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The Role of Lnc‐PINK1‐2:5 in Combating Influenza A Infections

Asthma and Allergy Awareness Month

May is Asthma and Allergy Awareness Month, an important time to recognize the challenges faced by individuals with asthma and allergies. Individuals suffering from asthma and respiratory allergies are more susceptible to respiratory viral infections, such as influenza, which could pose a serious risk to respiratory health as well as increasing the potential for complications.

Every year, influenza viruses, predominantly type A and B, account for an estimated 291,000 to 646,000 human deaths. Influenza typically targets the upper respiratory tract but can also lead to primary pneumonia affecting the lower respiratory tract. While vaccination is used as a preventive measure against this highly contagious seasonal illness, treatment options for the disease remains limited. The inherent unpredictability of the influenza virus, caused by antigenic shift and drift coupled with its zoonotic nature, can lead to the evolution of novel viral strains capable of human replication. By understanding the molecular mechanisms underlying the regulation of viral pathogenesis, we can formulate effective control and treatment strategies to better protect vulnerable populations from infection.

New Study Identifies Lnc-PINK-2.5 as a Regulator of Influenza Infection

Long non-coding RNAs (lncRNAs) are RNA molecules with more than 200 nucleotides that do not translate into proteins. lncRNAs have been shown to have critical functional roles in influenza virus replication and dysfunction of lncRNAs has previously been linked to influenza infection, which has led to more in depth examination of lnRNAs as potential therapeutic targets.

In a recent publication, Pushparaj and Colleagues used RNA sequencing to analyze influenza virus‐infected human lung epithelial cells to characterize their lncRNA profiles. The lncRNA Lnc‐PINK1‐2 demonstrated the highest expression in the lungs based on the Noncode database and was chosen for further characterization. In attempts to amplify lnc‐PINK1‐2:1 from human lung epithelial cell cDNA, the authors identified a new transcript that they named lnc‐PINK1‐2:5, which was upregulated during Influenza A infection. The authors utilized lung epithelial cell line A549 and primary human bronchial/tracheal epithelial cells (HBTECs) purchased from Lifeline® Cell Technology to characterize the transcript further to better understand its role during viral infection.

Influenza virus is known to activate type I interferon (IFN) signaling. To assess whether type I IFN affects Lnc‐PINK1‐2:5 expression, A549 cells infected with Influenza A Puerto Rico/8/34 (PR/8) were treated with IFNβ1α at various doses and time points. No induction in the expression levels of Lnc‐PINK1‐2:5 transcript was observed, suggesting that Lnc‐PINK1‐2:5 is not regulated by type I IFN. Using inhibitors for other signalling pathways, the authors determined that IAV‐induced upregulation of Lnc‐PINK1‐2:5 may be regulated by c‐Myc signalling.

Furthermore, in Lnc‐PINK1‐2:5-overexpressing A549 cells infected with PR/8, decreased viral replication as evidenced by a reduction in viral RNA, protein, and titres, was observed. Conversely, CRISPRi-mediated knockdown of Lnc‐PINK1‐2:5 enhanced influenza virus replication. These findings suggest that Lnc‐PINK1‐2:5 acts as an antiviral lncRNA, affecting viral replication.

To elucidate the mechanisms of action of Lnc‐PINK1‐2:5, RNA-seq analysis was conducted to identify genes altered in Lnc‐PINK1‐2:5-overexpressing A549 cells and HBTECs infected with PR/8. Thioredoxin interacting protein (TXNIP), claudin-2 (CLDN2), and dehydrogenase reductase 2 (DHRS2) mRNA levels were found to be upregulated. Because TXNIP has been implicated in activating inflammasomes linked to influenza virus infection, it was selected for further investigation.

TXNIP was knocked down in vector control‐ and lnc‐PINK1‐2:5‐overexpressing cells to determine if lnc‐PINK1‐2:5‐mediated reduction of influenza virus infection is via TXNIP. Knockdown using TXNIP using shRNA reduced TXNIP protein levels by ~70%, which led to an increase in viral protein levels, effectively reversing lnc‐PINK1‐2:5‐mediated effect, while overexpression of TXNIP reduced viral protein and titer levels. These results provide evidence that Lnc‐PINK1‐2:5 exerts its antiviral activity via upregulation of TXNIP, an antiviral factor. Overall, this study identifies a new lncRNA that could be potential therapeutic target to treat influenza infections in the future.

Lifeline Cell Technology Products to Support Respiratory Research

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Have you been using Lifeline cells and/or media in your research? If so, we want to know! Your published study could be featured next on the blog!

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