Factors affecting the escape of Francisella tularensis from the phagolysosome

Lindgren, Helena; Golovliov, Igor; Baranov, Vladimir; Ernst, Robert K.; Telepnev, Max; Sjöstedt, Anders

doi:10.1099/jmm.0.45685-0

Cited by 147 publications

(189 citation statements)

References 29 publications

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“…In order to evaluate the intracellular trafficking of the DpdpA mutant, we infected mouse macrophage-like cell line J774A.1 cells, and examined the co-localization of LAMP-1 with wild-type F. novicida, the DpdpA mutant, and a DiglC mutant. F. tularensis and F. novicida mutants in iglC have been shown by others to be defective for phagosome escape (Bonquist et al, 2008;Lindgren et al, 2004;Santic et al, 2005b). Our experimental results using deconvoluting fluorescence microscopy showed a clear separation of wild-type F. novicida and LAMP-1 localization at 12 h post-infection ( Fig.…”

Section: Lamp-1 Association Of the Pdpa Mutantsupporting

confidence: 50%

“…Other researchers have shown that mutation of some FPI genes leads to Francisella strains that fail to escape the phagosome (Bonquist et al, 2008;Lindgren et al, 2004;Santic et al, 2005b). Like this work, these studies are attempts to surmise the function of different FPI-encoded proteins by examining the intramacrophage phenotype of Francisella strains with lesions in FPI genes.…”

Section: Discussionmentioning

confidence: 99%

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A Francisella novicida pdpA mutant exhibits limited intracellular replication and remains associated with the lysosomal marker LAMP-1

et al. 2009

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Several genes contained in the Francisella pathogenicity island (FPI) encode proteins needed for intracellular growth and virulence of Francisella tularensis. The pdpA gene is the first cistron in the larger of the two operons found in the FPI. In this work we studied the intracellular growth phenotype of a Francisella novicida mutant in the pdpA gene. The ΔpdpA strain was capable of a small amount of intracellular replication but, unlike wild-type F. novicida, remained associated with the lysosomal marker LAMP-1, suggesting that PdpA is necessary for progression from the early phagosome phase of infection. Strains with in cis complementation of the ΔpdpA lesion showed a restoration of intracellular growth to wild-type levels. Infection of macrophages with the ΔpdpA mutant generated a host-cell mRNA profile distinct from that generated by infection with wild-type F. novicida. The transcriptional response of the host macrophage indicates that PdpA functions directly or indirectly to suppress macrophage ability to signal via growth factors, cytokines and adhesion ligands.

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Section: Lamp-1 Association Of the Pdpa Mutantsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

A Francisella novicida pdpA mutant exhibits limited intracellular replication and remains associated with the lysosomal marker LAMP-1

et al. 2009

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“…A gene (frgA; FTT0029) belonging to a family of hydroxamate-siderophore synthetic genes 33 was located downstream of fur, and a putative iron-box was found in the promoter region. Recent papers have described the ability of F. tularensis to escape the phagosome 34,35 . In the cytoplasmic environment, iron is highly insoluble, and a TonB-dependent system for complex-bound iron uptake would be expected.…”

Section: Virulence and Iron Acquisitionmentioning

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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“…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.…”

mentioning

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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Factors affecting the escape of Francisella tularensis from the phagolysosome

Cited by 147 publications

References 29 publications

A Francisella novicida pdpA mutant exhibits limited intracellular replication and remains associated with the lysosomal marker LAMP-1

A Francisella novicida pdpA mutant exhibits limited intracellular replication and remains associated with the lysosomal marker LAMP-1

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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