The Lyme Disease Spirochete<i>Borrelia burgdorferi</i>Utilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

Miller, Jennifer C.; Maylor-Hagen, Heather; Ma, Ying; Weis, John H.; Weis, Janis J.

doi:10.1128/iai.01070-09

Cited by 32 publications

(45 citation statements)

References 50 publications

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“…5). This is consistent with previous studies showing that type I IFN-responsive gene induction following stimulation of bone marrow-derived macrophages with B. burgdorferi was MyD88, TRIF, and Nod2 independent but IRF3 dependent (27), although a role for Nod2 was suggested by others (41). Furthermore, studies with human cells have suggested a role for various TLRs in B. burgdorferi-induced IFN production (42,43).…”

Section: Discussionsupporting

confidence: 81%

“…Infection with B. burgdorferi also induces TLR2-dependent and -independent IFN-␤ production by bone marrow-derived macrophages (26). Indeed, much of its production after B. burgdorferi infection appears to be induced independently of MyD88 and TRIF signaling (27). Together the data indicated that type I IFN is strongly induced by B. burgdorferi infection but might be induced independently of TLR signaling.…”

Section: Resultssupporting

confidence: 48%

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MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

et al. 2014

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Rapidly after infection, live Borrelia burgdorferi, the causative agent of Lyme disease, is found within lymph nodes, causing rapid and strong tissue enlargement, a loss of demarcation between B cell follicles and T cell zones, and an unusually large accumulation of B cells. We sought to explore the mechanisms underlying these changes, as lymph tissue disruption could be detrimental for the development of robust Borrelia-specific immunity. A time course study demonstrated that the loss of the normal lymph node structure was a distinct process that preceded the strong increases in B cells at the site. The selective increases in B cell frequencies were due not to proliferation but rather to cytokine-mediated repositioning of B cells to the lymph nodes, as shown with various gene-targeted and bone marrow irradiation chimeras. These studies demonstrated that B. burgdorferi infection induced type I interferon receptor (IFNR) signaling in lymph nodes in a MyD88-and TRIF-independent manner and that type I IFNR indirect signaling was required for the excessive increases of naive B cells at those sites. It did not, however, drive the observed histopathological changes, which occurred independently also from major shifts in the lymphocyte-homing chemokines, CXCL12, CXCL13, and CCL19/21, as shown by quantitative reverse transcription-PCR (qRT-PCR), flow cytometry, and transwell migration experiments. Thus, B. burgdorferi infection drives the production of type I IFN in lymph nodes and in so doing strongly alters the cellular composition of the lymph nodes, with potential detrimental effects for the development of robust Borrelia-specific immunity.

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Section: Discussionsupporting

confidence: 81%

Section: Resultssupporting

confidence: 48%

MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

et al. 2014

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“…Our findings that TRIF is necessary for induction of type I interferons downstream of B. burgdorferi are in contrast to the findings published by Miller et al (38). While there was an effect of TRIF deficiency on IL-6 secretion in response to B. burgdorferi stimulation, they did not observe an effect on interferon-inducible gene expression in TRIF-deficient cells.…”

Section: Discussioncontrasting

confidence: 57%

TRIF Mediates Toll-Like Receptor 2-Dependent Inflammatory Responses to Borrelia burgdorferi

et al. 2013

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TRIF is an adaptor molecule important in transducing signals from intracellularly signaling Toll-like receptor 3 (TLR3) and TLR4. Recently, TLR2 was found to signal from intracellular compartments. Using a synthetic ligand for TLR2/1 heterodimers, as well as Borrelia burgdorferi, which is a strong activator of TLR2/1, we found that TLR2 signaling can utilize TRIF. Unlike TRIF signaling by other TLRs, TLR2-mediated TRIF signaling is dependent on the presence of another adaptor molecule, MyD88. However, unlike MyD88 deficiency, TRIF deficiency does not result in diminished control of infection with B. burgdorferi in a murine model of disease. This appears to be due to the effects of MyD88 on phagocytosis via scavenger receptors, such as MARCO, which are not affected by the loss of TRIF. In mice, TRIF deficiency did have an effect on the production of inflammatory cytokines, suggesting that regulation of inflammatory cytokines and control of bacterial growth may be uncoupled, in part through transduction of TLR2 signaling through TRIF.

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“…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). We and others have begun to demarcate the pathways by which live Bb induces type I IFNs in both mouse and human cells (7,(19)(20)(21)(22). Miller et al (20) demonstrated that live Bb induces transcription of several ISGs in bone marrow-derived murine macrophages (BMDMs) independent of both MyD88 (20) and TRIF (21) yet requiring the transcription factor IFN regulatory factor (IRF) 3.…”

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.

143

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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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The Lyme Disease SpirocheteBorrelia burgdorferiUtilizes Multiple Ligands, Including RNA, for Interferon Regulatory Factor 3-Dependent Induction of Type I Interferon-Responsive Genes

Cited by 32 publications

References 50 publications

MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

MyD88- and TRIF-Independent Induction of Type I Interferon Drives Naive B Cell Accumulation but Not Loss of Lymph Node Architecture in Lyme Disease

TRIF Mediates Toll-Like Receptor 2-Dependent Inflammatory Responses to Borrelia burgdorferi

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

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