Influenza A virus (IAV) is an enveloped, negative-sense single-stranded, segmented RNA virus in the family Orthomyxoviridae, which circulates in animals in nature, including birds, pigs, bats, dogs and cats, marine mammals and humans [1–3]. As a zoonotic pathogen, IAV allows for interspecies transmission, reassortment events, and the emergence of novel pandemics, as was documented by the presence of a novel swine-origin IAV (H1N1) in 2009 [4]. While these viruses affect animal health, including livestock and domestic poultry, they also pose a persistent threat to global human health, with the potential to cause severe illness and life-threatening complications in high-risk groups.
Although studies on virus-host interactions have predominantly concentrated on protein factors, non-coding RNAs (ncRNAs) have emerged as critical factors participating in viral replication, pathogenesis and host antiviral immune responses, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). LncRNAs are a class of RNA molecules with more than 200 nucleotides, and the understanding of their importance and function has exploded in recent years [5]. Based on their genomic location, most lncRNAs can be categorized into intergenic lncRNAs (lincRNAs), anti-sense lncRNAs, sense lncRNAs, intronic lncRNAs, bi-directional lncRNAs and intronic lncRNAs [6]. It is well known that although they have poor coding potential, lncRNAs can act as signals, decoys, guides, or scaffolds through their primary sequences and higher-order structures [7]. Through direct interaction with DNA, RNA or protein, lncRNAs possess the potential to mediate a variety of biological processes, such as epigenetics, chromatin remodeling, transcription, apoptosis, response to virus and immune response [8].
Recently, accumulating evidence has suggested that host lncRNAs are implicated in regulating the IAV replication or host antiviral pathway. Several lncRNAs are reported to act on viral components to regulate IAV replication directly. LncRNA PAAN promotes the assembly of functional viral RNA-dependent RNA polymerase (RdRp, consists of PB1, PB2, and PA) thereby enhancing the synthesis of virus RNA [9]. By directly interacting with viral PB1, IPAN, an interferon (IFN)-independent lncRNA, stabilizes the PB1 protein, which in turn enhances the efficiency of viral RNA synthesis [10]. Lnc45, as a broad-spectrum antiviral factor, hampers IAV replication probably by inhibiting polymerase activity and impeding the nuclear accumulation of NP and PA via its stem ring arms [11]. However, more lncRNAs modulate IAV infection by regulating intracellular signaling and gene expression. For example, lncRNA-155, which is derived from MIR155HG, promotes innate immune responses to IAV infection by regulating the expression of protein tyrosine phosphatase 1B (PTP1B) in infected cells [12]. By acting as a molecular scaffold, lnczc3h7a facilitates tripartite motif-containing protein 25 (TRIM25)-mediated K63-linked ubiquitination of RIG-I, which supports a more potent innate immune response against RNA virus, including IAV [13]. Lnc-Cxcl2 restrains IAV-induced lung inflammation by binding to the Cxcl2 promoter and maintaining its repressed chromatin state in cis [14]. By directly interacting with the glutamate-oxaloacetate transaminase (GOT2), lncRNA ACOD1 effectively promotes GOT2 catalytic activity and the production of its metabolites, thereby facilitating the replication of IAV [15]. Of note, although IAV triggers a large number of differentially expressed lncRNAs in host cells, only a limited number of studies have substantiated their roles in the interplay between IAV and host. Hence, the specific role of numerous host lncRNAs in the progression of IAV infection still needs to be clarified.
A previous study has shown that LINC01197 (ENST00000508732) is significantly induced by hepatitis C virus (HCV) infection [16]. However, the expression of LINC01197 in response to different viruses, its effect on viral replication, and the detailed molecular mechanisms are yet to be elucidated. In this study, we have demonstrated that LINC01197 is an IAV-induced lncRNA controlled by the NF-κB pathway in A549 cells. LINC01197 exerts a significant inhibitory effect on the replication of IAV. Further mechanistic studies reveal that LINC01197 interacts with Poly(A) Binding Protein Cytoplasmic 1 (PABPC1) and competes with viral mRNA for PABPC1 binding, leading to the reduction of IAV replication. Collectively, the findings indicate that LINC01197 functions as an inducible antiviral host factor by acting as a protein decoy for PABPC1.