The Influenza NS1 Protein: What Do We Know in Equine Influenza Virus Pathogenesis?

Abstract

Equine influenza virus remains a serious health and potential economic problem throughout most parts of the world, despite intensive vaccination programs in some horse populations. The influenza non-structural protein 1 (NS1) has multiple functions involved in the regulation of several cellular and viral processes during influenza infection. We review the strategies that NS1 uses to facilitate virus replication and inhibit antiviral responses in the host, including sequestering of double-stranded RNA, direct modulation of protein kinase R activity and inhibition of transcription and translation of host antiviral response genes such as type I interferon. Details are provided regarding what it is known about NS1 in equine influenza, especially concerning C-terminal truncation. Further research is needed to determine the role of NS1 in equine influenza infection, which will help to understand the pathophysiology of complicated cases related to cytokine imbalance and secondary bacterial infection, and to investigate new therapeutic and vaccination strategies.

Keywords: equine influenza; interspecies transmission; non-structural protein; pathogenicity.

Figure 1

Predicted amino acid sequence of equine influenza strain A/equine/Uruguay/63 (H3N8) (GenBank accession number: CY032425). The N-terminal RNA-binding domain (residues 1–73) and C-terminal “effector” domain (residues 74–230) are indicated by the shaded bars above the amino acid sequence (red and green, respectively), with vertical lines marking every tenth amino acid. The green and blue text shading indicates the alpha and beta helices, respectively. The asterisk marks the position of the 11-amino-acid truncation seen in many recent equine influenza H3N8 isolates and the PDZ-binding domain (ESEV) is indicated in bold text.

Figure 2

Phylogenetic tree of equine influenza non-structural NS1 proteins. Amino acid sequences of 77 equine influenza virus NS1 proteins were downloaded from the Influenza Research Database and the phylogeny inferred using Phylogeny.fr [40]. Clusters of strains labeled with Roman numerals are described in the text. Outlier strains are individually labeled.

Figure 3

Cartoon representations of NS1 structure. Amino acid changes typically found in Florida sub-lineage viruses are indicated in: (A) the RNA-binding domain in red (amino acid, aa44), blue (aa59) and green (aa71); and (B) the effector domain in red (aa86). Images were created using RasMol for Windows v2.7.5.2 and PDB files 1NS1 (A) and 3DR (B).