Purified Lipopolysaccharide from<i>Francisella tularensis</i>Live Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon

Dreisbach, Valley; Cowley, Siobhán C.; Elkins, Karen L.

doi:10.1128/iai.68.4.1988-1996.2000

Cited by 93 publications

(83 citation statements)

References 46 publications

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“…6 and 7). The poor stimulatory capacity of Schu S4 LPS is in agreement with previous reports examining immunogenicity and the tolerogenic capacity of LPS derived from the more attenuated F. tularensis strain LVS (2,17). However, it is well established FIG.…”

Section: Discussionsupporting

confidence: 91%

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: Discussionsupporting

confidence: 91%

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

2009

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“…However, although T cell-deficient, nude mice pretreated with 100 ng Ft-LPS 3 days before challenge survive 2-3 weeks longer than euthymic control mice that were saline-pretreated, the nude mice eventually succumb (8). This indicates that T cells are important for long-term survival even though they are not required for the B-1a antibody responses that allow mice to initially survive the infection.…”

Section: Plasma Cell Development Is Accompanied By Increases In Anti-mentioning

confidence: 87%

“…with Ft-LPS protects against lethal i.p. challenge with Ft LVS (7,8). Here, we show that antigen-specific B-1a antibody responses are required for this protection and that protection is induced by Ft-LPS, but not Ft-lipid A.…”

mentioning

confidence: 83%

Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

Cole

Yang

Elkins

et al. 2009

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

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102

137

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“…In addition, mice can be immunized against F. tularensis LVS by administration of its purified LPS alone [49,50]. The observations that LpnA stimulates T cells of individuals previously exposed to F. tularensis [31] and that it can confer partial resistance to challenge with the LVS when given to mice in recombinant form [32,48] suggested a potentially important role for the lipoprotein in acquired immunity to F. tularensis.…”

Section: Discussionmentioning

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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Purified Lipopolysaccharide fromFrancisella tularensisLive Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon

Abstract: Previous results have demonstrated that nonspecific protective immunity against lethal

Cited by 93 publications

References 46 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

Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

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

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