Attenuated<i>Francisella novicida</i>Transposon Mutants Protect Mice against Wild-Type Challenge

Tempel, Rebecca; Lai, Xin; Crosa, Lidia M.; Kozlowicz, Briana; Heffron, Fred

doi:10.1128/iai.00598-06

Cited by 97 publications

(135 citation statements)

References 50 publications

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“…2) (4,(10)(11)(12)(13)15). The FTT0798 (capsule production) mutant was between 10-and 100-fold less virulent compared with wild-type bacteria, a milder phenotype than that of the FPI mutant.…”

Section: Francisella Encounters a Bottleneck For Systemic Spread Aftementioning

confidence: 96%

“…These responses may function to limit Francisella's intracellular growth niche and activate the powerful host innate immune system. Some of the genes Francisella uses to cause disease are known, including the genes in the Francisella pathogenicity island (FPI), which are essential for intracellular replication and the induction of cell death in macrophages as well as for bacterial growth in mice (10)(11)(12)(13)(14)(15). The transcription factor MglA regulates all of the genes in the FPI and is also required for replication in macrophages and mice (10,15,16).…”

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confidence: 99%

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In vivo negative selection screen identifies genes required for Francisella virulence

Weiss

Brotcke²,

Henry³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

301

432

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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. macrophage ͉ pathogenesis ͉ ASC ͉ caspase-1

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Section: Francisella Encounters a Bottleneck For Systemic Spread Aftementioning

confidence: 96%

mentioning

confidence: 99%

In vivo negative selection screen identifies genes required for Francisella virulence

Weiss

Brotcke²,

Henry³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

301

432

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“…These genes include clpB (Gray et al, 2002;Maier et al, 2007;Meibom et al, 2008;Su et al, 2007;Tempel et al, 2006;Weiss et al, 2007), hspG (Weiss et al, 2007), FTL_0663 (Kraemer et al, 2009;Su et al, 2007), dnaK (Tempel et al, 2006) and FTL_1806 [encoding major facilitator superfamily (MFS) transport protein] (Maier et al, 2007;Weiss et al, 2007). The identification of these genes, which are important for intracellular survival, may indicate that stress responses play a central role in the pathogenesis of F. tularensis and its ability to survive inside host cells.…”

Section: Defining An Rpoh Consensus Boxmentioning

confidence: 99%

“…Table S3 for detailed information). Gene numbers marked in italic type have been identified in screens or selections for determinants required for intracellular survival and/or virulence (Kraemer et al, 2009;Maier et al, 2007;Su et al, 2007;Tempel et al, 2006;Weiss et al, 2007). DCellular role category according to TIGR.…”

Section: Role Of Rpoh In F Tularensis Transcriptional Regulationmentioning

confidence: 99%

“…The pathogenicity of F. tularensis is largely dependent on its ability to replicate inside host cells, and in particular in macrophages in vivo. Several factors important for virulence have been identified, and in particular genes located in the Francisella pathogenicity island (FPI) (de Bruin et al, 2007;Golovliov et al, 2003;Lai et al, 2004;Ludu et al, 2008;Nano et al, 2004;Nano & Schmerk, 2007;Santic et al, 2007;Tempel et al, 2006;Weiss et al, 2007), but the molecular mechanisms underlying disease are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Pivotal role of the Francisella tularensis heat-shock sigma factor RpoH

et al. 2009

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Francisella tularensis is a highly infectious pathogen that infects animals and humans to cause the disease tularemia. The primary targets of this bacterium are macrophages, in which it replicates in the cytoplasm after escaping the initial phagosomal compartment. The ability to replicate within macrophages relies on the tightly regulated expression of a series of genes. One of the most commonly used means of coordinating the regulation of multiple genes in bacteria consists of the association of dedicated alternative sigma factors with the core of the RNA polymerase (RNAP). In silico analysis of the F. tularensis LVS genome led us to identify, in addition to the genes encoding the RNAP core (comprising the a1, a2, b, b9 and v subunits), one gene (designated rpoD) encoding the major sigma factor s 70 , and a unique gene (FTL_0851) encoding a putative alternative sigma factor homologue of the s 32 heat-shock family (designated rpoH). Hence, F. tularensis represents one of the minority of bacterial species that possess only one or no alternative sigma factor in addition to the main factor s 70 . In the present work, we show that FTL_0851 encodes a genuine s 32 factor. Transcriptomic analyses of the F. tularensis LVS heat-stress response allowed the identification of a series of orthologues of known heat-shock genes (including those for Hsp40, GroEL, GroES, DnaK, DnaJ, GrpE, ClpB and ClpP) and a number of genes implicated in Francisella virulence. A bioinformatic analysis was used to identify genes preceded by a putative s 32 -binding site, revealing both similarities to and differences from RpoH-mediated gene expression in Escherichia coli. Our results suggest that RpoH is an essential protein of F. tularensis, and positively regulates a subset of genes involved in the heat-shock response.

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The Proteome ofFrancisella Tularensis; Methodology And Mass Spectral Analysis for Studying One of the Most Dangerous Human Pathogens

Stulı́k¹,

Lenčo²,

Dresler³

et al. 2010

Mass Spectrometry for Microbial Proteomics

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AttenuatedFrancisella novicidaTransposon Mutants Protect Mice against Wild-Type Challenge

Cited by 97 publications

References 50 publications

In vivo negative selection screen identifies genes required for Francisella virulence

In vivo negative selection screen identifies genes required for Francisella virulence

Pivotal role of the Francisella tularensis heat-shock sigma factor RpoH

The Proteome ofFrancisella Tularensis; Methodology And Mass Spectral Analysis for Studying One of the Most Dangerous Human Pathogens

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