In vivo negative selection screen identifies genes required for Francisella virulence
Francisella tularensis subverts the immune system to rapidly grow within mammalian hosts, often causing tularemia, a fatal disease. This pathogen targets the cytosol of macrophages where it replicates by using the genes encoded in the Francisella pathogenicity island. However, the bacteria are recognized in the cytosol by the host's ASC/caspase-1 pathway, which is essential for host defense, and leads to macrophage cell death and proinflammatory cytokine production. We used a microarray-based negative selection screen to identify Francisella genes that contribute to growth and/or survival in mice. The screen identified many known virulence factors including all of the Francisella pathogenicity island genes, LPS O-antigen synthetic genes, and capsule synthetic genes. We also identified 44 previously unidentified genes that were required for Francisella virulence in vivo, indicating that this pathogen may use uncharacterized mechanisms to cause disease. Among these, we discovered a class of Francisella virulence genes that are essential for growth and survival in vivo but do not play a role in intracellular replication within macrophages. Instead, these genes modulate the host ASC/caspase-1 pathway, a previously unidentified mechanism of Francisella pathogenesis. This finding indicates that the elucidation of the molecular mechanisms used by other uncharacterized genes identified in our screen will increase our understanding of the ways in which bacterial pathogens subvert the immune system.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2007 |
|---|---|
| Erschienen: |
2007 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:104 |
|---|---|
| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 104(2007), 14 vom: 03. Apr., Seite 6037-42 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Weiss, David S [VerfasserIn] |
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| Themen: |
Caspase 1 |
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| Anmerkungen: |
Date Completed 29.06.2007 Date Revised 05.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM169251667 |
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| 100 | 1 | |a Weiss, David S |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a In vivo negative selection screen identifies genes required for Francisella virulence |
| 264 | 1 | |c 2007 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
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| 500 | |a Date Completed 29.06.2007 | ||
| 500 | |a Date Revised 05.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Francisella tularensis subverts the immune system to rapidly grow within mammalian hosts, often causing tularemia, a fatal disease. This pathogen targets the cytosol of macrophages where it replicates by using the genes encoded in the Francisella pathogenicity island. However, the bacteria are recognized in the cytosol by the host's ASC/caspase-1 pathway, which is essential for host defense, and leads to macrophage cell death and proinflammatory cytokine production. We used a microarray-based negative selection screen to identify Francisella genes that contribute to growth and/or survival in mice. The screen identified many known virulence factors including all of the Francisella pathogenicity island genes, LPS O-antigen synthetic genes, and capsule synthetic genes. We also identified 44 previously unidentified genes that were required for Francisella virulence in vivo, indicating that this pathogen may use uncharacterized mechanisms to cause disease. Among these, we discovered a class of Francisella virulence genes that are essential for growth and survival in vivo but do not play a role in intracellular replication within macrophages. Instead, these genes modulate the host ASC/caspase-1 pathway, a previously unidentified mechanism of Francisella pathogenesis. This finding indicates that the elucidation of the molecular mechanisms used by other uncharacterized genes identified in our screen will increase our understanding of the ways in which bacterial pathogens subvert the immune system | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a DNA, Bacterial |2 NLM | |
| 650 | 7 | |a Virulence Factors |2 NLM | |
| 650 | 7 | |a Caspase 1 |2 NLM | |
| 650 | 7 | |a EC 3.4.22.36 |2 NLM | |
| 700 | 1 | |a Brotcke, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Henry, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Margolis, Jeffrey J |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Kaman |e verfasserin |4 aut | |
| 700 | 1 | |a Monack, Denise M |e verfasserin |4 aut | |
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