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Title:Cellular interactions of the cytolethal distending toxins
Author(s):Gargi, Amandeep
Director of Research:Blanke, Steven R.
Doctoral Committee Chair(s):Blanke, Steven R.
Doctoral Committee Member(s):Wilson, Brenda A.; Tapping, Richard I.; Olsen, Gary J.
Department / Program:Microbiology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Molecular Pathogenesis
Cellular Trafficking
Cytolethal Distending Toxin
Nuclear Microbiology
Abstract:Over the course of evolution, pathogens have adapted and co-evolved with their respective hosts, with infectious diseases being one of the leading health concerns. Pathogens have developed several strategies to colonize the host, of which only a few have been characterized in molecular details. Utilizing host uptake and trafficking system, pathogenic effector proteins, called toxins, have exploited existing pathways as a mean to access intracellular targets and modulate host cellular functions. Among known targets in the human host, nucleus has been an infrequent, covert, and a coveted target, and very few external factors have been known to reach nucleus. Cytolethal Distending Toxin (CDT), the first known bacterial toxin to reach the mammalian-cell nucleus, presents an excellent model to study the retrograde trafficking of cargo to the nucleus. CDTs comprise a family of intracellular acting bacterial toxins whose actions upon eukaryotic cells cause DNA-damage, resulting in the induction of DNA-damage repair response, thus leading to the modulation of host cell functions. Most CDTs are hetero-tripartite assemblies of CdtA, CdtB, and CdtC, with CdtB required for CDT-mediated cell cycle arrest, and CdtA and CdtC required to deliver the catalytically active moiety inside the cell. Although all CDTs are generally considered to function as genotoxins, the extent of similarity and differences within the members of the CDT-family in their cellular intoxication properties, and the molecular components of host cellular machinery that plays a role in CDT-mediated intoxication, are poorly understood. In this dissertation I have identified the host factors that play an important role in the trafficking of CDTs to the nucleus. I have also characterized the similarities and divergence in the retrograde trafficking pathway utilized by different members of the CDT family, including the CDT produced by Aggregatibacter actinomycetemcomitans, Campylobacter jejuni Escherichia coli, and Haemophilus ducreyi. I have addressed the events spanning from cell-surface binding, to the trafficking of CDT through the subcellular compartments of the host cell, as a prerequisite for toxin to reach nucleus to exert its cytotoxic effects. My findings have enhanced the understanding of CDT intoxication mechanism and its potential role in the virulence properties of CDT-producing pathogens. Moreover, my studies will also aid in the design of novel tools to target specific subcellular compartments and host cell functions. For future studies, it will be interesting to test the premise that the functional differences between CDTs reflect the diversity of host cells, and tissues, that comprise the infection microenvironments targeted by CDT-producing pathogenic bacteria.
Issue Date:2015-04-22
Rights Information:Copyright 2015 Amandeep Gargi
Date Available in IDEALS:2015-07-22
Date Deposited:May 2015

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