Advisor: Dr. Krishnendu Roy (Engineering, Vanderbilt) 

Committee: 

Dr. Ankur Singh (School of Mechanical Engineering, Georgia Tech)

Dr. Ahmet Coskun (School of Biomedical Engineering, Georgia Tech)

Dr. Hang Lu (School of Chemical and Biomolecular Engineering, Georgia Tech)

Dr. Rabin Tirouvanziam (Department of Pediatric Infectious Diseases, Emory)

An immune-competent microvascularized human lung-on-chip device for studying immunopathologies of the lung

      Severe influenza affects 3-5 million people worldwide each year, resulting in >300,000 deaths. Standard-of-care antiviral therapeutics have limited effectiveness in these patients where infection severity is driven by an aberrant immune response. In severe influenza, the hyperactive immune system causes acute cytokine storm, cytopenia, and local tissue damage. Current preclinical models of severe influenza, in small animal models and in vitro, fail to recapitulate the human immune response to severe viral infection accurately. Here, we bioengineered a human lung tissue model that represents small airway structures with tissue-resident and circulatory immune cells. The immune-competent lung tissue model comprises of a 3D, perfusable microvascular network underneath a mature, differentiated epithelium at an air-liquid interface.

      With this model, we demonstrate that a conventional lung-on-chip (LOC) that lacks immune cells induces limited cytokine response to severe influenza infection, and while a LOC with tissue-resident macrophages induces significant response in the airway, the presence of both tissue-resident and circulatory immune cells was necessary to elicit a significant airway and interstitial cytokine storm. We demonstrate through extensive microscopy, secretome, and single-cell RNA sequencing analyses that severe flu infection results in significant lymphopenia, extracellular matrix remodeling, and transcriptional shutdown in fully immune-competent lung tissues. Lastly, we highlight the prominent role of stromal-immune interactions in the response to severe influenza infection, with stromal cells participating in both cytokine signaling and ECM remodeling. The introduction of both tissue-resident and circulatory immune cells into this lung-on-chip model allows for investigation into the distinct role of each immune cell type in the initiation and progression of influenza and may shed light on potential therapeutic avenues targeting immune dysregulation.