Detecting the Sensors

Graduate student Jon Hagar is uncovering how our immune systems can overreact to infection and trigger a life-threatening condition.

Jon Hagar/Photo by Mark Derewicz, UNC Health Care
Cells called macrophages explode when bacteria enter them and trigger an immune response through a sequence of events that UNC researchers uncovered. Credit: Jon Hagar and Ine Jørgensen.

The big world of dinosaurs might have inspired Jon Hagar to pursue science, but today he studies the tiniest bits of biology, trying to understand how our organs become collateral damage during battles between our immune system and bacteria that cause infection.

Hagar is a fourth-year graduate student in the lab of Edward Miao, MD, PhD, an associate professor of microbiology and immunology who has spearheaded breakthroughs in our understanding of the underlying causes of sepsis – a whole-body immune reaction to infection that often puts vital organs at risk.

We met with Jon for a student profile about why he chose microbiology and immunology, why he chose UNC and Ed Miao’s lab, and what his research has uncovered.

Name: Jon Hagar

Birthdate: July 6, 1988

Hometown: Canton, MI

Education: University of Michigan, BS, cell and molecular biology; UNC, PhD candidate, microbiology and immunology

Lab goal: to clarify how the immune system detects and clears virulent bacteria

Dissertation: characterization of caspase 11 in host defense against infection.

Mentor: Edward Miao, MD, PhD

Extracurriculars: graduate student business club, weight lifting, fishing, concerts,

History:

“I’ve always been a bit of a science nerd. I remember in first grade I used to spend recess pretending to be a paleontologist. I’d seen Jurassic Park. After that I was pretty much hooked on science. It was just a matter of what field I’d get into. The decision evolved over time.  I was torn between physics and life sciences until college and I decided on cell and molecular biology as a major because, initially, I thought I’d go to medical school. That major included all of the prerequisites for medical school.

“At Michigan, I had a work-study package and got lucky when I got a job in Mary O’Riordan’s lab in microbiology and immunology, studying listeria.

“After graduating, I stayed on in Mary’s lab as a full-time lab technician. At that point, I was torn between going to medical school or graduate school to do research. After some soul searching, I decided on the latter. Mary seemed to know I would be going to graduate school before I did, so she treated my position like it was an introduction to grad school; it was 80 percent research and 20 percent lab management.

“I helped publish two papers while in her lab. The process of writing a scientific paper can be a nightmare but I found it exciting.”

Why UNC?

“It came down to UNC and a handful of other schools.

“All of them were full of fantastic people. But you’ll hear this echoed – I’m sure quite a bit – but it really is true that the PI’s at UNC, especially in the microbiology and immunology department, really do take an interest in developing you as a scientist, not just as a pair of hands. This was really palpable at UNC- more so than elsewhere- during interviews. This interest in our development became really clear later during the 2nd year grant-writing course. The PIs just put in an incredible amount of time giving us feedback, editing our work, and making sure we were turning into capable, stand-alone scientists.

“Also, I loved the area. The cost of living in Chapel Hill is fantastic, especially when you factor in the stipend. That’s a big selling point, to be honest. There’s a lot to do here. And I like college towns.

“Another big plus was the flexibility of having the umbrella program [Biological and Biomedical Science Program]. I was largely sold on microbiology and immunology, but I liked the idea of potentially joining any lab once I got to school. Granted, I did rotate into only microbiology and immunology labs, and I loved all three, but I still liked having the option of going outside of the department.”

Why Edward Miao’s lab?

“Ed and I really got along great during my rotation. He’s a new PI. Some people say it’s risky to join a new PI’s lab. It’s a catch 22. New PI’s know that everything you do as a student is very much tied to their success, so they’re very invested. Their labs are usually small, so students get a lot of interaction. On the negative side, new PI’s generally don’t have a lot of experience with mentoring or running a lab, etc. 

“That small basket of downsides was minimized in Ed’s case because he actually came from a super-lab in Seattle that was a giant consortium of people. Ed was sort of his own boss of a little subunit of the lab. He had actually taken a student through the entire graduate school process and she did great.”

What’s the research focus of the lab?

“The lab focuses on how the immune system responds when bacteria fall out of their proper compartmentalization. You want certain bacteria in the GI tract, and we tolerate them on the skin, etc. But you don’t want them getting into tissues, in blood, or inside our own cells.

“So when they get out of place, our immune systems have many ways to detect what’s happening and can coordinate immune responses to get rid of the bugs.

“We style our research along two themes: how do cell pathways coordinate a proper immune response, and how are these pathways improperly activated during inflammatory diseases or something like sepsis, when you get wholesale activation of the immune response to the point that it’s extremely bad for patients.

“Ultimately, the goal is to identify pathways that are amenable to therapeutic intervention.

“When I first joined the lab, they were onto a story about how Burkholderia infection activates a new inflammasome pathway in mice. Inflammasomes are special proteins within a cell that sense signatures of the cell becoming infected – things like microbial DNA or virulence proteins being where they shouldn’t be. Upon detecting an infection, inflammasomes activate an enzyme called caspase-1 that signals to the rest of the immune system by, quite literally, blowing up the infected cell.

“Now, Burkholderia were causing all of these cells to blow up independently of all known inflammasome proteins, including caspase-1. In fact, the infection was actually activating a cousin of caspase-1 called caspase-11, which had in a sense been hiding behind its relative.

“To our surprise, caspase-11 was the primary way the immune system gets rid of Burkholderia. In a normal mouse, we could put a really large number of bacteria in and the mouse would be fine. However, when we put any amount of bacteria into a mouse without caspase-11, the mouse did not do well at all.

“Figuring this out put the lab on the map. Our first paper was published in Science in 2013 

“Then the big question was: What in particular does caspase-11 recognize in Burkholderia?”

And this became your project?

“Yes. Essentially, I conducted experiments where I boiled the bacteria, ground them into bits, and separated the pieces. We found that the bacterial cell membrane component LPS activated caspase-11.

“LPS is part of a universal detection system. All gram-negative bacteria contain LPS, and many have an LPS structure that can activate caspase-11 if the bug finds its way to a cell’s interior. Interestingly, certain pathogens, like those that cause bubonic plague or rabbit fever have actually evolved to modify their LPS so that they don’t trip this alarm pathway.

“One reason all of this is important is sepsis. When an infection gets too severe, the immune system activates all throughout the body, causing organs to fail; this is in contrast to, for example, a localized immune response to bacteria in a paper cut.

“Gram-negative bacteria are a common cause of sepsis, and LPS activation of immune sensors is believed to be a major driver of patient decompensation.  My work shows that the caspase-11 sensor may play a major role in this detrimental overreaction of the immune system. Sepsis is one of the leading killers in the United States, and its mortality rate is rising because there are more and more immune-compromised people.

“We have to balance killing bacteria during infections while avoiding damaging tissue. We found that caspase-11 drives both pathogen clearance and tissue damage in gram-negative bacterial infections. Just figuring out that this pathway exists identifies it as a target for therapy.”

What does your future hold?

“The plan is to graduate in late winter of this year or spring of next.

“I’d like to be a principal investigator. Right now, I’m looking into postdocs. I’d like to find a fellowship that positions me to become a PI and run a microbiology / immunology lab but still provides me with options outside of academia should my path run that route.”

Molecule
Graphic by Max Englund/UNC Health Care
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