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MYCOBACTERIOPHAGE LYSINS: BIOINFORMATIC CHARACTERIZATION OF LYSIN A AND IDENTIFICATION OF THE FUNCTION OF LYSIN B IN INFECTION

Payne, Kimberly M (2011) MYCOBACTERIOPHAGE LYSINS: BIOINFORMATIC CHARACTERIZATION OF LYSIN A AND IDENTIFICATION OF THE FUNCTION OF LYSIN B IN INFECTION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Tuberculosis kills nearly 2 million people each year, and more than one-third of the world�s population is infected with the causative agent, Mycobacterium tuberculosis. Mycobacteriophages, or bacteriophages that infect Mycobacterium species including M. tuberculosis, are already being used as tools to study mycobacteria and diagnose tuberculosis. More than 60 mycobacteriophage genomes have been sequenced, revealing a vast genetic reservoir containing elements useful to the study and manipulation of mycobacteria. Mycobacteriophages also encode proteins capable of fast and efficient killing of the host cell. In most bacteriophages, lysis of the host cell to release progeny phage requires at minimum two proteins: a holin that mediates the timing of lysis and permeabilizes the cell membrane, and an endolysin (lysin) that degrades peptidoglycan. Accessory lysis proteins have also been discovered, often with functions specific to that phage�s host.Many lysins of phages infecting Gram-positive bacteria are proving to be potent antibacterials. Further, lysis proteins can provide insight into the properties and composition of the host cell wall. Given the complexity of the mycobacterial cell wall and its medical relevance in tuberculosis as an immunogenic barrier that complicates treatment, as well as the urgent need for new therapeutic options, the mycobacteriophage lysins clearly warrant further scientific investigation.This work focuses on the mycobacteriophage lysin LysA and the accessory lysis protein LysB. Bioinformatic characterizations show that LysA proteins posess a variety of domains arranged in modular organizations, reflecting extensive recombination within the mycobacteriophage population. In addition to known peptidoglycan-hydrolytic activities, novel cell wall-binding domains are identified, as well as several domains of unknown function found only in mycobacteriophages. LysB proteins are unique to mycobacteriophages and perform a singular role as mycolylarabinogalactan esterases that sever the connection between the mycobacterial outer membrane and the peptidoglycan cell wall complex to ensure efficient lysis and progeny phage release. There is also preliminary evidence of peptidoglycan hydrolytic ability, inducible cell lysis, and growth inhibition of Mycobacterium smegmatis by LysA and LysB proteins. These studies suggest that mycobacteriophage lysis proteins can be exploited as useful tools, both in the laboratory and clinical setting.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Payne, Kimberly Mkmc83@pitt.eduKMC83
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHatfull, Graham Fgfh@pitt.eduGFH
Committee MemberLawrence, Jeffrey Gjlawrenc@pitt.eduJLAWRENC
Committee MemberBrodsky, Jeffrey Ljbrodsky@pitt.eduJBRODSKY
Committee MemberKinchington, Paul Rkinchingtonp@upmc.eduKINCH
Committee MemberHendrix, Roger Wrhx@pitt.eduRHX
Date: 25 February 2011
Date Type: Completion
Defense Date: 30 September 2010
Approval Date: 25 February 2011
Submission Date: 1 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Integrative Molecular Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bacteriophage; cell wall; evolution; holin; hydrolase; LysA; LysB; lysis; mycobacteria; mycolic acid; peptidoglycan; phage; recombination
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12012010-000803/, etd-12012010-000803
Date Deposited: 10 Nov 2011 20:07
Last Modified: 19 Dec 2016 14:37
URI: http://d-scholarship.pitt.edu/id/eprint/9933

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