MEMP PhD Thesis Defense (2:00pm): Aditya Misra

Tissue-encoded Design Principles of Host Defense

Inflammatory diseases have been rising in incidence over the past few decades and are a result of inappropriate activation of tissue-resident immunity. This inappropriate activation can be derived from any number of cell types, including inputs from non-canonical immune cells such as epithelial cells. In this thesis, we investigated tissue metabolism and inflammation across different temporal and spatial scales using a unique combination of metabolomics, mathematical modeling, metabolic assays, and chemical characterization. Our aim was to protect against inflammation-induced tissue damage and improve clinical outcomes. Thus, we studied A) chronic local tissue inflammation using a colitis model (Chapter 1) and B) acute systemic inflammation using a sepsis model (Chapter 2). In each disease, we studied changes in tissue architecture and the resulting cross-talk among cell types in the microenvironment.  In colitis, we found that upon release during tissue damage, IL-18 launches a unique metabolic program in macrophages that 1) exhibits bistable and hysteretic behavior, 2) provides protective memory against inflammatory challenge, and 3) relies on positive feedback with intestinal epithelial cells to maintain the program. In our mouse model of bacterial sepsis, we performed liver tissue metabolomics. We identified a class of metabolites called branched-chain ketoacids (BCKAs) that are released during systemic inflammation and serve as endogenous antioxidants that neutralize extracellular peroxides. BCKA supplementation thus reduces tissue damage and increases survival rates by more than double. Through this thesis, we show tissue-intrinsic mechanisms that 1) organize a positive feedback loops among cells to establish protective memory against inflammation and 2) secrete endogenous antioxidants to limit pathogenic extracellular oxidants induced by inflammation without quenching bactericidal intracellular oxidants.

Thesis Supervisor:
Roni Nowarski, PhD
Assistant Professor of Neurology, HMS, BWH

Thesis Committee Chair:
Arup Chakraborty, PhD
Institute Professor, MIT; Professor of Chemical Engineering, Physics and Chemistry, MIT

Thesis Readers:
Jonathan C. Kagan, PhD
Marian R. Neutra, PhD Professor of Pediatrics, HMS, BCH

Naama Kanarek, PhD
Assistant Professor of Pathology, HMS, BCH

Miles Miller, PhD
Associate Professor of Radiology, HMS, MGH

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Zoom invitation – 

Aditya Misra is inviting you to a scheduled Zoom meeting.

Topic: Aditya Misra MEMP PhD Thesis Defense
Time: Thursday, August 8, 2024, 2:00 PM Eastern Time (US and Canada)

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