Dissecting mechanisms of bacterial pathogenesis using chemical probes
Abstract/Contents
- Abstract
- Host-pathogen interactions are highly regulated at the post-translational level, making small molecules useful tools for dissecting many aspects of these events. This dissertation describes the development and application of chemical probes to examine aspects of bacterial infection on either side of the host-pathogen interface. We rationally designed a set of inhibitors and activity-based probes to study the substrate recognition and activation mechanisms of the internal cysteine protease domain (CPD) of Clostridium difficile's large gluocosylating toxin TcdB; a major virulence factor of this important nosocomial pathogen. Subsequent work with these tools has helped elucidate the biochemical details of CPD allosteric activation within a eukaryotic environment, and has provided evidence that TcdB contributes to hypervirulence in some C. difficile strains. We also developed an optimized activity-based probe for studying inflammasome-mediated caspase-1 activation, which is a fundamental part of the host's response to intracellular bacterial pathogens. We used this tool to discover that when cells are unable to activate caspase-1 upon intracellular bacterial infection, they instead undergo apoptosis. This work provides insight into a potential intracellular arms race between the host and pathogens capable of suppressing caspase-1 activation, and also highlights the balance that exists between pro- and non-inflammatory cellular responses. Together, these studies show there is much to be gained from adding chemical probes to the repertoire of tools used to study mechanisms of bacterial pathogenesis.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Puri, Aaron Webster |
|---|---|
| Associated with | Stanford University, Department of Chemical and Systems Biology. |
| Primary advisor | Bogyo, Matthew, 1971- |
| Thesis advisor | Bogyo, Matthew, 1971- |
| Thesis advisor | Chen, James |
| Thesis advisor | Mochly-Rosen, Daria |
| Thesis advisor | Monack, Denise M |
| Advisor | Chen, James |
| Advisor | Mochly-Rosen, Daria |
| Advisor | Monack, Denise M |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Aaron Webster Puri. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Ph.D. Stanford University 2012 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Aaron Webster Puri
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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