Divergence of Protection Induced by Bacterial Products and Sepsis-Induced Immune Suppression

Sterns, Theo; Pollak, Nils; Echtenacher, Bernd; Männel, Daniela N.

doi:10.1128/iai.73.8.4905-4912.2005

Cited by 23 publications

(33 citation statements)

References 46 publications

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“…For example, the temporary state of refractoriness to endotoxin and other microbial products following sepsis (referred to as "microbial tolerance") tempers the inflammatory response and development of septic shock (as reviewed in reference 35). However, this state of tolerance also leaves the host susceptible in a hyporesponsive state and, thus, more susceptible to secondary infection (23,25,34,49). It has been postulated that some pathogens may use induction of tolerance as a mechanism by which to evade the immune response to successfully infect and replicate in the host (28).…”

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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“…Whereas in the CASP model no published work to date has determined the state of the immune response beyond 24 h, different parameters associated with immunosuppression have been reported in other models. Old work reports that the injection of moderate doses of LPS daily reduces the capacity to generate antibodies for between 1 and 7 days (42,43), and using the CLP model, a low clearance capacity and an increased sensitivity to a second infection were observed (40,50).…”

Section: Discussionmentioning

confidence: 99%

Model of Polymicrobial Peritonitis That Induces the Proinflammatory and Immunosuppressive Phases of Sepsis

et al. 2011

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Severe sepsis is associated with early release of inflammatory mediators that contribute to the morbidity and mortality observed during the first stages of this syndrome. Although sepsis is a deadly, acute disease, high mortality rates have been observed in patients displaying evidence of sepsis-induced immune deactivation. Although the contribution of experimental models to the knowledge of pathophysiological and therapeutic aspects of human sepsis is undeniable, most of the current studies using animal models have focused on the acute, proinflammatory phase. We developed a murine model that reproduces the early acute phases but also the long-term consequences of human sepsis. We induced polymicrobial acute peritonitis (AP) by establishing a surgical connection between the cecum and the peritoneum, allowing the exit of intestinal bacteria. Using this model, we observed an acute phase with high mortality, leukopenia, increased interleukin-6 levels, bacteremia, and neutrophil activation. A peak of leukocytosis on day 9 or 10 revealed the persistence of the infection within the lung and liver, with inflammatory hepatic damage being shown by histological examination. Long-term (20 days) derangements in both innate and adaptive immune responses were found, as demonstrated by impaired systemic tumor necrosis factor alpha production in response to an inflammatory stimulus; a decreased primary humoral immune response and T cell proliferation, associated with an increased number of myeloid suppressor cells (Gr-1 ؉ CD11b ؉ ) in the spleen; and a low clearance capacity. This model provides a good approach to attempt novel therapeutic interventions directed to augmenting host immunity during late sepsis.Local inflammatory mechanisms triggered by an infection are usually enough to eradicate the pathogen. However, if the infection is not contained, the pathogen, its toxins, and diverse mediators of the host are released to the circulation, producing a systemic inflammatory response syndrome that can cause severe sepsis or septic shock (8). Sepsis is usually treated in intensive care units (ICUs), and about 30% of the patients with severe sepsis die; this percentage rises to 50 to 70% if septic shock, the main cause of mortality in the ICU, develops (46).As death by septic shock has been associated with an early excessive inflammatory response, most of the treatment strategies have been designed to block the inflammatory mediators involved in this phenomenon. This theory is based on animal models where the administration of large amounts of bacteria or lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, generates a cytokine storm and where the blockade of these molecules increases the survival of animals (11). Nevertheless, clinical trials designed to neutralize inflammatory mediators have failed (45). The sepsis syndrome is not restricted to the activation of the inflammatory response, as compensatory anti-inflammatory mechanisms are also triggered, usually leading to immunosuppressio...

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“…This cytokine is markedly elevated in human infectious diseases (2) and is reported to be required for survival following cecal ligation and puncture (CLP) 3 (3), which represents a mouse model of polymicrobial peritonitis simulating human sepsis (4). However, both TNF-and TNFR-deficient mice fail to develop the usual sepsis-induced immunosuppression after CLP (5). In addition in chronic inflammatory states TNF-deficient mice also exhibit more severe inflammation (6 -8).…”

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confidence: 99%

Interaction of TNF with TNF Receptor Type 2 Promotes Expansion and Function of Mouse CD4+CD25+ T Regulatory Cells

Chen

Bäumel

Männel

et al. 2007

The Journal of Immunology

477

517

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Although TNF is a major proinflammatory cytokine, increasing evidence indicates that TNF also has immunosuppressive feedback effects. We have demonstrated in this study that, in both resting and activated states, mouse peripheral CD4+CD25+ T regulatory cells (Tregs) expressed remarkably higher surface levels of TNFR2 than CD4+CD25− T effector cells (Teffs). In cocultures of Tregs and Teffs, inhibition of proliferation of Teffs by Tregs was initially transiently abrogated by exposure to TNF, but longer exposure to TNF restored suppressive effects. Cytokine production by Teffs remained continually suppressed by Tregs. The profound anergy of Tregs in response to TCR stimulation was overcome by TNF, which expanded the Treg population. Furthermore, in synergy with IL-2, TNF expanded Tregs even more markedly up-regulated expression of CD25 and FoxP3 and phosphorylation of STAT5, and enhanced the suppressive activity of Tregs. Unlike TNF, IL-1β and IL-6 did not up-regulate FoxP3-expressing Tregs. Furthermore, the number of Tregs increased in wild-type mice, but not in TNFR2−/− mice following sublethal cecal ligation and puncture. Depletion of Tregs significantly decreased mortality following cecal ligation and puncture. Thus, the stimulatory effect of TNF on Tregs resembles the reported costimulatory effects of TNF on Teffs, but is even more pronounced because of the higher expression of TNFR2 by Tregs. Moreover, our study suggests that the slower response of Tregs than Teffs to TNF results in delayed immunosuppressive feedback effects.

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Divergence of Protection Induced by Bacterial Products and Sepsis-Induced Immune Suppression

Cited by 23 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

Model of Polymicrobial Peritonitis That Induces the Proinflammatory and Immunosuppressive Phases of Sepsis

Interaction of TNF with TNF Receptor Type 2 Promotes Expansion and Function of Mouse CD4+CD25+ T Regulatory Cells

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