Researchers Find Important Pathway in Viral Infections

By Robert Silverman, PhD

Viruses are a significant cause of life-threatening diseases worldwide. However, despite considerable advances over the past two decades, development of antiviral drugs has lagged behind other types of anti-infective agents such as antibiotics used to treat bacterial infection.

The body recognizes and mounts a rapid response to invading microbes, including viruses, through the innate immune system. Serious viral infections can occur when the virus manages to evade the innate immune system.

Understanding how viruses interact with the innate immune system could lead to new therapeutic approaches for combating viral diseases. Therefore, our new research, published in Cell Host & Microbe that helps us understand the innate immune system’s intricate mechanisms could lead to quicker relief and better outcomes for patients with viral infections.

Lessons on viral RNA learned

Through years of research on the innate immune system, we know that viral RNA molecules have properties that differ from RNA in healthy, uninfected cells — and, it is those viral RNA molecules that alert the infected cell to the infection within it. The viral RNA triggers defensive responses in the infected cell, including one response mediated by the RNase L system and another caused by inflammasomes — large protein complexes that process cytokines.

Virus destruction from the first pathway happens when the enzyme RNase L cuts the RNA in the virus-infected cells. In the second pathway, NOD-like receptor proteins (NLRPs) assemble with other proteins into inflammasomes to facilitate the inflammatory response.

Researchers always believed these two pathways functioned independently of each other. But what we have discovered in our most recent research is that they do, in fact, work in tandem: the RNase L system actually activates the inflammasomes. The process happens when the RNase L cuts the RNA. This produces small RNA molecules — and it is those molecules that trigger the activation of inflammasomes.

A look at our study’s design

To learn more about the effect of RNase L on the immune response, we infected two types of mice models with mouse-adapted influenza A virus: wild type and those with a deletion of RNase L. Fifteen days after the infection, 80 percent of the wild-type mice had survived compared to only 34 percent of those missing RNase L.

In addition, we measured the levels of interleukin-1 beta (IL-ß) — an important proinflammatory cytokine in fighting off the invader — – in the lung tissue and brochoaveolar lavage fluid (BALF) of the mice. The RNase L-deleted mice had 90 percent less IL-1ß in the lungs and 75 percent less in the BALF than their wild-type counterparts. The evidence suggested that the improved survival in the wild-type animals was at least partly due to increased inflammasome activity resulting in more IL-1ß. This suggests that if we could find a way to create this type of response in people fighting viruses, we could improve their recovery.

Our team then conducted a series of detailed experiments that broke down every step to follow the process through to understanding the exact role of RNase L in inflammasome assembly and activation.

Findings and what lies ahead

We discovered and validated that the nuclease function of RNase L leads to cleaved RNA products that interact with the protein DHX33. In turn, DHX33 signals and stimulates the NLRP3 inflammasome. This then increases the secretion of IL-1ß, which ultimately contributes to animal survival.

In further research, we hope to discover if this process works the same way for viruses other than influenza A and, ultimately, how it could be manipulated for therapeutic benefits to humans.