Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells

Mancuso, Giuseppe; Gambuzza, Maria Elsa; Midiri, Angelina; Biondo, Carmelo; Papasergi, Salvatore; Akira, Shizuo; Teti, Giuseppe; Beninati, Concetta

doi:10.1038/ni.1733

Cited by 304 publications

(346 citation statements)

References 40 publications

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“…However, unpublished data from our laboratory indicate that pDCs are unable to effect yeast phagocytosis, a process that is required for IFN induction, as discussed above. These data are in agreement with the previous observations that human [25] or mouse [19] pDCs have a limited ability to internalize bacteria and to produce type I IFN after stimulation with whole organisms, as opposed to purified bacterial DNA.Recent studies have highlighted the mechanisms underlying the induction of proinflammatory cytokines by purified DNA from different species of fungi [10,11,26]. However, thus far, the immunostimulatory properties of fungal RNA have not been studied.…”

supporting

confidence: 82%

“…C. albicans RNA was also tested since bacterial RNA is known to potently induce IFN-b [19]. Figure 4D shows that, after complexing with the cationic lipid DOTAP, both DNA and RNA readily stimulated IFN-b secretion.…”

Section: Identification Of Yeast Components Capable Of Inducing Ifn-bmentioning

confidence: 99%

“…Every 3 days, half of the medium was removed and substituted with fresh cytokine-supplemented culture medium. To obtain pDCs, BM cells were grown in FLT3-ligand (100 ng/mL, Peprotech) and pDCs were purified by the Plasmacytoid Dendritic Cells Isolation Kit (Miltenyj) as described previously [19]. Cells cultured in M-CSF were found to be 495% positive for CD11b, 485% positive for F4/80, and o5% positive for CD11c by flow cytometric analysis.…”

Section: Bm-derived Cellsmentioning

confidence: 99%

“…Quantity and purity of all DNA and RNA preparations were determined by a Nanodrop (ThermoFisher Scientific) using the instruction of the manufacturer and by electrophoresis on denaturating agarose gels. DNA and RNA preparations were ''complexed'' with DOTAP (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate; Sigma) as described previously [19] before cell stimulation. …”

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Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

et al. 2011

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Although type I interferons (IFN-a/b) have been traditionally associated with antiviral responses, their importance in host defense against bacterial pathogens is being increasingly appreciated. Little is known, however, about the occurrence and functional role of IFN-a/b production in response to pathogenic yeasts. Here, we found that conventional DCs, but not macrophages nor plasmacytoid DCs, mounted IFN-b responses after in vitro stimulation with Candida spp. or Saccharomyces cerevisiae. These responses absolutely required MyD88, a Toll-like receptor (TLR) adaptor molecule, and were partially dependent on TLR9 and TLR7. Moreover, Candida DNA, as well as RNA, could recapitulate the IFN-b response. After intravenous challenge with Candida albicans, most mice lacking the IFN-a/b receptor died from their inability to control fungal growth, whereas all WT controls survived. These data suggest that recognition of yeast nucleic acids by TLR7 and TLR9 triggers a host-protective IFN-a/b response.Key words: Candida albicans . Cytokines . DCs . Fungal infections . Macrophages Supporting Information available online IntroductionCandida albicans (C. albicans) is, among fungi, the most common pathogen of humans. Although they are normally harmless commensals of the intestinal and urinary tract, C. albicans and other Candida species can cause recurrent mucosal infections in otherwise healthy subjects and life-threatening conditions in hospitalized or immunocompromised patients [1]. In recent years, C. albicans has become the fourth most common cause of bloodstream infections, with an incidence of between 1 and 24 cases per 100 000 and a mortality rate of 30-50% [2]. Since the host immune status is the major factor that determines the transition of C. albicans from commensalism to pathogenicity, elucidating the mechanisms underlying immune response initiation, particularly those underlying recognition of fungal components, is crucial to developing new and more effective strategies to combat these infections. In fact, despite the availability of new classes of antifungal drugs, current available therapies are only partially effective and are associated with significant side effects.Antimicrobial responses are initiated by the activation of germ-line-encoded receptors (pattern-recognition receptors, PRRs) expressed by cells of the innate immune system, mainly by macrophages and DCs, which monitor potential portals of pathogen entry. Each PRR binds directly or indirectly to one or more evolutionary conserved microbial molecules (pathogenassociated molecular patterns, PAMPs) and triggers intracellular signal transduction cascades culminating in distinctive transcriptional and nontranscriptional responses. By this mechanism, PRRs link microbial recognition with the selective activation of specific arms of the innate immune system [3].Ã These authors have contributed equally to this study. Eur. J. Immunol. 2011. 41: 1969-1979 DOI 10.1002 Immunity to infection 1969Considerable progress has been recently made in the identification ...

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supporting

confidence: 82%

Section: Identification Of Yeast Components Capable Of Inducing Ifn-bmentioning

confidence: 99%

Section: Bm-derived Cellsmentioning

confidence: 99%

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Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

et al. 2011

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“…Although production of type I IFNs was previously ascribed solely to antiviral immune responses (10), it now is well established that both intracellular (11)(12)(13)(14) and extracellular bacteria (11,(15)(16)(17) also induce transcription of these cytokines. Bacteria can elicit type I IFNs either by activating TLRs (11,12) or through TLR-independent recognition of bacterial pathogenassociated molecular patterns (PAMPs) within the host cell cytosol (11,18).…”

mentioning

confidence: 99%

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

Cervantes¹,

Dunham-Ems²,

Vake³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Phagocytosed Borrelia burgdorferi (Bb) induces inflammatory signals that differ both quantitatively and qualitatively from those generated by spirochetal lipoproteins interacting with Toll-like receptor (TLR) 1/2 on the surface of human monocytes. Of particular significance, and in contrast to lipoproteins, internalized spirochetes induce transcription of IFN-β. Using inhibitory immunoregulatory DNA sequences (IRSs) specific to TLR7, TLR8, and TLR9, we show that the TLR8 inhibitor IRS957 significantly diminishes production of TNF-α, IL-6, and IL-10 and completely abrogates transcription of IFN-β in Bb-stimulated monocytes. We demonstrate that live Bb induces transcription of TLR2 and TLR8, whereas IRS957 interferes with their transcriptional regulation. Using confocal and epifluorescence microscopy, we show that baseline TLR expression in unstimulated monocytes is greater for TLR2 than for TLR8, whereas expression of both TLRs increases significantly upon stimulation with live spirochetes. By confocal microscopy, we show that TLR2 colocalization with Bb coincides with binding, uptake, and formation of the phagosomal vacuole, whereas recruitment of both TLR2 and TLR8 overlaps with degradation of the spirochete. We provide evidence that IFN regulatory factor (IRF) 7 is translocated into the nucleus of Bb-infected monocytes, suggesting its activation through phosphorylation. Taken together, these findings indicate that the phagosome is an efficient platform for the recognition of diverse ligands; in the case of Bb, phagosomal signaling involves a cooperative interaction between TLR2 and TLR8 in pro-and antiinflammatory cytokine responses, whereas TLR8 is solely responsible for IRF7-mediated induction of IFN-β.Lyme disease | endosomal receptors | type I interferons | phagocytosis

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Innate Immune Recognition of Nucleic Acids

Bauer

2010

The Chemical Biology of Nucleic Acids

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Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells

Cited by 304 publications

References 40 publications

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

Phagosomal signaling byBorrelia burgdorferiin human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β

Innate Immune Recognition of Nucleic Acids

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