<i>Francisella tularensis</i>-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Woolard, Matthew D.; Wilson, Justin E.; Hensley, Lucinda L.; Jania, Leigh A.; Kawula, Thomas H.; Drake, James R.; Frelinger, Jeffrey A.

doi:10.4049/jimmunol.178.4.2065

Cited by 76 publications

(96 citation statements)

References 67 publications

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“…3 and data not shown). We along with others have observed induction of antiinflammatory cytokines and type I IFN by F. tularensis following infection of antigen-presenting cells (7,8,26,51). As expected, DCs responded to E. coli LPS by secreting IL-12, TNF-␣, IL-1␤, and TGF-␤ into culture supernatant (Fig.…”

Section: Resultssupporting

confidence: 80%

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: Resultssupporting

confidence: 80%

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

2009

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“…Pseudomonas aeruginosa secretes an enzyme (also a toxin) that degrades extracellular molecules and facilitates tissue invasion leading to necrosis. A number of bacterial species have toxins that generate pores in the host cell membranes for the parasite to enter but which then lead to cell lysis and damage (Woolard et al 2007). A different aspect is demonstrated by parasites critically depending on colonization factors.…”

Section: Pathogenesismentioning

confidence: 99%

“…Instead, peptidoglycan fragments and other molecules (e.g. teichoic acids) induce the same responses ( Woolard et al 2007). Similarly, parasite-derived proteases aid in migration across host tissue barriers, degradation of host blood proteins, direct evasion of host immunity but are also instrumental in inflammation and pathogenesis (McKerrow et al 2006).…”

Section: Pathogenesismentioning

confidence: 99%

“…Depending on their precise function, virulence factors can be adhesins (factors that allow the parasite to attach to the host's surfaces), colonization factors (allowing the parasite to survive in a difficult host environment, such as the acid stomach in the case of Helicobacter pylori; Atherton 2006), invasins (aiding the parasite's spread through the host body but outside the cells, such as in Streptococcus aureus) or, more generally, are considered to be toxins with a general strong adverse effect on the host ( Woolard et al 2007). In many respects, toxins act as enzymes and are, in general, highly antigenic.…”

Section: Pathogenesismentioning

confidence: 99%

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Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence

Schmid‐Hempel

2008

Phil. Trans. R. Soc. B

206

177

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The discussion of host-parasite interactions, and of parasite virulence more specifically, has so far, with a few exceptions, not focused much attention on the accumulating evidence that immune evasion by parasites is not only almost universal but also often linked to pathogenesis, i.e. the appearance of virulence. Now, the immune evasion hypothesis offers a deeper insight into the evolution of virulence than previous hypotheses. Sensitivity analysis for parasite fitness and life-history theory shows promise to generate a more general evolutionary theory of virulence by including a major element, immune evasion to prevent parasite clearance from the host. Also, the study of dose-response relationships and multiple infections should be particularly illuminating to understand the evolution of virulence. Taking into account immune evasion brings immunological processes to the core of understanding the evolution of parasite virulence and for a range of related issues such as dose, host specificity or immunopathology. The aim of this review is to highlight the mechanism underlying immune evasion and to discuss possible consequences for the evolutionary ecology analysis of host-parasite interactions.

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“…3), and possibly also enhanced their T cell stimulatory function. This possibility is supported by the inhibitory effect of individual COX products including PGE 2 and PGI 2 on DC maturation, inflammatory cytokine, and chemokine production, and their ability to stimulate and activate T cells (21)(22)(23). PGE 2 and PGI 2 may exert their T cell suppressive effect not only indirectly by inhibiting DCs, but also directly by decreasing T cell activation and effector cytokine production (24 -26).…”

Section: Discussionmentioning

confidence: 84%

Cyclooxygenase Inhibition during Allergic Sensitization Increases STAT6-Independent Primary and Memory Th2 Responses

Zhou

Newcomb

Moore

et al. 2008

The Journal of Immunology

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Immune sensitization and memory generation are required for the development of allergic inflammation. Our previous studies demonstrate that the cyclooxygenase (COX) metabolic pathway is actively involved in allergic responses and COX inhibition increases allergic airway inflammation in a STAT6-independent fashion. To test the hypothesis that COX inhibition augments allergic inflammation by enhancing immune sensitization and memory, we sensitized STAT6 knockout mice with an i.p. injection of OVA with aluminum hydroxide as an adjuvant and treated the mice with the COX inhibitor indomethacin or vehicle for analyses of the primary and memory immune responses. We found that COX inhibition during immune sensitization, but not the allergic challenge phase, was necessary and sufficient to increase allergic inflammation. COX inhibition during sensitization increased the numbers of mature dendritic cells and activated CD4 T cells in the spleen and augmented OVA-specific IL-5 and IL-13 responses of the splenic CD4 T cells at day 5 after sensitization. COX inhibition during sensitization also augmented allergic Th2 response to OVA challenge 90 days after the sensitization. Therefore, COX inhibition during allergic sensitization augments allergic responses by enhancing Th2 cell activation and memory generation and the proallergic effect is STAT6-independent. These findings provide a mechanistic explanation for the increased allergic inflammation previously shown in the mice treated with COX inhibitors and in COX-deficient mice and suggest that use of COX-inhibiting drugs during initial allergen exposure may increase the risk of developing allergic responses.

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Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

Cited by 76 publications

References 67 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

Immune defence, parasite evasion strategies and their relevance for ‘macroscopic phenomena’ such as virulence

Cyclooxygenase Inhibition during Allergic Sensitization Increases STAT6-Independent Primary and Memory Th2 Responses

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