Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Adam Fleming
Program: PhD in Biosciences
 
Date:   Wednesday June 21, 2017
Time:   10:00 AM
Place:  George Mason University
             Science & Tech campus
             IABR, Room 1004            
  
Title: "Exosomes From Cells Infected With Yersinia pestis Amplify Innate Immunity Through p38 and Jak2, Inducing Macrophage Differentiation and IL-6 Dependent Bacterial Clearance"

Committee Chair: Dr. Ramin Hakami
Committee Members:
  Dr. Monique van Hoek, Dr. Aarthi Narayanan, Dr. Carolina Salvador-Morales

All are invited to attend the defense.

ABSTRACT:
Little is known about the mechanisms by which the trafficking of extracellular vesicles (EV) such as exosomes modulate innate immune responses. We have used our model of infection with the highly pathogenic bacterium Yersinia pestis (Yp) to address significant gaps of knowledge in exosomal regulation of innate immunity during bacterial infections. By performing a comprehensive and quantitative protein microarray analysis (172 antibodies), we have demonstrated that exosomes of infection origin (EXi) strongly modulate a small set of proteins in target human monocytes, including Jak2 and p38. We have also demonstrated that EXi induce monocyte differentiation to macrophages and specifically induce dramatic release of IL-6, IL-8, and IL-10 from among 10 inflammatory cytokines analyzed. Addressing another significant gap in knowledge, we have also shown that EXi effects lead to substantial increase in bacterial uptake and clearance by recipient immune cells in an IL-6 dependent manner. Interestingly, we found that all the observed responses are largely dependent on protein moieties exposed on the surface of the EXi. These findings have laid the foundation for an integrated mechanistic model in which EXi surface proteins prime distant na´ve monocytes through modulation of distinct pathways such as p38 and Jak2 to mount immune responses similar to when they become infected with Yp. These include differentiation to macrophages and migration to infection site for increased IL-6 dependent bacterial clearance. The insights from these studies provide a deeper understanding of a largely unexplored aspect of host response to infection, aiding in future development of innovative countermeasures.


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