NS1: A Key Protein in the “Game” Between Influenza A Virus and Host in Innate Immunity

Abstract

Since the influenza pandemic occurred in 1918, people have recognized the perniciousness of this virus. It can cause mild to severe infections in animals and humans worldwide, with extremely high morbidity and mortality. Since the first day of human discovery of it, the “game” between the influenza virus and the host has never stopped. NS1 protein is the key protein of the influenza virus against host innate immunity. The interaction between viruses and organisms is a complex and dynamic process, in which they restrict each other, but retain their own advantages. In this review, we start by introducing the structure and biological characteristics of NS1, and then investigate the factors that affect pathogenicity of influenza which determined by NS1. In order to uncover the importance of NS1, we analyze the interaction of NS1 protein with interferon system in innate immunity and the molecular mechanism of host antagonism to NS1 protein, highlight the unique biological function of NS1 protein in cell cycle.

The Contribution of Viral Proteins to the Synergy of Influenza and Bacterial Co-Infection

“…NA facilitates access to receptors and nutrients for S. pneumoniae , which promotes the development of bacterial infection [ 23 , 138 , 139 ]. NS1 and PB1-F2 affect the regulation of the interferon response, the disruption of the inflammatory response, and/or the manipulation of the processes of autophagy and apoptosis [ 35 , 140 , 141 ]. Other IAV proteins have not yet been shown to play a direct role in the development of bacterial co-infection, but M1 [ 142 ], NP [ 143 , 144 ], and HA [ 119 , 129 ] facilitate the manipulation of apoptosis.…”

“…Non-structural protein 1 (NS1) has many functions and is known as a major viral antagonist of the interferon response [ 274 , 275 , 276 ]. Thus, NS1 represents a very important virulence factor affecting the pathogenesis of influenza disease, as well as viral and bacterial co-infection [ 35 , 141 , 277 ].…”

“…NS1 is a product of alternative splicing of the NS gene, occurring as a homodimer. The monomer is composed of two functional domains, the N-terminal RNA-binding domain (RBD) and the C-terminal effector domain, which are joined by a short inter-domain linker region [ 35 , 141 , 278 ]. Each domain interacts with different cellular factors.…”

“…Subsequently, the RIG-I-mediated signaling pathway induces the expression of interferons [ 283 ]. However, NS1 is capable of inhibiting this pathway in several ways: first, by the direct interaction with E3 ubiquitin ligases TRIM25 [ 166 ] and Riplet [ 167 ], which prevents the activation of the RIG-I receptor; second, indirectly by interaction with host factors through its effector domain at the C-terminus, which leads to the inhibition of IRF3 phosphorylation [ 141 , 174 ] and subsequent inhibition of the type I IFN response mediated by IRF-3, as well as interferon-stimulated genes (ISGs) [ 141 , 175 , 284 ]. These steps result in the prevention of virus detection by host cells [ 166 , 276 , 285 , 286 , 287 ].…”

Uncovering Novel Viral Innate Immune Evasion Strategies: What Has SARS-CoV-2 Taught Us?

“…Influenza NS1, perhaps a prime example of innate immune evasion ( Ji et al, 2021 ), perturbs innate immunity in the following ways: (a) inhibiting the type I interferons through a variety of methods (including but not limited to interacting with the CARD domain of RIG-I) ( Jureka et al, 2015 ), (b) inhibiting the general expression of genes by inhibiting the mRNA export complex ( Satterly et al, 2007 ), and (c) directly interacting with ISGs (such as protein kinase R) to antagonize their effects ( Min et al, 2007 ; Immunoprecipitation, Min et al, 2007 ; Satterly et al, 2007 ; Nuclear Magnetic Resonance, Jureka et al, 2015 ). ZIKV (Zika virus) NS4A interacts with the CARD domain of the mitochondrial antiviral signaling protein (MAVS), thereby interfering with the interaction between MAVS and RIG-I/MDA5, ultimately preventing the expression of type I IFNs ( Ma et al, 2018 ) ( CRISPR screen ).…”