In the Immune System’s Trenches, a New Discovery

Molecular bioscientist Curt Horvath reveals previously unknown cellular-level reactions to viral infection. The findings could eventually help fight disease better

By Roger AndersonJanuary 10, 2019

Few everyday scenarios illicit as much trepidation as a nearby sneeze during flu season. Suddenly surrounded by tens of thousands of potentially virus-filled particles, a person’s evolving cellular reaction actually matters far more than the ability to shield one’s face.

“Most people know about the body’s immune system, but not as many understand that every cell has its own immune defenses,” says Curt Horvath, molecular biosciences, who studies the cellular recognition of and response to ribonucleic acid (RNA) viruses, as well as the manner in which viruses employ immune-evasion tactics. “The cell’s defense system acts as an initial barrier and is what prevents us from getting sick from every infectious particle we’re exposed to.”

Horvath and Northwestern graduate student Roli Mandhana recently published a pathbreaking study of RNA viruses in Scientific Reports, in which they identified hundreds of new such viruses induced by infection. RNAs are responsible for the signaling cascades  — the innate immune response — that result in widespread changes to gene expression when a virus is recognized as foreign. RNAs also carry out many biological functions that keep humans healthy, including the coding, decoding, regulation, and expression of genes.

The most widely studied virus-inducible RNAs (viRNAs) encode proteins that mediate virus response; however, the completion of the Human Genome Project in 2003 and technological advances in genome-wide sequencing since have provided researchers with an opportunity to explore viral dynamics further.  

“As we looked more closely, we found a lot of RNAs unable to encode proteins but whose levels change because of a response to infection,” says Horvath, a professor in the Weinberg College of Arts and Sciences as well as coleader of the Membranes, Organelles, and Metabolism Research Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. He is also director of the High Throughput Analysis Laboratory within the Lurie Cancer Center’s Shared Resources. “As our lab and others identify more of these noncoding viRNAs, researchers are finding unexpected functions for them.”

The Horvath lab’s experiments most frequently involve infecting cell cultures with viruses and then monitoring the RNA response with the support of Northwestern’s NUSeq Core Facility, the High Throughput Analysis Laboratory within the Chemistry of Life Processes Institute (CLP), and the University’s Quest High Performance Computing Facility.

High throughput screening is a critical aspect of Horvath’s work because it greatly reduces the time it takes to scan large numbers of cell lines.

“We can now look at every gene in the cell simultaneously through these deep sequencing approaches,” he says. “At Northwestern, we are lucky to have the support of expert core facilities to enable us to easily pursue new and technologically advanced research directions. University investment in state-of-the-art support infrastructure pays dividends to every research area.”

Having identified the novel viRNAs — which the lab refers to as nviRNAs — Horvath set out to screen different viruses, including influenza A and herpes simplex virus 1. The goal was to cast a broad net and determine which nviRNAs were generalizable and which were virus specific.

The recent discoveries build upon prior research by former graduate student Jonathan Freaney, who investigated regulators of antiviral response and found widespread activity well beyond what researchers knew. The latest findings may someday help reveal why some viral infections — like HIV — are adept at evading immune response.

“We still don’t know what role these newly discovered noncoding RNAs play, but we now know that they exist and we can further explore if they are controlling the virus infection or helping the virus to replicate,” says Horvath. “Knowing those answers would introduce the possibility of targeting them for diagnostics or therapeutics.”

As a basic scientist, Horvath will rely on his lab’s latest discoveries to apply for new grants as he continues to help construct a more complete understanding of the total cellular response to virus infection.

“The ability to take these basic research findings and translate them into some diagnostic, therapeutic, or antiviral remedy really relies on our ability to take the next steps and connect our observation to some functional mechanistic consequence during the course of a virus infection,” he says. “We will continue to make these characterizations at the cellular level, but the long-term plan is to work with additional collaborators to explore what is happening in living models.”