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Defining the temporal and immunological dynamics of adaptive T cell responses in tuberculosis granulomas

Grant, Nicole (2022) Defining the temporal and immunological dynamics of adaptive T cell responses in tuberculosis granulomas. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

It is estimated that one-quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb) resulting in over 1 million deaths per year. Despite efforts to rectify this tragic toll, tuberculosis (TB) disease remains a global health problem. Novel vaccines and therapeutics are necessary to reduce the mortality and morbidity caused by this dynamic and complex pathogen. However, correlates of protection in the context of TB disease are still not well understood. One of the main contributors to protection are adaptive T cell responses through production of pro-inflammatory cytokines and cytotoxic mediators. The work contained in this dissertation focuses on developing a deeper understanding of the adaptive T cell responses in the pathologic hallmark of TB disease, the lung granuloma. Lung granulomas are comprised of immune and non-immune cells which can be identified in non-human primates (NHPs) by 4 weeks post-infection. These histopathologic structures are a major site of bacterial killing and control throughout the course of infection, with granulomas isolated at later timepoints post-infection having lower bacterial burdens. The contributors to this reduction in bacterial burden are largely unknown. We investigated the cellular, spatial, and functional components of granulomas identified at 4 weeks post-infection and analyzed at different timepoints post infection (4 weeks, 12 weeks, or 20 weeks), correlating a reduction in bacterial burden with the presence of T-bet+ adaptive T cells. Secondarily, we successfully epitope-mapped two Mtb immunodominant proteins leading to the production of Mtb-specific tetramers. Using these two tetramers in combination with two previously developed tetramers, we provide novel data into the transcription factor and activation profile of Mtb-specific T cells within lung granulomas, showing an activated Th1 profile. Overall, this dissertation holds significant public health importance through providing insight into potential targets for future TB vaccine design focusing on the rapid development of T-bet+ adaptive T cells.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Grant, Nicolenlp25@pitt.edunlp250000-0001-6376-4022
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMattila, Joshuajmattila@pitt.edujmattila
Thesis AdvisorFlynn, JoAnnejoanne@pitt.edujoanne
Committee MemberBomberger, Jenniferjbomb@pitt.edujbomb
Committee MemberBarratt-Boyes, Simonsmbb@pitt.edusmbb
Date: 4 January 2022
Date Type: Publication
Defense Date: 16 November 2021
Approval Date: 4 January 2022
Submission Date: 6 December 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 192
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Mtb Mycobacterium tuberculosis T cell Transcription factor Non-human primate MCM Tetramers
Date Deposited: 04 Jan 2022 15:23
Last Modified: 04 Jan 2022 15:23
URI: http://d-scholarship.pitt.edu/id/eprint/42010

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