New Study Reveals How Respiratory Syncytial Virus Inhibits Human Immune Response

Respiratory syncytial virus (RSV) causes a significant disease burden in the global population, with an estimated 33.1 million cases each year, and is the leading cause of bronchitis and viral pneumonia in infants. It particularly affects children and the elderly, and treatment options are limited and relatively ineffective.

In a new study, researchers from Trinity College Dublin, Ireland, have discovered how the dangerous RSV eliminates our immune response, and in doing so have found an exciting new target for drug developers. The relevant research results were published in the journal Frontiers in Immunology in June 2024, and the paper is titled "Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1".

Using human airway epithelial cells, these authors found that the RSV protein NS1 (RSV-NS1) inhibits a key biological pathway in these cells (called the "JAK/STAT pathway"), preventing key "immune system igniters" from entering the cell nucleus. This immune system igniter, called STAT1, is normally activated by our own natural antiviral, interferon alpha (IFNα).

Expression of RSV-NS1 significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2. Total protein levels of both STAT1 and STAT2 were not affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced the activity of ISRE and GAS promoters and the expression of antiviral IRGs. Further mechanistic studies showed that RSV-NS1 binds to STAT1, and protein modeling revealed a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. In addition, the interaction of STAT1 with the nuclear translocation adaptor protein KPNA1 was also reduced. In fact, reduced entry of STAT1 into the nucleus may be the reason why RSV inhibits IFN JAK/STAT promoter activation and antiviral gene induction.

Figure 1. RSV-NS1 suggested binding to STAT1. (Efstathiou C, et al., 2024)

"IFNα activates signals in our cells through the JAK/STAT pathway that are responsible for turning on hundreds of antiviral genes that then attack the virus in many different ways," Stevenson said. "So when RSV blocks interferon from communicating with these genes, the virus puts the brakes on our immune response, which can cause the virus to take over and quickly cause very serious medical problems."

The findings are an exciting revelation because they identify the JAK/STAT pathway as a prime target for therapeutic immune restoration. This new knowledge is extremely valuable to drug designers, who need to fully understand how the virus evades our immune system before they can successfully develop therapies that turn the tables.

JAK/STAT Signaling Pathway Product Panel

The researchers predict that this type of therapy could have a major impact in treating RSV and even clearing RSV infections, which would be a much-needed solution for children and the elderly, who are very susceptible to this dangerous virus.

Reference

Efstathiou C, et al. Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1. Frontiers in Immunology, 2024, 15: 1395809.