H1N1 Influenza A Virus Protein NS2 Inhibits Innate Immune Response by Targeting IRF7

Abstract

Influenza A virus (IAV) is a globally distributed zoonotic pathogen and causes a highly infectious respiratory disease with high morbidity and mortality in humans and animals. IAV has evolved various strategies to counteract the innate immune response, using different viral proteins. However, the mechanisms are not fully elucidated. In this study, we demonstrated that the nonstructural protein 2 (NS2) of H1N1 IAV negatively regulate the induction of type-I interferon. Co-immunoprecipitation experiments revealed that NS2 specifically interacts with interferon regulatory factor 7 (IRF7). NS2 blocks the nuclear translocation of IRF7 by inhibiting the formation of IRF7 dimers, thereby prevents the activation of IRF7 and inhibits the production of interferon-beta. Taken together, these findings revealed a novel mechanism by which the NS2 of H1N1 IAV inhibits IRF7-mediated type-I interferon production.

A single-cell atlas of the peripheral immune response in patients with influenza A virus infection

“…Among these, IRF7 is a major regulator of type I IFN-dependent immune responses, while STAT1 is the major mediator of the cellular response to IFNs. 17 , 18 , 19 Notably, the mRNA expression levels of IRF7 and STAT1 were higher in neutrophils_ISG15 cells from adult cases than those from healthy individuals ( Figure 6 E), suggesting that IRF7 and STAT1 are critical for neutrophils_ISG15 cell activation upon IAV infection. Furthermore, we predicted 5 TFs - RFX5, RFX4, ZNF782, and RELB - that appear to affect IAV infection-associated transcriptomic changes in neutrophils_ISG15 cells in pregnant individuals ( Figure 6 E).…”

Roles and functions of IAV proteins in host immune evasion

“…Furthermore, the indispensable domain in NS2 was determined based on its interaction with IRF7. Amino acid residues 1-53 in the N-terminal domain were found to be responsible for interacting with IRF7, while amino acid residues 54-121 in the C-terminal domain did not interact with IRF7; hence, amino acid residues 1-53 in the N-terminal domain of NS2 are responsible for inhibiting IFN-I production ( 12 ).…”

“…Several NSPs have been discovered, including PA-X, PB1-N40, PA-N155, PA-N182, and M42 NS3, whose roles in host immune evasion need to be determined ( 92 – 96 ). Additionally, some gaps also exist in the existing research, e.g., NS2 interacts with both IRF3 and IRF7 and inhibits the nuclear translocation of IRF7 ( 12 ); however, the mechanism of IRF3 nuclear translocation still needs to be determined. Similarly, the PB1-F2 protein colocalizes with MAVS to inhibit IFN induction ( 48 ); however, the physical interaction between PB1-F2 and MAVS still needs to be evaluated.…”

“…Influenza A virus (IAV) is a serious risk to both animals and humans because it causes annual seasonal epidemics and has resulted in severe pandemic outbreaks ( 11 , 12 ). A novel IAV strain can be generated after the coinfection of a host with two or more different viruses followed by a reassortment process, after which, the strain expresses new combinations of HA and NA subtypes; therefore, IAVs are subtyped by the antigenic characteristics of their HA and NA glycoproteins ( 13 ).…”

“…Interferons (IFNs) are the first line of host defense against invading viruses. The innate immune response is activated by the recognition of viral pathogen-associated molecular patterns (PAMPs) by retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) ( 12 ) ( Figure 1 ). After activation, RIG-I and MDA5 interact with mitochondrial antiviral signaling protein (MAVS) and eventually activate MAVS.…”