The 17 kDa lipoprotein and encoding gene of Francisella tularensis LVS are conserved in strains of Francisella tularensis

Sjöstedt, Anders; Kuoppa, Kerstin; Johansson, Thorsten; Sandström, Gunnar

doi:10.1016/0882-4010(92)90025-j

Cited by 39 publications

(35 citation statements)

References 22 publications

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“…The capacity of other F. tularensis-associated molecular patterns to trigger the release of granular stores or to stimulate de novo production of MMP-9 is being evaluated. Other bacterial components known to induce MMP-9 activity, which F. tularensis also possess (44), include lipoproteins such as those found in Borrelia burgdorferi, a Gramnegative bacterium which happens to lack LPS (45).…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

Malik

Bakshi

McCabe

et al. 2007

The Journal of Immunology

102

113

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A striking feature of pulmonary infection with the Gram-negative intracellular bacterium Francisella tularensis, a category A biological threat agent, is an intense accumulation of inflammatory cells, particularly neutrophils and macrophages, at sites of bacterial replication. Given the essential role played by host matrix metalloproteinases (MMPs) in modulating leukocyte recruitment and the potentially indiscriminate destructive capacity of these cells, we investigated whether MMP-9, an important member of this protease family released by neutrophils and activated macrophages, plays a role in the pathogenesis of respiratory tularemia. We found that F. tularensis induced expression of MMP-9 in FVB/NJ mice and that the action of this protease is associated with higher bacterial burdens in pulmonary and extrapulmonary tissues, development of more extensive histopathology predominated by neutrophils, and increased morbidity and mortality compared with mice lacking MMP-9 (MMP-9−/−). Moreover, MMP-9−/− mice were able to resolve infection with either the virulence-attenuated type B (live vaccine strain) or the highly virulent type A (SchuS4) strain of F. tularensis. Disease resolution was accompanied by diminished leukocyte recruitment and reductions in both bacterial burden and proinflammatory cytokine production. Notably, neutrophilic infiltrates were significantly reduced in MMP-9−/− mice, owing perhaps to limited release of Pro-Gly-Pro, a potent neutrophil chemotactic tripeptide released from extracellular matrix through the action of MMP-9. Collectively, these results suggest that MMP-9 activity plays a central role in modulating the clinical course and severity of respiratory tularemia and identifies MMPs as novel targets for therapeutic intervention as a means of modulating neutrophil recruitment.

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Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

Malik

Bakshi

McCabe

et al. 2007

The Journal of Immunology

102

113

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“…These include the relatively high expression of LpnA in the outer membrane of F. tularensis [27], its high conservation among subspecies of Francisella [28], its immunogenicity [32], and its identity as a lipoprotein [27]. Bacterial lipoproteins can be predicted from genomic sequences by the presence of a lipobox, a consensus signal sequence at their N-terminus that is recognized and subsequently cleaved by the enzyme signal peptidase II [38].…”

Section: Discussionmentioning

confidence: 99%

“…LpnA (also called Tul4) is an immunodominant 17-kDa lipoprotein [27] that is conserved throughout Francisella strains [28]. LpnA is associated with the outer membrane [29], stimulates T cells from F. tularensis-primed individuals [30,31], confers partial protective immunity to tularemia in mice when administered in recombinant form [32], and is predominantly expressed relative to other F. tularensis lipoproteins [27].…”

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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“…Extracted DNA was captured by overnight incubation at room temperature in a silica matrix with sodium iodide. Primers were 5 0 end-labeled with gamma 32 P adenosine triphosphate, and DNA amplification was performed by PCR using previously published primers for a 211-bp fragment of the 17 kDa FT Tul4 lipoprotein gene, 8,10 present in both biovars of FT 8,10,14,24 Pure lyophilized genomic DNA served as a positive control. Reagent blanks were used as negative controls.…”

Section: Molecular Analysismentioning

confidence: 99%

“…A PCR product could be detected from amplicons containing a lower limit of approximately 10 copies of the Tul4 gene. 24 However, it is recognized that limits of detection determined with purified DNA may not correlate exactly with that of extracted DNA from archival tissue.…”

Section: Limits Of Detection and Specificity Of Pcr Assaymentioning

confidence: 99%

Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America

et al. 2004

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The 17 kDa lipoprotein and encoding gene of Francisella tularensis LVS are conserved in strains of Francisella tularensis

Cited by 39 publications

References 22 publications

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

Matrix Metalloproteinase 9 Activity Enhances Host Susceptibility to Pulmonary Infection with Type A and B Strains of Francisella tularensis

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

Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America

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