'Backup alarm system' gives the body another way to fight infections

Herpes simplex virus

The innate immune system is the body’s first line of defense against infection. Its job is to detect bacteria and viruses and begin taking general steps to fight back, like triggering inflammation and recruiting immune cells to ward off the invaders. Sometimes this is enough to clear an infection. When it's not, the innate immune system can activate the adaptive immune system we develop over our lifetimes (sometimes with the help of vaccines) to fight off specific pathogens like the flu or measles.

For years, scientists thought the innate immune system primarily responded to foreign bodies, molecules derived from bacteria or viruses that pose a threat. But in a recent study, UChicago virologist Michaela Gack and her team show that sometimes the innate immune system responds to the body’s own molecules following a pathogen attack, revealing a kind of backup alarm system that could lead to new tactics for fighting viruses.

When a virus infects a host, it often hijacks the machinery of cells to make the proteins it needs to function and reproduce. Herpesvirus, for instance, shuts off up to 80 percent of the host’s protein production once it infects a cell. This radical takeover lets the virus do its own thing, but it can have a downside for the virus, too.

In the new study, published in Nature Immunology, Gack and her team showed that viruses like herpes simplex virus can unwittingly trigger an innate immune response with this overzealous assault. Cells have sensors that detect viral infections. One of these sensors, called RIG-I, usually detects viral RNA and alarms the host’s immune system. But when the researchers infected cells with two different herpesviruses, RIG-I reacted to some of the host’s own RNA molecules, not virus-derived ones, and triggered an immune response.

Normally, the innate immune system wouldn’t react to its own RNA, but when it is unmasked by the virus that’s a sign that there is something bad going on.

The same thing happened when they infected cells with an influenza virus.

“We always thought it had to be molecules from the virus that triggered an antiviral response, because if the immune system recognized the host’s own RNA, this may have bad consequences and potentially lead to autoimmune diseases,” Gack said. “But we were always a bit puzzled by this concept because viral RNA has many of the same molecular features as some of our own RNAs. Until now though, it has never been shown that they can also trigger this alarm system to fight off viral pathogens.”

The reason this happens may be collateral damage from the virus shutting off so many proteins in the cell. Normally, the host RNA molecules that triggered the immune response, called 5S ribosomal RNA pseudogene transcripts, are primarily found in the nucleus of the cell. Once in the cytoplasm surrounding the nucleus, they are tightly packaged with a bunch of proteins.

Herpesvirus and influenza virus disrupt the membrane of the nucleus and allow these host RNAs to float into the cytoplasm, where the RIG-I sensors are present. By shutting down the infected cell’s protein production, the viruses unmask these host RNA molecules and lay them bare, allowing them to be recognized by the innate immune system’s surveillance machinery.

It’s like a security system for a building with backup systems to detect different types of break-ins. A savvy burglar might cut the power to the main alarm and get inside, but the loss of power triggers a second, delayed alert to call the police and catches them in the act.

Understanding how the host’s own RNA can trigger immune responses could help design new treatments, like triggering antiviral immunity by turning down production of the proteins that normally bind to these host immunostimulatory RNAs, simulating what the virus does. Gack and her colleagues are continuing studies on other viruses, to see if they trigger the same, unexpected innate response.

“We don’t know yet how broad this mechanism of innate immune activation is. We think that the immune system has evolved a way to detect the presence of a virus inside the cell by sensing the disruption of key cellular processes by the virus,” she said. “Normally, the innate immune system wouldn’t react to its own RNA, but when it is unmasked by the virus that’s a sign that there is something bad going on.”

 


 

The study, “Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity,” was published Nov. 27, 2017. Additional authors include Jessica Chiang from Harvard Medical School; Konstantin Sparrer and Michiel van Gent from the University of Chicago; Charlotte Lässig and Karl-Peter Hopfner from Ludwig-Maximilians-Universität München, Germany; and Teng Huang and Nikolaus Osterrieder from Freie Universität Berlin, Germany.

Michaela Gack, PhD

Michaela Gack, PhD

Michaela Gack, PhD, is an associate professor in the Department of Microbiology and the Committee on Microbiology at the University of Chicago. Her research focuses on understanding how viruses interact with the immune system and how that impacts infection and disease.

Read more about Prof. Gack