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Infection and Immunity, January 2009, p. 232-244, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00978-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Genome-Wide Screen in Francisella novicida for Genes Required for Pulmonary and Systemic Infection in Mice {triangledown}

Petra S. Kraemer,1 Allison Mitchell,1 Mark R. Pelletier,2 Larry A. Gallagher,3 Mike Wasnick,3 Laurence Rohmer,3 Mitchell J. Brittnacher,3 Colin Manoil,3 Shawn J. Skerett,2 and Nina R. Salama1*

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington,1 Department of Medicine, University of Washington, Seattle, Washington,2 Department of Genome Sciences, University of Washington, Seattle, Washington3

Received 5 August 2008/ Returned for modification 5 September 2008/ Accepted 19 October 2008

Francisella tularensis is a gram-negative, highly infectious, aerosolizable facultative intracellular pathogen that causes the potentially life-threatening disease tularemia. To date there is no approved vaccine available, and little is known about the molecular mechanisms important for infection, survival, and dissemination at different times of infection. We report the first whole-genome screen using an inhalation mouse model to monitor infection in the lung and dissemination to the liver and spleen. We queried a comprehensive library of 2,998 sequence-defined transposon insertion mutants in Francisella novicida strain U112 using a microarray-based negative-selection screen. We were able to track the behavior of 1,029 annotated genes, equivalent to a detection rate of 75% and corresponding to ~57% of the entire F. novicida genome. As expected, most transposon mutants retained the ability to colonize, but 125 candidate virulence genes (12%) could not be detected in at least one of the three organs. They fell into a variety of functional categories, with one-third having no annotated function and a statistically significant enrichment of genes involved in transcription. Based on the observation that behavior during complex pool infections correlated with the degree of attenuation during single-strain infection we identified nine genes expected to strongly contribute to infection. These included two genes, those for ATP synthase C (FTN_1645) and thioredoxin (FTN_1415), that when mutated allowed increased host survival and conferred protection in vaccination experiments.

* Corresponding author. Mailing address: FHCRC, 1100 Fairview Ave. N., Mailstop C3-168, Seattle WA 98109-1024. Phone: (206) 667-1540. Fax: (206) 667-6524. E-mail: nsalama{at}fhcrc.org

{triangledown} Published ahead of print on 27 October 2008.

Editor: A. J. Bäumler

Infection and Immunity, January 2009, p. 232-244, Vol. 77, No. 1
0019-9567/09/$08.00+0     doi:10.1128/IAI.00978-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Grall, N., Livny, J., Waldor, M., Barel, M., Charbit, A., Meibom, K. L. (2009). Pivotal role of the Francisella tularensis heat-shock sigma factor RpoH. Microbiology 155: 2560-2572 [Abstract] [Full Text]  


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