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Decoding Early Immune Events in Non-human Primates Infected with Mycobacterium tuberculosis

Cadena, Anthony M. (2017) Decoding Early Immune Events in Non-human Primates Infected with Mycobacterium tuberculosis. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Tuberculosis (TB) continues to pose a significant health risk to morbidity and mortality worldwide. Mycobacterium tuberculosis, the causative agent of TB, is responsible for nearly 10 million new cases of active disease and 2 million deaths annually. While the majority of M. tuberculosis infected individuals are asymptomatic (termed latent TB) and contain the infection, a subset (~10%) of infected individuals either present initially with primary active disease or reactivate subsequently over the course of their lifetime. The precise immune mechanisms responsible for this observed spectrum remain unclear but recent evidence suggests that early events in M. tuberculosis infection influence host outcome. In this dissertation, we utilized established non-human primate (NHP) models of M. tuberculosis to examine the early immunologic, pathologic, and contextual responses following infection. The primary aim of this thesis was to develop a novel genomic barcoding approach to add to our in vivo toolbox permitting single-bacterial tracing to probe early events in a variety of infection contexts. Our work validated the use of these bacterial tags and provided a unique ability to quantitatively track individual founding bacilli and their descendants in infected macaques. We found that the majority of bacteria are able to establish infection (i.e. a primary granuloma) but only a subset of bacteria contributes to productive dissemination. In addition, our barcode strategy permitted reinfection studies in which primary and secondary infections are separately evaluated using library-specific identifiers. Our initial observations suggest that an ongoing primary infection substantially limits secondary granuloma establishment and bacterial growth. By adapting our current NHP model of TB with new genomic barcoding tools, our work has provided insight into bacterial dissemination, reinfection, and host variability. Finally, our most recent studies are looking into the earliest context of the lung by probing the lung microbiome and its interaction with M. tuberculosis. Our latest observations suggest that the microbial lung landscape is highly variable across individuals, is distinct from the oral cavity, and undergoes significant alterations following infection. Overall, this body of work reiterates the importance of appreciating the influence that early infection and single lesion dynamics contributes to host outcome.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cadena, Anthony M.amc201@pitt.eduAMC201
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFlynn, JoAnnejoanne@pitt.edu
Committee MemberKane, Lawrencelkane@pitt.edu
Committee MemberBomberger, Jenniferjbomb@pitt.edu
Committee MemberGhedin, Elodieelodie.ghedin@nyu.edu
Committee MemberNorris, Karenkarennorris22@gmail.com
Date: 18 May 2017
Date Type: Publication
Defense Date: 2017
Approval Date: 18 May 2017
Submission Date: 1 May 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 159
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Mycobacterium tuberculosis, early infection, host-pathogen interaction, infectious disease, microbiome, macaque tuberculosis
Date Deposited: 18 May 2017 15:02
Last Modified: 18 May 2017 15:02
URI: http://d-scholarship.pitt.edu/id/eprint/31742

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