Studying innate immunity, the body’s first line of defense
December 4, 2024 – Jérémie Le Pen wants to understand the workings of the “innate immune system”—the part of the human immune system that puts up an immediate defense when it encounters a pathogen.
Unlike some other parts of the immune response—such as antibodies, which take time for the body to make—the innate immune system is ready right away to fight any new pathogen. It includes various components, ranging from physical barriers like the skin to antimicrobial molecules naturally produced by cells.
“Even though it’s quite an [evolutionarily] ancient form of immunity—it has many characteristics that are conserved between different organisms, from animals to plants—it’s incredibly important,” said Le Pen, a newly appointed assistant professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health. Previously a research associate at Rockefeller University working under Charles M. Rice, an American virologist and Nobel laureate, he started his position in the Department of Immunology and Infectious Diseases on Dec. 1.
Le Pen conducts basic research focused on uncovering the biological mechanisms of how the innate immune system responds to RNA viruses, which cause diseases such as COVID-19, influenza, West Nile fever, yellow fever, and a host of others.
“What’s fun about this field is that viruses reveal a lot about the biology of their hosts,” he said. “The cell is a beautiful and complex machine, and as biologists, we are reverse engineers trying to understand how it works.”
With this one goal, Le Pen has divided his time between infecting two different hosts with RNA viruses: human cells and a worm known as C. elegans. The small worm species, about one millimeter long—roughly the thickness of a dime—is easy to study in laboratory settings. Consequently, researchers have used C. elegans for decades to investigate fundamental biological processes, leading to many breakthroughs in biology and medicine. “By working with both human cells and C. elegans, you get the best of both worlds,” Le Pen said. “Human cells provide direct relevance for studying genes crucial in combating viral infections. Meanwhile, C. elegans allows for ambitious experiments observing how whole animals—or even entire populations—defend themselves against viruses.”
Over the years, researchers have developed a wide range of genetic tools to study C. elegans. Le Pen uses these tools to modify specific genes in the worm and measure how these changes affect the animal’s response to viral infection—a process that is not as easily accomplished in mouse models or humans. With this method, he has identified genes that are involved in innate immunity in both C. elegans and humans.
Le Pen and his colleagues have further found that certain innate immunity genes significantly influence how people respond to viruses. This finding helps explain why different individuals react differently to infections.
For example, Le Pen has conducted research on the yellow fever virus, a mosquito-borne flavivirus, similar to West Nile, dengue, and Zika viruses. Due to climate change, these diseases pose a greater risk as mosquitoes and ticks that transmit the viruses are spreading to new locations. The vaccine currently used to prevent yellow fever, developed in the 1930s, is based on a weakened version of the virus. While highly effective for most people, the vaccine can cause serious disease in rare cases. To study this vaccine-induced disease, Le Pen and his colleagues analyzed the genome of a patient who developed illness after receiving the yellow fever vaccine. They found that mutations in an innate immunity gene were involved. Because of these mutations, the patient reacted to the vaccine as if it were a virulent virus.
In other studies, Le Pen and his colleagues explored why some young people develop severe COVID-19. By comparing the genomes of patients who experienced severe disease with those who did not, they identified mutations that hindered the innate immune response in some individuals with severe COVID-19, indicating that there is a hereditary component involved.
“We hope that in the future, we’re going to be able to turn this knowledge into medicine that’s personalized to everyone’s needs—instead of what we have at the moment, which is based on the average population most of the time,” he said.
Quick hits
Do you have any pets? My cat’s name is Guinness. [My wife and I] adopted her seven years ago. She’s a very beautiful black cat.
What hobbies do you enjoy? I love sailing—it’s one of my favorite hobbies. I play guitar, jazz specifically.
– Jay Lau
Photo: Brandon Razooky
