IPiB Thesis Defense Dec. 12: Josh Mitchell

Eosinophils (EOS) have broad immunomodulatory and inflammatory effects — these white blood cells are implicated in eosinophilic asthma, eradicating parasitic infections, involvement in the gut microbiome and tumor microenvironment, and more — yet scientists still don’t have a complete understanding of how they are activated, or how they release granular content and deliver their noxious payloads.

Josh Mitchell
Josh Mitchell

“Our understanding of EOS activation is underdeveloped,” says IPiB graduate student Josh Mitchell, a member of the Mosher Lab. Mitchell has spent the last five years developing an integrated overview of biochemical and cellular processes that cause eosinophils to activate, leave blood circulation, and degranulate in tissue upon exposure to two cytokines, interleukins (IL) IL5 and IL33, which call eosinophils into tissues.

Mitchell observed that EOS experience dramatic morphological changes when they’re placed on surfaces coated with extracellular matrix proteins found in inflamed tissues. IL5-activated EOS look like an acorn, with granules forming the ‘head’ of the highly mobile EOS. IL33-activated EOS, on the other hand, look more like a pancake and don’t move around as much.

His correlative immunofluorescence microscopy, cryo-electron tomography (cryo-ET), and proteomics studies revealed that contents of EOS granules can be released by an unsuspected pathway. His research also suggests that while activation by IL5 and IL33 moves EOS into tissues by common biological processes, distinct signaling pathways downstream from IL5 and IL33 receptors result in gene transcription specific to each cytokine. These results may have implications for diseases associated with eosinophilic inflammation.

“One of the takeaways of this set of projects, in a certain sense, is that a lot of the classical techniques we’ve been doing are not suitable to define the questions that need to be answered,” Mitchell says. “We need to keep bringing in these new technologies to dig into some of the finer parts of these cells, and that’s really improved our takeaway. We’re coming up with a lot of novel observations and data that is kind of reworking what we thought about these cells.”

Mitchell thanks his colleagues and friends with supporting him on this research journey.

“This research really benefitted from weekly meetings with Laura [Laura Muehlbauer, Coon Lab] and Justin [Justin Mabin, Brow/Lewis Labs] that began during the COVID-19 pandemic shut-down. We are also doing all of this exciting cryo-ET work in our new cryo-ET facilities with professor and cryo-ET center director Elizabeth Wright and scientist Jae Yang. Without their expertise and dedication, we’d never had made this project work,” Mitchell says.

During his time in IPiB, Mitchell was an active member (and chair) of the Graduate Leadership & Development Committee (GLDC) in IPiB. He was also Chair of the Graduate School Dean’s Advisory Board, a member of the Graduate School Strategic Planning Steering Committee, and a student government representative on the Council on Academic Advising. (Little known fact: Mitchell was instrumental in the effort to make Adobe Illustrator available to UW–Madison graduate students.)

“To other graduate students, I would emphasize that I think it’s important to be involved in many different things in many different ways,” Mitchell says. “Graduate school is a wonderful opportunity to get excellent training in the sciences, but school is still in the name, so it’s a great opportunity to also explore your interests and gain a lot of skills. A lot of the weird things you learn and do can come back to help you in ways you don’t always expect. There’s a lot of advocacy and service that we can do to help the community function that much better — make it more inclusive, make it a better place.”

Mitchell was a Hematology Training Grant trainee from 2019-2022. After defending his Ph.D. research, he will begin a postdoc in an immunology lab at the Stryker M.D. School of Medicine.

To learn more about Mitchell’s research, attend his Ph.D. defense on Monday, December 12 at 9:00 a.m. CT in Room 1211 of the DeLuca Biochemical Sciences Building.

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