A
            <i>Francisella tularensis</i>
            Pathogenicity Island Required for Intramacrophage Growth

Nano, Francis E.; Zhang, Na; Cowley, Siobhán C.; Klose, Karl E.; Cheung, Karen K. M.; Roberts, Michael J.; Ludu, Jagjit S.; Letendre, Gregg W.; Meierovics, Anda I.; Stephens, Gwen; Elkins, Karen L.

doi:10.1128/jb.186.19.6430-6436.2004

Cited by 329 publications

(428 citation statements)

References 31 publications

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“…In addition to microbial tolerance, there are other potential bacterial components and mechanisms that may contribute to the suppression of human DC activity. F. tularensis encodes a pathogenicity island (FPI) that is critical for survival and replication of the bacterium (36,37,43). Specifically, several of these genes have been shown to be important for F. tularensis escape from the phagosome, enabling replication of the bacterium in host cell cytoplasm (43).…”

Section: Discussionmentioning

confidence: 99%

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

2009

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The gram-negative, facultative intracellular bacterium Francisella tularensis causes acute, lethal pneumonic disease following infection with only 10 CFU. The mechanisms used by the bacterium to accomplish this in humans are unknown. Here, we demonstrate that virulent, type A F. tularensis strain Schu S4 efficiently infects and replicates in human myeloid dendritic cells (DCs). Despite exponential replication over time, Schu S4 failed to stimulate transforming growth factor ␤, interleukin-10 (IL-10), IL-6, IL-1␤, IL-12, tumor necrosis factor alpha, alpha interferon (IFN-␣), and IFN-␤ throughout the course of infection. Schu S4 also suppressed the ability of directly infected DCs to respond to different Toll-like receptor agonists. Furthermore, we also observed functional inhibition of uninfected bystander cells. This inhibition was mediated, in part, by a heat-stable bacterial component. Lipopolysaccharide (LPS) from Schu S4 was present in Schu S4-conditioned medium. However, Schu S4 LPS was weakly inflammatory and failed to induce suppression of DCs at concentrations below 10 g/ml, and depletion of Schu S4 LPS did not significantly alleviate the inhibitory effect of Schu S4-conditioned medium in uninfected human DCs. Together, these data show that type A F. tularensis interferes with the ability of a central cell type of the immune system, DCs, to alert the host of infection both intra-and extracellularly. This suggests that immune dysregulation by F. tularensis operates on a broader and more comprehensive scale than previously appreciated.Francisella tularensis is a gram-negative, facultative intracellular bacterium and the causative agent of tularemia. Although the bacteria was identified nearly 100 years ago, the nature of its interaction with host cells and tissues has remained largely undefined until recent times. The unfortunate realization of the potential of F. tularensis as a biological weapon has resulted in a resurgence of research on tularemia. Much of our recent understanding of tularemia pathogenesis has come from manipulation of the mouse model of Francisella infections. While these murine studies have yielded many important advances in our understanding of tularemia pathogenesis, very little is understood about how Francisella, especially the most virulent type A strains such as Schu S4, interacts with human cells.Dendritic cells (DCs) serve as a central cell type in the immune system, bridging the innate and adaptive immune response to effectively eradicate invading pathogens.

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Section: Discussionmentioning

confidence: 99%

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

2009

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“…In contrast to the genomic islands of other species, there are no flanking insertion elements or tRNA genes on both sides, although both copies are flanked on one side by rRNA operons and on the other an ISFtu1 element. Mutation of some genes within the duplicated regions can be attenuating [5][6][7] ; therefore, we believe that these regions are pathogenicity islands.…”

Section: General Featuresmentioning

confidence: 96%

“…Mutation of the genes iglA, iglC or pdpD in the 33.9-kb duplicated region reduces the ability of F. tularensis to survive in amoebae or macrophages and is attenuating [5][6][7] . These genes, and others in this region, are regulated by the transcriptional regulator MglA 6 .…”

Section: Candidate Mechanisms Of Virulencementioning

confidence: 99%

“…The bacterium infects macrophages 1 , and a few virulence determinants have been proposed, including an ill-defined capsule 3 and a 23-kDa protein that seems to have a role in downregulating proinflammatory cytokines 4 . Some other genes required for growth in macrophages have been identified [5][6][7] , but their roles are uncertain. There is currently no licensed vaccine for the prevention of tularemia.…”

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confidence: 99%

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The complete genome sequence of Francisella tularensis, the causative agent of tularemia

et al. 2005

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Francisella tularensis is one of the most infectious human pathogens known. In the past, both the former Soviet Union and the US had programs to develop weapons containing the bacterium. We report the complete genome sequence of a highly virulent isolate of F. tularensis (1,892,819 bp). The sequence uncovers previously uncharacterized genes encoding type IV pili, a surface polysaccharide and iron-acquisition systems. Several virulence-associated genes were located in a putative pathogenicity island, which was duplicated in the genome. More than 10% of the putative coding sequences contained insertion-deletion or substitution mutations and seemed to be deteriorating. The genome is rich in IS elements, including IS630 Tc-1 mariner family transposons, which are not expected in a prokaryote. We used a computational method for predicting metabolic pathways and found an unexpectedly high proportion of disrupted pathways, explaining the fastidious nutritional requirements of the bacterium. The loss of biosynthetic pathways indicates that F. tularensis is an obligate host-dependent bacterium in its natural life cycle. Our results have implications for our understanding of how highly virulent human pathogens evolve and will expedite strategies to combat them.

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“…novicida also results in defects in virulence and growth within macrophages [9]. The pdpA and pdpD genes, along with iglC and several others, are thought to represent a Francisella pathogenicity island regulated by MglA, another protein that is required for virulence [9,10]. Type IV pili play a major role in the pathogenicity of many bacteria [11].…”

Section: Introductionmentioning

confidence: 99%

A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

Forestal

Gil

Monfett

et al. 2008

Microbial Pathogenesis

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Francisella tularensis is a highly virulent bacterium that causes tularemia, a disease that is often fatal if untreated. A live vaccine strain (LVS) of this bacterium is attenuated for virulence in humans but produces lethal disease in mice. F. tularensis has been classified as a Category A agent of bioterrorism. Despite this categorization, little is known about the components of the organism that are responsible for causing disease in its hosts. Here, we report the deletion of a well-characterized lipoprotein of F. tularensis, designated LpnA (also known as Tul4), in the LVS. An LpnA deletion mutant was comparable to the wild-type strain in its ability to grow intracellularly and cause lethal disease in mice. Additionally, mice inoculated with a sublethal dose of the mutant strain were afforded the same protection against a subsequent lethal challenge with the LVS as were mice initially administered a sublethal dose of the wild-type bacterium. The LpnA-deficient strain showed an equivalent ability to promote secretion of chemokines by human monocyte-derived macrophages as its wild-type counterpart. However, recombinant LpnA potently stimulated primary cultures of human macrophages in a Toll-like receptor 2-dependent manner. Although human endothelial cells also were activated by recombinant LpnA, their response was relatively modest. LpnA is clearly unnecessary for multiple functions of the LVS, but its inflammatory capacity implicates it and other Francisella lipoproteins as potentially important to the pathogenesis of tularemia.

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A Francisella tularensis Pathogenicity Island Required for Intramacrophage Growth

Cited by 329 publications

References 31 publications

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

Direct and Indirect Impairment of Human Dendritic Cell Function by VirulentFrancisella tularensisSchu S4

The complete genome sequence of Francisella tularensis, the causative agent of tularemia

A conserved and immunodominant lipoprotein of Francisella tularensis is proinflammatory but not essential for virulence

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