Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection

BenMohamed, Fatima; Medina, Mathieu; Wu, Yongzheng; Maschalidi, Sophia; Jouvion, Grégory; Guillemot, Laurent; Chignard, Michel; Manoury, Bénédicte; Touqui, Lhousseine

doi:10.1371/journal.pone.0090466

Cited by 32 publications

(30 citation statements)

References 36 publications

(54 reference statements)

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“…Pseudomonas aeruginosa is a Gram-negative bacterium that activates several TLRs including TLR9 on alveolar macrophages (AM) and epithelial cells 24 . TLR9-deficient mice were shown to be resistant to P. aeruginosa infection, suggesting that TLR9 signaling can have deleterious effects in this model 25 . In order to test whether TLR9-dependent hyperactivation observed in IRAP-deficient mice could affect survival upon bacterial pulmonary infection, we intranasally inoculated IRAP-deficient and wild-type mice with 10 6 CFU of P. aeruginosa and monitored them for survival.…”

Section: ! 6!mentioning

confidence: 93%

“…Lysosomal localization of TLR9 in IRAP-deficient cells might be a consequence of accelerated trafficking of its ligand, which normally is retained in IRAP + endosomes for a long time. The aberrant trafficking of both the ligand and the receptor led to an uncontrolled inflammatory response to TLR9 ligands, which culminated with animal death following an infection with P. aeruginosa, a bacterium sensed by TLR9 25 . Altogether, our results show that IRAP is required to avoid excessive TLR9-driven inflammatory responses.…”

Section: ! Disscussionmentioning

confidence: 99%

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IRAP+ endosomes restrict TLR9 activation and signaling

et al. 2017

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Retention of intracellular Toll-Like Receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal/lysosomal compartments. Here, we describe the identification of insulin responsive aminopeptidase (IRAP) endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand CpG were found as cargo in IRAP endosomes. In the absence of IRAP, CpG and TLR9 trafficking to lysosomes and TLR9 signaling were enhanced in DCs and in mice following bacterial infection. IRAP stabilized CpG-containing endosomes by interacting with the actin nucleation factor FHOD4, slowing down TLR9 trafficking towards lysosomes. Thus, endosome retention of TLR9 via IRAP interaction with the actin cytoskeleton is a mechanism that prevents TLR9hyper-activation in DCs. discriminate between different classes of microbial products and initiate specific signaling cascades. While microbial products with no equivalent in mammalian cells, such as the components of the bacterial wall, are recognized by surface TLRs (1, 2, 4, 5 and 6), pathogen derived nucleic acids are sensed by intracellular TLRs (3,7, 8 and 9). Recognition of nucleic acids by intracellular TLRs has the potential to trigger autoimmune diseases through interaction with self nucleic acids 1 . To avoid inappropriate activation of endosomal TLRs, their trafficking is tightly controlled. Thus, in basal conditions the receptors are located in the endoplasmic reticulum (ER) and translocate to endocytic vesicles only after cell stimulation by TLR ligands. Although all intracellular TLRs reside in the ER 2,3 , the trafficking pathways that move the receptors into the endocytic pathway show considerable variation among intracellular TLRs 4-6 . For example, TLR7 traffics from Golgi stacks directly to endosomes using the clathrin adaptor AP4, whereas the TLR9 is directed to the cell surface and reaches the endosomes via AP2-mediated clathrin-dependent endocytosis 6 .In addition to the transfer into the endocytic pathway, a second step that controls the activation of endosomal TLRs is their partial proteolysis by an array of different proteases, specific for each TLR 5,7-12 .Although less often mentioned, the intracellular trafficking of its ligand also controls the activation of TLR9. TLR9 ligands (CpG) are internalized via clathrin-mediated endocytosis in early endosomes and translocate to late LAMP + compartments 2 . TLR9 activation depends on CpG localization, since the abrogation of CpG translocation to LAMP + compartments by specific inhibitors decreased TLR9 signaling 13,14 . Thus, the intracellular trafficking of both, the ligand and the receptor are essential for the control of TLR9 activation. RESULTS IRAP deletion increases TLR9 responseTo address the role of IRAP in TLRs signaling, wild-type and IRAP-deficient bone marrow derived dendritic cells (BMDCs) were stimulated with specific TLR ligands: polyIC for TLR3, Imiquimod fo...

