Deletion of TolC orthologs in
            <i>Francisella tularensis</i>
            identifies roles in multidrug resistance and virulence

Gil, Horacio; Platz, Gabrielle J.; Forestal, Colin A.; Monfett, Michael; Bakshi, Chandra Shekhar; Sellati, Timothy J.; Furie, Martha B.; Benach, Jorge L.; Thanassi, David G.

doi:10.1073/pnas.0602582103

Cited by 103 publications

(158 citation statements)

References 44 publications

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“…The AcrAB inner membrane efflux platform (30), coupled with the TolC outer membrane transporter (91,178), forms a pump that facilitates the active efflux of toxic compounds and detergents from the bacteria, preventing their antimicrobial action. This multidrug efflux pump is important for Francisella resistance to ␤-lactams, tetracyclines, aminoglycosides, quinolones, detergents (notably bile salts), and antimicrobial dyes (30,91).…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

Subversion of Host Recognition and Defense Systems by Francisella spp

Jones

Napier

Sampson

et al. 2012

Microbiol Mol Biol Rev

123

151

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SUMMARY Francisella tularensis is a Gram-negative intracellular pathogen and the causative agent of the disease tularemia. Inhalation of as few as 10 bacteria is sufficient to cause severe disease, making F. tularensis one of the most highly virulent bacterial pathogens. The initial stage of infection is characterized by the “silent” replication of bacteria in the absence of a significant inflammatory response. Francisella achieves this difficult task using several strategies: (i) strong integrity of the bacterial surface to resist host killing mechanisms and the release of inflammatory bacterial components (pathogen-associated molecular patterns [PAMPs]), (ii) modification of PAMPs to prevent activation of inflammatory pathways, and (iii) active modulation of the host response by escaping the phagosome and directly suppressing inflammatory pathways. We review the specific mechanisms by which Francisella achieves these goals to subvert host defenses and promote pathogenesis, highlighting as-yet-unanswered questions and important areas for future study.

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Section: Antimicrobial Peptidesmentioning

confidence: 99%

Subversion of Host Recognition and Defense Systems by Francisella spp

Jones

Napier

Sampson

et al. 2012

Microbiol Mol Biol Rev

123

151

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“…The resultant mutagenesis plasmid was designated pPVΔlpnA. This plasmid then was used to generate an LpnA-deficient strain of F. tularensis, designated F. tularensis LVS ΔlpnA, by following a previously described conjugation protocol [7], with some modifications [14].…”

Section: Generation Of Lpna-deficient F Tularensis Lvsmentioning

confidence: 99%

“…Deletion of one of the putative pilin genes in a type B strain of F. tularensis results in attenuation of virulence [13], further implicating type IV pili in the pathogenesis of tularemia. Finally, deletion of the tolC or ftlC genes in the LVS decreases the resistance of the organism to anti-bacterial agents, and, in the case of the former, causes attenuation of virulence in mice [14].…”

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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“…Regarding endothelial cells, Staphylococcus aureus produces b-hemolysin, which inhibits endothelial production of CXCL8, a chemoattractant for neutrophils (43). These bacteria manipulate the host via secretion systems that are not known to exist in F. tularensis (44)(45)(46). Nevertheless, a factor shed from F. tularensis recently has been implicated in the suppression of activation of dendritic cells (17).…”

Section: Discussionmentioning

confidence: 99%

Francisella tularensis Suppresses the Proinflammatory Response of Endothelial Cells via the Endothelial Protein C Receptor

Bublitz

Noah

Benach

et al. 2010

The Journal of Immunology

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Various bacterial pathogens activate the endothelium to secrete proinflammatory cytokines and recruit circulating leukocytes. In contrast, there is a distinct lack of activation of these cells by Francisella tularensis, the causative agent of tularemia. Given the importance of endothelial cells in facilitating innate immunity, we investigated the ability of the attenuated live vaccine strain and virulent Schu S4 strain of F. tularensis to inhibit the proinflammatory response of HUVECs. Living F. tularensis live vaccine strain and Schu S4 did not stimulate secretion of the chemokine CCL2 by HUVECs, whereas material released from heat-killed bacteria did. Furthermore, the living bacteria suppressed secretion in response to heat-killed F. tularensis. This phenomenon was dose and contact dependent, and it occurred rapidly upon infection. The living bacteria did not inhibit the activation of HUVECs by Escherichia coli LPS, highlighting the specificity of this suppression. The endothelial protein C receptor (EPCR) confers anti-inflammatory properties when bound by activated protein C. When the EPCR was blocked, F. tularensis lost the ability to suppress activation of HUVECs. To our knowledge, this is the first report that a bacterial pathogen inhibits the host immune response via the EPCR. Endothelial cells are a critical component of the innate immune response to infection, and suppression of their activation by F. tularensis is likely a mechanism that aids in bacterial dissemination and evasion of host defenses.

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Deletion of TolC orthologs in Francisella tularensis identifies roles in multidrug resistance and virulence

Cited by 103 publications

References 44 publications

Subversion of Host Recognition and Defense Systems by Francisella spp

Subversion of Host Recognition and Defense Systems by Francisella spp

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

Francisella tularensis Suppresses the Proinflammatory Response of Endothelial Cells via the Endothelial Protein C Receptor

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