Keystone Symposia 2008 Conference Schedule Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on March 26, 2007, 10.1073/pnas.0609675104 OPEN ACCESS ARTICLE


This Article
Free via Open Access: OA
Right arrow Full Text (PDF)
Right arrow Supporting Information
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Weiss, D. S.
Right arrow Articles by Monack, D. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Weiss, D. S.
Right arrow Articles by Monack, D. M.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

Microbiology
In vivo negative selection screen identifies genes required for Francisella virulence

( macrophage | pathogenesis | ASC | caspase-1 )

David S. Weiss, Anna Brotcke, Thomas Henry, Jeffrey J. Margolis, Kaman Chan *, and Denise M. Monack {dagger}

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

Edited by E. Peter Greenberg, University of Washington School of Medicine, Seattle, WA, and approved February 12, 2007 (received for review November 2, 2006)

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.

Author contributions: A.B. and T.H. contributed equally to this work; D.S.W. and D.M.M. designed research; D.S.W., A.B., T.H., J.J.M., and K.C. performed research; D.S.W., A.B., T.H., and D.M.M. analyzed data; and D.S.W. and D.M.M. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

*Present address: Department of Microbiology and Immunology, University of California, 600 16th Street, MC 2200, San Francisco, CA 94143.

{dagger}To whom correspondence should be addressed at: Stanford University, 299 Campus Drive, Fairchild Building, Room D041, Stanford, CA 94305.

Denise M. Monack, E-mail: dmonack{at}stanford.edu

www.pnas.org/cgi/doi/10.1073/pnas.0609675104
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?


This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 Appl. Environ. Microbiol.Home page
B. W. Buchan, M. K. McLendon, and B. D. Jones
Identification of Differentially Regulated Francisella tularensis Genes by Use of a Newly Developed Tn5-Based Transposon Delivery System
Appl. Envir. Microbiol., May 1, 2008; 74(9): 2637 - 2645.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
A. P. White, D. L. Gibson, G. A. Grassl, W. W. Kay, B. B. Finlay, B. A. Vallance, and M. G. Surette
Aggregation via the Red, Dry, and Rough Morphotype Is Not a Virulence Adaptation in Salmonella enterica Serovar Typhimurium
Infect. Immun., March 1, 2008; 76(3): 1048 - 1058.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. A. Scott, S. M. Hickerson, T. J. Vickers, and S. M. Beverley
The Role of the Mitochondrial Glycine Cleavage Complex in the Metabolism and Virulence of the Protozoan Parasite Leishmania major
J. Biol. Chem., January 4, 2008; 283(1): 155 - 165.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
T. M. Maier, M. S. Casey, R. H. Becker, C. W. Dorsey, E. M. Glass, N. Maltsev, T. C. Zahrt, and D. W. Frank
Identification of Francisella tularensis Himar1-Based Transposon Mutants Defective for Replication in Macrophages
Infect. Immun., November 1, 2007; 75(11): 5376 - 5389.
[Abstract] [Full Text] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
D. S. WEISS, T. HENRY, and D. M. MONACK
Francisella Tularensis: Activation of the Inflammasome
Ann. N.Y. Acad. Sci., June 1, 2007; 1105(1): 219 - 237.
[Abstract] [Full Text] [PDF]