Type
Text
Type
Dissertation
Advisor
van der Velden, Adrianus W.M. | Bliska, James | Krug, Laurie | Zong, Wei-Xing | Macian, Fernando.
Date
2014-12-01
Keywords
Microbiology
Department
Department of Genetics.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77635
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) are pathogenic bacteria that suppress T cell responses to avoid clearance by the immune system, yet the mechanisms that mediate this immunosuppression remain largely unknown. Our laboratory previously showed that L-Asparaginase II produced by S. Typhimurium inhibits T cell responses and mediates virulence. The goal of my dissertation research was to determine the mechanism by which L-Asparaginase II produced by S. Typhimurium inhibits T cell responses. As described in my dissertation, I have found that L-Asparaginase II of S. Typhimurium exhibits L-asparagine hydrolysis activity and that this activity is required for the inhibition of T cells. Furthermore, I have found that exogenous L-asparagine is a resource important for T cell function and that L-Asparaginase II-mediated deprivation of exogenous L-asparagine inhibits T cell responses through suppression of metabolic reprogramming. The suppression of T cell metabolism was characterized by the inhibition of mTOR signaling, autophagy, c-Myc expression and new protein synthesis required for the activation, proliferation and differentiation of naïve T cells into effector T cells. These findings advance knowledge of a mechanism used by S. Typhimurium to delay onset of protective immune responses and thus have fundamental implications for understanding host interactions with bacterial pathogens. | Salmonella enterica serovar Typhimurium (S. Typhimurium) are pathogenic bacteria that suppress T cell responses to avoid clearance by the immune system, yet the mechanisms that mediate this immunosuppression remain largely unknown. Our laboratory previously showed that L-Asparaginase II produced by S. Typhimurium inhibits T cell responses and mediates virulence. The goal of my dissertation research was to determine the mechanism by which L-Asparaginase II produced by S. Typhimurium inhibits T cell responses. As described in my dissertation, I have found that L-Asparaginase II of S. Typhimurium exhibits L-asparagine hydrolysis activity and that this activity is required for the inhibition of T cells. Furthermore, I have found that exogenous L-asparagine is a resource important for T cell function and that L-Asparaginase II-mediated deprivation of exogenous L-asparagine inhibits T cell responses through suppression of metabolic reprogramming. The suppression of T cell metabolism was characterized by the inhibition of mTOR signaling, autophagy, c-Myc expression and new protein synthesis required for the activation, proliferation and differentiation of naïve T cells into effector T cells. These findings advance knowledge of a mechanism used by S. Typhimurium to delay onset of protective immune responses and thus have fundamental implications for understanding host interactions with bacterial pathogens. | 139 pages
Recommended Citation
Torres, AnnMarie, "L-Asparaginase II produced by S. Typhimurium inhibits T cell responses through hydrolysis of L-asparagine and suppression of metabolic reprogramming" (2014). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 3430.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/3430