Study: Researchers Find New Drug Target to Treat RSV

Scientists from Trinity College Dublin have found a new target for drug developers that could aid immune response among individuals infected with respiratory syncytial virus (RSV). The researchers found that RSV suppresses the JAK/STAT pathway, which prevents immune system igniters that are stimulated by interferon-alpha (IFN) from moving into the nuclei of cells, according to study authors.¹

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RSV accounts for 33.1 million illnesses annually in the global population, resulting in severe outcomes among older adults and individuals with chronic conditions. The RSV genome consists of 10 genes producing 11 proteins, including fusion glycoprotein (F), attachment glycoprotein (G), small hydrophobic protein (SH), nucleoprotein (N), large RNA polymerase (L), phosphoprotein (P), matrix protein (M), and 2 non-structural (NS) proteins, NS1 and NS2. Additionally, the study authors noted that the NS proteins are connected to suppression of the IFN response.²

“Interferon-alpha, which activates signals in our cells through the JAK/STAT pathway, is responsible for kick-starting hundreds of antiviral genes into action, which then target the virus in a number of different ways. So, when RSV prevents interferon from communicating to these genes the virus slams the brakes on our immune response, which can result in the virus taking hold and quite quickly causing very serious medical issues,” said Nigel Stevenson, assistant professor of Virology Immunology in Trinity’s School of Biochemistry and Immunology, in a news release.¹

In the study, the researchers found that RSV-NS1 enhanced IFN-a-induced STAT1 phosphorylation, but it also reduced IFN-a-induced STAT1 nuclear translocation, IFN-stimulated response element (ISRE), and Gamma IFN activation site (GAS) promoter activity, while downstreaming antiviral IFN response genes (IRGs) expression.²

The results showed that RSV-NS1 inhibits IFN-a responses due to blocking STAT1 nuclear translocation. The impaired KPNA1 binding to STAT1 in the company of RSV-NS1 displayed an evolved approach of RSV escaping innate antiviral immunity. However, when controlling the nuclear translocation of STAT1, RSV limits normal anti-viral JAK/STAT signaling, according to study authors.²

“Our discovery is an exciting revelation because it identifies the JAK/STAT pathway as a prime target for therapeutic immune restoration. And this new knowledge is very valuable to drug designers, as they need to fully understand how a virus evades our immune system before they can successfully create a therapeutic to turn the tide,” said Stevenson, in a news release.¹

The study authors noted that the findings further the understanding of respiratory virus immune evasion mechanisms and uncover how RSV-NS1 can target therapeutic intervention.²

“We predict such a therapeutic could make a significant impact in treating RSV and even clear an RSV infection, which would represent a much-needed solution for both children and the elderly, who are very vulnerable to this dangerous virus,” said Stevenson, in a news release.¹

REFERENCES

1. Scientists pinpoint new drug target for RSV. EurekAlert!. News release. July 19, 2024. Accessed August 29, 2024. https://www.eurekalert.org/news-releases/1051947.

2. Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1. Frontiers. News release. June 12, 2024. Accessed August 29, 2024. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1395809/full#hsm.