Virulent and Avirulent Strains of<i>Francisella tularensis</i>Prevent Acidification and Maturation of Their Phagosomes and Escape into the Cytoplasm in Human Macrophages

Clemens, Daniel L.; Lee, Bai‐Yu; Horwitz, Marcus A.

doi:10.1128/iai.72.6.3204-3217.2004

Cited by 316 publications

(468 citation statements)

References 52 publications

(46 reference statements)

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“…Each of these portals of entry is a unique immunological niche so F. tularensis needs multiple ways to evade and/or modulate the immunological response. To date, the best-characterized F. tularensis immune evasion is its ability to invade host macrophages and escape the phagolysosomal degradation pathway (53)(54)(55). In this study, we identified a mechanism used by F. tularensis to alter both innate and adaptive immunity.…”

Section: Discussionmentioning

confidence: 99%

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

Woolard

Wilson

Hensley

et al. 2007

The Journal of Immunology

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Francisella tularensis is a highly infectious bacterial pathogen, and is likely to have evolved strategies to evade and subvert the host immune response. In this study, we show that F. tularensis infection of macrophages alters T cell responses in vitro, by blocking T cell proliferation and promoting a Th2-like response. We demonstrate that a soluble mediator is responsible for this effect and identify it as PGE2. Supernatants from F. tularensis-infected macrophages inhibited IL-2 secretion from both MHC class I and MHC class II-restricted T cell hybridomas, as well as enhanced a Th2-like response by inducing increased production of IL-5. Furthermore, the soluble mediator blocked proliferation of naive MHC class I-restricted T cells when stimulated with cognate tetramer. Indomethacin treatment partially restored T cell proliferation and lowered IL-5 production to wild-type levels. Macrophages produced PGE2 when infected with F. tularensis, and treatment of infected macrophages with indomethacin, a cyclooxygenase-1/cyclooxygenase-2 inhibitor, blocked PGE2 production. To further demonstrate that PGE2 was responsible for skewing of T cell responses, we infected macrophages from membrane PGE synthase 1 knockout mice (mPGES1−/−) that cannot produce PGE2. Supernatants from F. tularensis-infected membrane PGE synthase 1−/− macrophages did not inhibit T cell proliferation. Furthermore, treatment of T cells with PGE2 recreated the effects seen with infected supernatant. From these data, we conclude that F. tularensis can alter host T cell responses by causing macrophages to produce PGE2. This study defines a previously unknown mechanism used by F. tularensis to modulate adaptive immunity.

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Section: Discussionmentioning

confidence: 99%

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

Woolard

Wilson

Hensley

et al. 2007

The Journal of Immunology

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“…SCHU S4 lacks coding potential for several expected features. The ability to import complexed ferric (Fe 3+ ) iron should be important for Francisella, because it can escape from the phagosome 22,35 , thereby losing its access to soluble iron present in the acidic milieu. But no previously known ferric iron uptake systems were found in the genome sequence.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, undiscovered mechanisms of virulence are probably encoded in the 33.9-kb pathogenicity island in F. tularensis. Within the macrophage, the bacterium can degrade the phagosomal membrane and escape into the cytosol 22 . We identified genes encoding a phospholipase C acpA (FTT0221) and a phospholipase D family protein (FTT0490), which may have a role in this process.…”

Section: Candidate Mechanisms Of Virulencementioning

confidence: 99%

The complete genome sequence of Francisella tularensis, the causative agent of tularemia

et al. 2005

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Francisella tularensis is one of the most infectious human pathogens known. In the past, both the former Soviet Union and the US had programs to develop weapons containing the bacterium. We report the complete genome sequence of a highly virulent isolate of F. tularensis (1,892,819 bp). The sequence uncovers previously uncharacterized genes encoding type IV pili, a surface polysaccharide and iron-acquisition systems. Several virulence-associated genes were located in a putative pathogenicity island, which was duplicated in the genome. More than 10% of the putative coding sequences contained insertion-deletion or substitution mutations and seemed to be deteriorating. The genome is rich in IS elements, including IS630 Tc-1 mariner family transposons, which are not expected in a prokaryote. We used a computational method for predicting metabolic pathways and found an unexpectedly high proportion of disrupted pathways, explaining the fastidious nutritional requirements of the bacterium. The loss of biosynthetic pathways indicates that F. tularensis is an obligate host-dependent bacterium in its natural life cycle. Our results have implications for our understanding of how highly virulent human pathogens evolve and will expedite strategies to combat them.

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“…8 Its ability to cause disease is tightly linked to its ability to rapidly escape from the phagosome into the host cytosol where it can replicate to very high numbers. 9,10 Deletion of a genetic locus, the Francisella Pathogenicity Island (FPI), abolishes the ability of F. tularensis to escape into the host cytosol. 11,12 The DFPI mutant remains in a vacuolar compartment, is unable to replicate intracellularly and is highly attenuated in vivo.…”

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confidence: 99%

AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages

Pierini¹,

Juruj²,

Perret³

et al. 2012

Cell Death Differ

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The inflammasome is a signalling platform leading to caspase-1 activation. Caspase-1 causes pyroptosis, a necrotic-like cell death. AIM2 is an inflammasome sensor for cytosolic DNA. The adaptor molecule ASC mediates AIM2-dependent caspase-1 activation. To date, no function besides caspase-1 activation has been ascribed to the AIM2/ASC complex. Here, by comparing the effect of gene inactivation at different levels of the inflammasome pathway, we uncovered a novel cell death pathway activated in an AIM2/ASC-dependent manner. Francisella tularensis, the agent of tularaemia, triggers AIM2/ASC-dependent caspase-3-mediated apoptosis in caspase-1-deficient macrophages. We further show that AIM2 engagement leads to ASCdependent, caspase-1-independent activation of caspase-8 and caspase-9 and that caspase-1-independent death is reverted upon caspase-8 inhibition. Caspase-8 interacts with ASC and active caspase-8 specifically colocalizes with the AIM2/ASC speck thus identifying the AIM2/ASC complex as a novel caspase-8 activation platform. Furthermore, we demonstrate that caspase-1-independent apoptosis requires the activation of caspase-9 and of the intrinsic pathway in a typical type II cell manner. Finally, we identify the AIM2/ASC-dependent caspase-1-independent pathway as an innate immune mechanism able to restrict bacterial replication in vitro and control IFN-c levels in vivo in Casp1 KO mice. This work underscores the crosstalk between inflammasome components and the apoptotic machinery and highlights the versatility of the pathway, which can switch from pyroptosis to apoptosis.

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Virulent and Avirulent Strains ofFrancisella tularensisPrevent Acidification and Maturation of Their Phagosomes and Escape into the Cytoplasm in Human Macrophages

Cited by 316 publications

References 52 publications

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

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

The complete genome sequence of Francisella tularensis, the causative agent of tularemia

AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages

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