Molecular mechanisms of the innate immune response to Francisella tularensis
Abstract/Contents
- Abstract
- Francisella tularensis is a facultative intracellular pathogen that causes the disease tularemia. The ability of F. tularensis to escape phagosomal degradation and replicate in the macrophage cytosol is central to its pathogenesis. The macrophage responds to the presence of cytosolic F. tularensis with the production of type-I interferons (IFN) and subsequent activation of the inflammasome. We conducted a forward genetic screen of a F. novicida transposon library to identify mutants that resulted in an increased or decreased cytosolic response in macrophages. We identified 164 F. novicida mutants that lead to increased type-I IFN production and inflammasome activation in macrophages. We also identified 74 mutants that resulted in decreased type-I IFN and inflammasome responses in macrophages. Finally, we identified AIM2 as the host receptor responsible for inflammasome activation in response to cytosolic F. novicida. We showed that lysing cytosolic F. novicida leads to release of bacterial DNA that triggers type-IFN through a pathway involving the adaptor STING. STING-dependent type-I IFN production increases the expression of AIM2, which complexes with the bacterial DNA and initiates inflammasome activation. We further demonstrate that AIM2 is critical for innate immunity to F. novicida infection in vivo. Thus we identified a novel bacterial ligand and novel cytosolic sensing components that play a role in the host defense to bacterial infections.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Jones, Jonathan Wiley | |
|---|---|---|
| Associated with | Stanford University, Department of Microbiology and Immunology | |
| Primary advisor | Monack, Denise M | |
| Thesis advisor | Monack, Denise M | |
| Thesis advisor | Amieva, Manuel | |
| Thesis advisor | Falkow, Stanley | |
| Thesis advisor | Nelson, W. J. (W. James) | |
| Thesis advisor | Schneider, David (David Samuel) | |
| Advisor | Amieva, Manuel | |
| Advisor | Falkow, Stanley | |
| Advisor | Nelson, W. J. (W. James) | |
| Advisor | Schneider, David (David Samuel) |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Jonathan Wiley Jones. |
|---|---|
| Note | Submitted to the Department of Microbiology and Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2010. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Jonathan Wiley Jones
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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