By Lindsay Key
In the best, most heart-wrenching action movies, the heroine—faced with a fast approaching enemy army—steps out in front of her comrades, raises her spear and rides headfirst into the danger, sacrificing herself for the greater good of her crew.
In the same way, when invaded by a dangerous pathogen, immune cells in our bodies sacrifice themselves, and—as immunologist Ed Miao, MD, PhD, has observed—sometimes they do it in the most dramatic, explosive way.
Miao joined Duke’s Department of Immunology in the School of Medicine in April 2020, recruited with support from the Duke Endowment to advance faculty recruitment in the sciences. He studies pyroptosis—a type of programmed cell death in which a cell, once compromised by an enemy pathogen, literally blows itself up to prevent the pathogen from spreading in the body.
In his bright window-lined laboratory in Medical Science Research Building (MSRB) III, Miao infects immune cells with bacteria and watches them balloon quickly until they ultimately pop. Other immune cells are quick on the scene to mop up the mess.
Pyroptosis is just one flavor of programmed cell death, but it’s Miao’s favorite. He started studying programmed cell death as a side project while a microbiology graduate student in the joint MD/PhD program at the University of Washington. Although his thesis lab’s main focus was to study how different types of bacteria evolve the ability to invade a human host, over time he became more interested in how the host responded.
“I sort of stepped over the fence,” said Miao. “I started out trying to figure out how the bacteria are winning the game, but now we think more about how the immune cell detects the bacteria.”
Today, Miao’s side project is his main gig. After finishing graduate school, he was a postdoctoral researcher at the Institute for Systems Biology in Seattle, Washington, before becoming a faculty member at the University of North Carolina.
During his eight-year tenure at UNC, he researched how a family of immune system sensory cells known as inflammasomes detect the bacterial pathogens including Salmonella typhimurium and Listeria monocytogenes. He chose those pathogens because of their importance in human health—Salmonella causes diarrhea, fever, and abdominal cramps, and Listeria causes fever and muscle aches and can cause severe infections in people who are elderly or immunocompromised.
As he observed the interaction between the bacterial pathogens and immune cells in the lab dish, he began to realize just how smart the Salmonella and Listeria pathogens were. They were always one step ahead of the immune cells, evading detection and replicating like mad.
But his experiments showed that other types of bacteria—like Chromobacterium violaceum and Burkholderia thailandensis— rarely make it past the inflammasomes. They are armed to the teeth, and they intend to invade our cells and cause infection. But the minute they set foot in the door, they’re sacked by the immune system. Miao decided he wanted to study these unevolved or “dumb” bacteria who live abundantly in the dirt outside our windows but are never successful in invading a human host.
“By studying how the immune system wipes those two out, we might be able to figure out how to program it to detect Salmonella and Listeria too, basically demoting them in the tree of evolution to being more like the dumb bacteria,” said Miao.
Once the body detects that a pathogen has compromised cells, Miao said, the immune system has to decide how to respond, and it’s usually by killing off the infected cells, either by having them explode themselves (pyroptosis), dividing them into little harmless membrane bodies (apoptosis), or deciding to explode themselves as a back-up plan if apoptosis doesn’t work (necroptosis). Necroptosis uses a different signaling pathway than pyroptosis, but both rely on cell explosion. How and why the immune system programs one flavor of death over another is one of the big mysteries remaining in the cell death field, said Miao.
While still at UNC, he began to collaborate with several researchers at Duke, serving as a cell death consultant. Among many collaborations, he worked with Mari Shinohara, PhD, Associate Professor of Immunology to understand how inflammasomes may affect multiple sclerosis. He also consulted with Soman Abraham, PhD, Grace Kerby Distinguished Professor of Pathology, to better understand how inflammasomes and pyroptosis operate in urinary tract infections. He worked with Jorn Coers, PhD, Associate Professor of Molecular Genetics and Microbiology, to study how the inflammasome pathways might be interwoven with the guanylate binding proteins used by the immune system.
When he got the call from Mike Krangel, PhD, chair of the Department of Immunology, inviting him to consider Duke, he was elated. The transition was seamless. Miao and his family — including 10 year old Ella and 8 year old Theo—could stay put in their Carborro, NC home. He was also able to bring six of his graduate students and three postdoctoral fellows from UNC over to Duke with him.
Even the COVID-19 pandemic—which intensified just as he was starting up his lab— hasn’t put a damper on Miao’s research. He goes to campus a few times a week and works from home the rest of the time. Over the summer he took on several new roles outside of work during the pandemic as well—the role of “Dungeon Master” while playing Dungeons and Dragons with his kids, and serving as the neighborhood science teacher.
“I’ve been teaching my kids and one of the neighborhood kids. I give them science lectures throughout the week. I’m actually teaching them about the immune system,” said Miao.
At Duke, he hopes to continue to expand the repertoire of pathogens that he studies, in order to help the immune system learn how to shut them down. In recent years, his lab group has expanded to study viral and fungal pathogens as well, in order to understand the basics of the battle between viruses and human hosts.
“I think that infectious diseases had become something we didn’t worry about as much about, with the advent of sanitation, antibiotics, and modern medicine,” said Miao. “But now, the pandemic reminds us that infectious diseases have killed more people than any other cause in the history of the world.”
“My goal is to understand the basics, to paint a full landscape of knowledge, that someday could inspire new treatments,” said Miao. “That probably will be done by someone else decades down the road. What draws me to this area of science is that it’s a very rich and complex field of study where we have so much still to learn.”