to better understand the mechanisms of virus infection and replication, and thus propose more effective antiviral approaches. In this review, we assess the structure of NS1, its dynamics, and multiple functions and interactions, to highlight the central role of this protein in viral biology and its potential use as an effective therapeutic target to tackle seasonal and pandemic influenza.

Dual R108K and G189D Mutations in the NS1 Protein of A/H1N1 Influenza Virus Counteract Host Innate Immune Responses

“…The NS1 protein, which weakens the IFN response through a variety of mechanisms during influenza virus infection, is the most important IFN-antagonistic protein encoded by the virus [ 19 ]. The protein is highly expressed in the cytoplasm and nucleus of infected cells and can interact with different components involved in the IFN response [ 20 ]. During influenza virus infection, the host cell initiates a cascade of antiviral signals through pattern recognition receptor (PRR)-mediated recognition of pathogen-related molecular patterns (PAMPs).…”

The Crossroads between Host Copper Metabolism and Influenza Infection

“…Data on various aspects of the lifecycle of the influenza virus (the morphology of the IAV virion, structure and function of viral proteins, infection factors and factors limiting IAV infection, implementation of the viral genome strategy, as well as the effect of the virus on host cells and the whole organism) are considered in modern reviews [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Here, the details of influenza virus biology, specifically the IAV replication cycle, are reviewed in relation to cellular copper metabolism.…”

RNA-Targeted Therapies and High-Throughput Screening Methods

“…However, further research needs to be undertaken to evaluate their efficacy, bioavailability and safety before entering the clinical studies. Beyond these three examples, therapies targeting viral RNAs [187,188], RNA cleavage through RNase recruitment [189,190], mRNA translation by inhibiting eukaryotic translation initiation factors [191], as well as premature translational termination caused by nonsense mutations [192], are being developed. With respect to the huge number of RNA-targeted therapies in preclinical studies and clinical trials, it is apparent that these therapies will form a key part of personalised, precision medicine in the future.…”