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

Petnicki‐Ocwieja, Tanja; Chung, Erin; Acosta, David; Ramos, Laurie; Shin, Ok Sarah; Ghosh, Sanjukta; Kobzik, Lester; Li, Xin; Hu, Linden T.

doi:10.1128/iai.00890-12

Cited by 57 publications

(80 citation statements)

References 59 publications

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“…Induction of type I IFN production is one downstream effect of TLR stimulation. Previous studies have indicated roles for MyD88 and TRIF in the type I IFN response of bone marrow-derived macrophages following B. burgdorferi stimulation (40). Our data show, however, that the B. burgdorferi infection-induced B cell accumulation is dependent on type I IFNR signaling but independent of the major TLR adapter proteins MyD88 and TRIF (Fig.…”

Section: Discussioncontrasting

confidence: 54%

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: Discussioncontrasting

confidence: 54%

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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“…However, TLR2 has been shown to traffic to the endosomal membrane upon recognition of B. burgdorferi lipoproteins and contributes to MyD88/TRIF-dependent transcriptional activation of type I IFN gene products (28,48). Therefore, it was important to establish the potential contribution of TLR2-specific ligands to the type I IFN response we observed.…”

Section: Discussionmentioning

confidence: 99%

“…In mouse bone marrow-derived macrophages, transcriptional activation of IFN-responsive genes occurs via an IRF3-dependent but MyD88-and TRIF-independent pathway following recognition of B. burgdorferi RNA and multiple proteins by an unidentified cytosolic receptor (12). Petnicki-Ocwieja and colleagues demonstrated that B. burgdorferi initiates IFNA and IFNB gene transcription in mouse macrophages through activation of endosomally localized TLR2 and contributions from both MyD88-and TRIF-dependent signaling pathways (28). These studies with isolated immune cell populations, while providing crucial mechanistic insights into the production of B. burgdorferi-induced type I IFNs by specific cell types, are limited by the fact that these observations may not fully reflect the immune response in vivo, which results from an intricate network of interactions among multiple cell types.…”

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confidence: 99%

Borrelia burgdorferi RNA Induces Type I and III Interferons via Toll-Like Receptor 7 and Contributes to Production of NF-κB-Dependent Cytokines

2014

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Borrelia burgdorferi elicits a potent cytokine response through activation of multiple signaling receptors on innate immune cells. Spirochetal lipoproteins initiate expression of NF-B-dependent cytokines primarily via TLR2, whereas type I interferon (IFN) production is induced through the endosomal receptors TLR7 and TLR9 in human dendritic cells and TLR8 in monocytes. We demonstrate that DNA and RNA are the B. burgdorferi components that initiate a type I IFN response by human peripheral blood mononuclear cells (PBMCs). IFN-␣ protein and transcripts for IRF7, MX1, and OAS1 were induced by endosomal delivery of B. burgdorferi DNA, RNA, or whole-cell lysate, but not by lysate that had been treated with DNase and RNase. Induction of IFN-␣ and IFN-1, a type III IFN, by B. burgdorferi RNA or live spirochetes required TLR7-dependent signaling and correlated with significantly enhanced transcription and expression of IRF7 but not IRF3. Induction of type I and type III IFNs by B. burgdorferi RNA could be completely abrogated by a TLR7 inhibitor, IRS661. In addition to type I and type III IFNs, B. burgdorferi RNA contributed to the production of the NF-B-dependent cytokines, IFN-␥, interleukin-10 (IL-10), IL-1␤, IL-6, and tumor necrosis factor alpha (TNF-␣), by human PBMCs. Collectively, these data indicate that TLR7-dependent recognition of RNA is pivotal for IFN-␣ and IFN-1 production by human PBMCs, and that RNA-initiated signaling contributes to full potentiation of the cytokine response generated during B. burgdorferi infection.

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“…We are currently delineating the underlying mechanism by which OspC affects phagocytosis by macrophage. In this regard, it is known that phagocytosis of B. burgdorferi by macrophages involves several phagocytic receptors (91)(92)(93) and pattern recognition receptors (28,94). One possibility is that OspC alters phagocytic receptor profiles upon contact with macrophages.…”

Section: Discussionmentioning

confidence: 99%

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

et al. 2015

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cOuter surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2r␥ null mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis. L yme disease, the most prevalent vector-borne illness in the United States (1), is a multisystem inflammatory disorder caused by infection with the spirochete Borrelia burgdorferi (2, 3). This spirochete is maintained in nature through a complex enzootic cycle involving Ixodes ticks and various small-mammal hosts. Humans, as accidental hosts, become infected after B. burgdorferiinfected ticks feed on them (4). Spirochetes replicate in the skin, spread locally, and induce an inflammatory response with a symptom known as erythema migrans, observed in most patients (2, 4). During disseminated infection, B. burgdorferi colonizes multiple tissues, leading to different clinical manifestations, including arthritis, myocarditis, and neurological and/or cutaneous abnormalities (2, 4). This acute, disseminated stage of human Lyme disease is largely recapitulated using inbred mouse strains which are susceptible to B. burgdorferi infection and develop carditis and subacute arthritis (5). Thus, the murine model provides a powerful tool to elucidate the role of spirochete virulence factors and host immunological responses during Lyme disease pathogenesis (4).The B. burgdorferi genome encodes a large number of surface lipoproteins, many of which are expressed during mammalian infection (4, 6, 7). One of these lipoproteins is the major outer surface protein C (OspC), whose production is induced within inf...

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

Cited by 57 publications

References 59 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

Borrelia burgdorferi RNA Induces Type I and III Interferons via Toll-Like Receptor 7 and Contributes to Production of NF-κB-Dependent Cytokines

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

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