Host–pathogen scientist studies viruses that exploit immune defenses to drive infection

Viruses are microscopic invaders that employ many tricks to sneak past your immune system defenses and into your cells, causing havoc and destruction. One particular group of these invaders that pose a significant threat to human health are called “enteroviruses”, or viruses that cause illness by infecting your digestive tract. You’re likely familiar with Hand, Foot, and Mouth disease, a contagious illness caused by an enterovirus named coxsackievirus A16 (CA16). This disease is common among young children and associated with fever, skin rashes, and mouth ulcers. In addition to CA16, there are many other enteroviruses capable of causing serious illness in humans. One of these viruses being studied by scientists here at CU Anschutz is coxsackievirus B3, or CVB3. Although it is generally less well-known by the public and is reported less frequently compared to CA16, CVB3 can still cause severe disease and remains a significant public health concern. Understanding how CVB3 operates helps researchers build a more complete picture of viral infections and could inform strategies to prevent and treat a range of illnesses.

Dr. Marijke Keestra-Gounder studies Coxsackievirus B3 (CVB3) and how it gains access to your digestive tract

Coxsackievirus B3 (CVB3) is a common, highly contagious virus that infects the intestines of humans and causes symptoms such as fever, fatigue, muscle spasms, and gastrointestinal distress. CVB3 can spread from your intestines to other areas of your body, such as the heart, brain, and pancreas, where it can cause serious illness. How CVB3 spreads to these other organs, however, is poorly understood. Studying how this pathogen spreads could lead to treatments that prevent it from escaping the intestines and causing further harm in other areas of your body.

While there is still much more to learn about how CVB3 causes infection in humans, there are currently roadblocks that complicate the study of CVB3 and how it leads to illness in humans. While mouse models are commonly used to study this virus, healthy mice are resistant to CVB3 intestinal infections. To successfully infect mice with CVB3 and study the disease, researchers must expose a different body site to the virus, known as the intraperitoneal cavity, the space in the abdomen that holds our internal organs. This bypasses the natural route of infection, which originates in the intestines, and leaves us with many unanswered questions about how CVB3 starts an infection in the intestines.

Marijke and her team are turning to our bodies’ defense systems for answers 

The cells in your body have natural alarm systems to detect microbes called “pattern recognition receptors”, which act as motion detectors that sit on the surface of your cells and detect “intruders”, such as bacteria or viruses that are not ‘self’ components in the human body. When these receptors are triggered, they send signals through your immune cells to awaken them and prepare them to kill these foreign intruders. While pattern recognition receptors (PRRs) are important in keeping us healthy and preventing infections by viruses and bacteria, the Keestra-Gounder lab has found that two of these receptors, named NOD1 and NOD2, contribute to worse disease when it comes to CVB3. Marijke and her team believe that this virus is somehow exploiting these receptors in order to spread infection, but how CVB3 changes the function of these receptors for its own benefit is unknown.

How are Marijke and her team studying the roles of NOD1 and NOD2 in CVB3 infection?

The Keestra-Gounder lab has a variety of tools to study the function of NOD1 and NOD2 during CVB3 infection. One tool is the use of cultured human intestinal cells, which have the NOD1 and NOD2 genes removed, allowing them to understand how losing these receptors changes the course of disease in the intestinal environment. Another research tool is mice that lack these receptors. Studying these mice allows the lab to analyze differences in CVB3 infection by comparing mice with and without these (NOD1 and NOD2) receptors present. 

What has the Keestra-Gounder lab discovered about CVB3 so far?

Marijke and her team have found that CVB3 cannot infect intestinal cells that are missing either the NOD1 or NOD2 receptor, suggesting that both receptors play a role in promoting infection. Interestingly, their current studies suggest that each receptor plays a different role in worsening CVB3 infection.

The Keestra-Gounder lab has shown that NOD2 is activated when it senses friendly bacteria living in your intestines, known as the “gut microbiota”. This activation of NOD2 can cause your cells to eat up damaged mitochondria inside of themselves, a process called “mitophagy”, which is a normal function of healthy human cells. Mitochondria, what you might think of as the “powerhouse of the cell”, also play a role in fighting off viruses by serving as a “relay station” for antiviral signaling. MDA5 is a sensor in the cytoplasm, or the fluid-filled space within our cells. When MDA5 detects viral genetic material within the cell, it functionally connects with mitochondria to send a ‘viral intruder’ alarm signal to alert the immune system. This alarm helps trigger antiviral defenses, allowing the body to respond quickly and limit infection. Marijke’s lab believes that this NOD2-activated process of mitophagy cuts off the connection between MDA5 and the mitochondria, preventing these important antiviral systems from being activated.

While the role of NOD1 in CVB3 infection has been less extensively studied, current data from Marijke’s lab suggests that NOD1 suppresses important components inside our cells called APOBEC3 proteins, which play a role in stopping the growth and spreading of viruses inside human cells. Further research is needed to understand exactly how NOD1 and NOD2 regulate these separate processes, and how this regulation affects CVB3 infection.

What are the implications of this research beyond the lab and out in the real world?

Studying the roles of NOD1 and NOD2 in potentially aiding CVB3 infection will broaden our understanding of how viruses interact with the cells in our bodies. Discovering the ways that viruses sneak past our bodies’ “alarm systems” can help us understand how to build better defenses against viral infections in the future. This research may also uncover the additional functions of NOD1 and NOD2 in health and disease, including diseases that affect the other body sites that CVB3 spreads to, such as myocarditis, pancreatitis, diabetes, and various inflammatory intestinal diseases. 

Future directions for this research…

Future directions for this research…

The Keestra-Gounder lab wants to study other pathogens that commonly infect the human digestive tract, such as Salmonella and Citrobacter, and figure out how NOD1 and NOD2 affect the severity of infections by these pathogens. Answering these research questions has important implications for intestinal health, as these findings could identify new therapeutic targets and improve treatment for common intestinal diseases and the microbes that cause them.

If you want to learn more about the scientist, please head to their official CU profile page