by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology
In Lewis Carroll’s Through the Looking-Glass, Alice finds herself in a perplexing circumstance: she keeps running faster and faster but goes nowhere. The Red Queen remarks, “Here, you see, it takes all the running you can do to keep in the same place.”
This whimsical story gave name to a classic evolutionary idea (posited by famed UChicago biologist Leigh Van Valen) called the Red Queen effect: that organisms must constantly adapt just to survive against other opposing organisms. This evolutionary dynamic arises not only between large, charismatic mammals—say, cheetah vs. gazelle—but also in the molecular realm. A constant “arms race” exists between viruses and their hosts, driving their co-evolution. Thus, although humans have intricate systems to detect and combat pathogens, viruses have equally cunning ways to counter these defenses and fight back.
Michaela Gack, a professor of microbiology at the University of Chicago and last year’s recipient of the prestigious Vilcek Prize, is an expert at unraveling the complex interactions between virus and host. By helping us better understand how viruses evade the immune response, Gack’s research may lay the groundwork for new vaccines and antiviral treatments that help us outpace our viral nemeses.
The first and most important step in defeating microbial invaders: detection. When viruses invade a cell, they often trip cellular alarms that distinguish “self” from “non-self.” The human immune system has two main parts, innate and adaptive. Evolutionarily older, the innate immune system provides a broad defense against bacteria and viruses. Vigilantly scanning for tell-tale features of pathogenic intruders, innate immunity is indispensable for our well-being. Once triggered, this defense system springs into action within hours to eliminate the threat and keep us safe.
One star player in the innate immune response and a recurring protagonist in Gack’s research is RIG-I. Despite its lackluster name, RIG-I proteins are present in nearly every cell of the body, functioning as viral sensors. After latching onto specific viral molecules (specifically, a unique portion of viral RNA), RIG-I undergoes a dramatic transformation: it changes shape, and another cellular protein paints it with specific chemical tags. Thus adorned, RIG-I flashes the alarm for viral invasion. (Indeed, this work, which significantly advanced our understanding of the activation process, earned Gack her PhD degree).
Of course, like any talented thief, successful pathogens have ways to circumvent the cell’s intruder warning system. Dengue virus, which the Gack lab studies along with several other viruses, is particularly adept at evading detection and represents a serious global health threat. Belonging to the same virus family as Zika and the West Nile virus, dengue is spread by mosquitoes. Alarmingly, nearly 400 million cases of dengue infection are reported each year, with about two-thirds of the world’s population at risk. While many people infected with dengue show relatively mild symptoms or none at all, for others, the virus can be life threatening—in fact, its alternative name is “breakbone fever.” Given the urgent need for better vaccines and antiviral treatments, it is critical that we better understand how dengue virus outmaneuvers the immune system.
A 2016 report by Gack and former graduate student, Ying Kai Chan, solves part of this mystery. They discovered that both dengue and West Nile make a protein that prevents RIG-I from raising the alarm.
How? One straightforward possibility—that the viral proteins directly target and destroy RIG-I—didn’t seem to happen. Instead, Chan and Gack found that the virus acts to block an intermediary messenger, the cellular protein that shuttles RIG-I to deliver its warning—operating somewhat like a classic movie villain who cuts the phone cord before the police can be called. By stopping the partner protein from interacting with RIG-I, the virus can remain hidden from the immune system.
Gack’s team took this a step further, testing what would happen if they altered the viral region that alerts the messenger and prevents the “emergency call” from connecting. They showed that the mutant dengue virus could no longer stifle RIG-I but prompted a strong immune response.
Gack’s work, with its valuable insights for future vaccine development, has broader resonance. Dengue virus is far from alone in targeting RIG-I: her additional research revealed that the measles virus and human papillomavirus also have ways to subvert this pathway. Other labs have unmasked even more strategies that Ebola and influenza viruses use to disable RIG-I as well.
Millions of years of evolutionary conflict between virus and host have given rise to an astonishingly complex immune system and elaborate viral evasion tactics. By better understanding both how cells sense pathogens and how viruses elude recognition, we can develop not only more effective antiviral treatments but also new strategies to boost the immune response. As the Red Queen reminds us, “If you want to get somewhere else, you must run at least twice as fast as that!”