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Section: ! 6!mentioning

confidence: 93%

Section: ! Disscussionmentioning

confidence: 99%

IRAP+ endosomes restrict TLR9 activation and signaling

et al. 2017

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“…TLR5 is activated by P. aeruginosa flagellin, with receptor-PAMP interactions occurring once bacteria access the basolateral surface of epithelia where the receptor is expressed. Unmethylated bacterial CpG DNA strongly stimulates TLR9 [28] and likely contributes to sensing of P. aeruginosa bacteria and extracellular-DNA-containing biofilms, as TLR9 −/− mice can resist lethal challenge with P. aeruginosa [29]. P. aeruginosa also releases outer membrane vesicles (OMVs) that activate TLR-dependent responses in epithelial cells via delivered protein and LPS cargo [30].…”

Section: Immune Recognition and Response To P Aeruginosa Infectionmentioning

confidence: 99%

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

Lin

Kazmierczak²

2017

J Innate Immun

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The Gram-negative opportunistic pathogen Pseudomonas aeruginosa exploits failures of barrier defense and innate immunity to cause acute infections at a range of anatomic sites. We review the defense mechanisms that normally protect against P. aeruginosa pulmonary infection, as well as the bacterial products and activities that trigger their activation. Innate immune recognition of P. aeruginosa is critical for pathogen clearance; nonetheless, inflammation is also associated with pathogen persistence and poor host outcomes. We describe P. aeruginosa adaptations that improve this pathogen's fitness in the inflamed airway, and briefly discuss strategies to manipulate inflammation to benefit the host. Such adjunct therapies may become increasingly important in the treatment of acute and chronic infections caused by this multi-drug-resistant pathogen.

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“…In contrast, a detrimental role of TLR9 during the pulmonary host response was observed during both P. aeruginosa and methicillin-resistant S. aureus pneumonia. For P. aeruginosa, signaling through TLR9 reduces production of IL-1b and nitric oxide (NO), impairing the ability of activated macrophages to clear bacteria (33). Additionally, during methicillin-resistant S. aureus pneumonia, deleterious type I IFN signaling and TNF-a up-regulation are induced downstream of TLR9 in DCs (34).…”

Section: Tlr9mentioning

confidence: 99%

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

Baral

Batra

Zemans

et al. 2014

Am J Respir Crit Care Med

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Lower respiratory tract infections caused by bacteria are a major cause of death in humans irrespective of sex, race, or geography. Indeed, accumulated data indicate greater mortality and morbidity due to these infections than cancer, malaria, or HIV infection. Successful recognition of, followed by an appropriate response to, bacterial pathogens in the lungs is crucial for effective pulmonary host defense. Although the early recruitment and activation of neutrophils in the lungs is key in the response against invading microbial pathogens, other sentinels, such as alveolar macrophages, epithelial cells, dendritic cells, and CD41 T cells, also contribute to the elimination of the bacterial burden. Pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors, are important for recognizing and responding to microbes during pulmonary infections. However, bacterial pathogens have acquired crafty evasive strategies to circumvent the pattern recognition receptor response and thus establish infection. Increased understanding of the function of TLRs and evasive mechanisms used by pathogens during pulmonary infection will deepen our knowledge of immunopathogenesis and is crucial for developing effective therapeutic and/or prophylactic measures. This review summarizes current knowledge of the multiple roles of TLRs in bacterial lung infections and highlights the mechanisms used by pathogens to modulate or interfere with TLR signaling in the lungs.

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Toll-Like Receptor 9 Deficiency Protects Mice against Pseudomonas aeruginosa Lung Infection

Cited by 32 publications

References 36 publications

IRAP+ endosomes restrict TLR9 activation and signaling

IRAP+ endosomes restrict TLR9 activation and signaling

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

Divergent Functions of Toll-like Receptors during Bacterial Lung Infections

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