Insights into the European rabbit (Oryctolagus cuniculus) innate immune system: genetic diversity of the toll-like receptor 3 (TLR3) in wild populations and domestic breeds

Abstract The innate immune system detects invading pathogens through several pattern-recognition receptors and represents the first line of mucosal host defense. Mutations of the NOD2/CARD15 and Toll like receptor −2, −4, −9 genes have been associated with an increased incidence of inflammatory bowel disease due to a diminished response to bacterial cell wall products. Moreover, it was reported that mutations of NOD2 gene loci might be associated with an increased risk for TRM and severe GVHD in patients who underwent allogeneic blood stem cell transplantation. Here we analyzed 201 patients and their respective donors for NOD2, TLR-2, TLR-4 and TLR-9 mutations and correlated the results with the incidence of overall acute GVHD and intestinal GVHD. Further, we evaluated if the occurrence of NOD2/CARD15 and TLR allele mutations are accompanied with an increased risk for transplant-related mortality and overall survival. Mutated alleles of the NOD2 gene were observed in 17% of the patients and 16% of the donors. NOD2 gene mutations in patients and donors together were associated with an increased incidence of severe acute GVHD grade III-IV (6/11 patients; 55% versus 35/145 patients; 24%). If a mutated allele of the NOD2 gene was found either in patients or in donors only no correlation with increased incidence of severe acute GVHD was seen in this study. Patients with mutated alleles in TLR-4 genes (Asp299Gly and Thr399Ile) had a higher incidence of intestinal GVHD (p<0.02), whereas mutations of donor alleles only had no influence on the occurrence of intestinal GVHD in this analysis. No correlation with intestinal GVHD or overall acute GVHD was seen in patients with mutated alleles for TLR-2 and TLR-9. Overall survival, TRM and relapse risks was not influenced in none of the patients with mutated alleles of the innate immune system genes. Multivariate analysis including all potential factors, confirmed that that mutations of NOD2/CARD15 in patients and donors together influenced the occurrence of severe acute GVHD, whereas the occurrence of intestinal GVHD was influenced in patients by mutated alleles of TLR-4 gene. But mutations in alleles of the NOD2 or TLR-2,−4,−9 had no influence on the outcome of allogeneic transplant (TRM and overall survival) in the multivariate analysis. Since all patients in our institution had received an intestinal bacterial decontamination using metronidazole and ciprofloxacin after allogeneic stem cell transplantation, it might be speculative, if the reduction of concentrations of anaerobic bacteria in the intestinum might have protected patients from the occurrence of increased TRM. Decontamination of anaerobic bacteria is associated with a reduced risk for severe acute GVHD as reported earlier (Blood1999; 93:3267–75).

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Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

Infection and Immunity ◽

10.1128/iai.00573-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 1

Author(s):

John Ruby ◽

Michael Martin ◽

Michael J. Passineau ◽

Valentina Godovikova ◽

J. Christopher Fenno ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

Treponema Denticola ◽

Toll Like Receptor ◽

Wild Type ◽

Content Type ◽

Tnf Α ◽

Toll Like Receptor 2 ◽

Periplasmic Flagella

ABSTRACTTreponema denticolais an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated thatT. denticolastimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible forT. denticolaactivation of the innate immune system are currently not well defined. In this study, we investigated the role played byT. denticolaperiplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-typeT. denticolastimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-typeT. denticolaand the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positiveT. denticolastrain restored the activation. These findings suggest thatT. denticolastimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.

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Mastitis Increases Mammary mRNA Abundance of β-Defensin 5, Toll-Like-Receptor 2 (TLR2), and TLR4 but Not TLR9 in Cattle

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.1.174-185.2004 ◽

2004 ◽

Vol 11 (1) ◽

pp. 174-185 ◽

Cited By ~ 173

Author(s):

T. Goldammer ◽

H. Zerbe ◽

A. Molenaar ◽

H.-J. Schuberth ◽

R. M. Brunner ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

Mrna Abundance ◽

Strong Increase ◽

Sequence Information ◽

Toll Like Receptor ◽

Tlr4 Mrna ◽

Coordinated Regulation ◽

The Impact

ABSTRACT Coordination of the primary defense mechanisms against pathogens relies on the appropriate expression of pathogen recognition receptors (PRRs) triggering the early release of effector molecules of the innate immune system. To analyze the impact of this system on the counteraction of infections of the mammary gland (mastitis), we characterized the bovine gene encoding the key PRR Toll-like receptor 9 (TLR9) and mapped its precise position on chromosome BTA22. The sequence information was used to establish real-time PCR quantification assays to measure the mRNA abundances of TLR9, TLR2, and TLR4 together with those of β-defensin 5 (BNBD5), an early bactericidal effector molecule of the innate system, in healthy and infected mammary glands. Mastitis strongly increased (4- to 13-fold) the mRNA abundances of all of these genes except TLR9. Slight subclinical infections already caused a substantial increase in the copy numbers, though they did so the least for TLR9. Induction was not systemic, since mRNA abundance was low in uninfected control quarters of the udder but high in the severely infected quarters of the same animal. The number of TLR2 copies correlated well with those of TLR4, indicating coordinated regulation of these two PRRs during infection of the udder. Their coordinated regulation explains our unexpected observation that pure Staphylococcus aureus infections caused a strong increase also in TLR4 mRNA abundance. In situ hybridizations revealed that BNBD5 is expressed predominantly in the mammary epithelial cells (MEC) of the infected gland. Our data therefore suggest a significant contribution of the innate immune system to counteract mastitis and attribute a prominent effector function to the MEC.

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