Pathogen associated molecular pattern motifs from Gram-positive and Gram-negative bacteria induce different inflammatory mediator profiles in equine blood

DeClue, Amy E.; Johnson, Philip J.; Day, Jonathan; Amorim, Juliana; Honaker, Allison R.

doi:10.1016/j.tvjl.2011.09.001

Cited by 27 publications

(28 citation statements)

References 43 publications

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“…Naturally occurring sepsis might be initiated and maintained by repeated hits of a combination of PAMPs and endogenous DAMPs, as is thought to be the case in severely ill horses with ischemic intestinal segments and transmural migration of gut bacteria to circulating blood. However, the value of LPS studies is supported by DeClue et al [52], who only reported of minor differential effects in the equine leukocyte cytokine response to combinations of in vitro LPS and Gram-positive PAMPs (lipoteichoic acid and peptidoglycan) compared with each of these motifs alone. In addition, important considerations to take on from this study to future studies are to relate expression levels to the concurrent composition of white blood cells, and to investigate expression dynamics over time as regulation of gene expressions is orchestrated in such a highly dynamic manner.…”

Section: Discussionmentioning

confidence: 99%

Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

et al. 2015

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BackgroundIn horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic inflammation was induced in 6 adult horses by the intravenous injection of 1 μg lipopolysaccharide (LPS) per kg btw. Sixteen blood samples were collected for each horse at predetermined intervals and analyzed by reverse transcription quantitative real-time PCR. Post-induction expression levels for each gene were compared with baseline levels.ResultsSystemic inflammation was confirmed by the presence of clinical and hematological changes which were consistent with SIRS. The clinical response to LPS was transient and brief as all horses except one showed unaltered general demeanor after 24 h. Twenty-two leukocyte genes were significantly regulated at at least one time point during the experimental period. By close inspection of the temporal responses the dynamic changes in mRNA abundance revealed a very rapid onset of both pro- and anti-inflammatory mediators and a substantial variation in both expression magnitudes and duration of changes between genes. A majority of the 22 significantly regulated genes peaked within the first 8 h after induction, and an on-going, albeit tightly controlled, regulation was seen after 24 h despite approximate clinical recovery.ConclusionsThis first broad study of gene expressions in blood leukocytes during equine acute LPS-induced systemic inflammation thoroughly characterized a highly regulated and dynamic innate immune response. These results provide new insights into the molecular mechanisms of equine systemic inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0450-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

et al. 2015

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“…Lipoteichoic acid and lipopolysaccharide, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo [25], [26]. Lipoteichoic acid is a cell wall component exclusive to Gram-positive bacteria and is shed during bacterial replication and after antibiotic administration [27].…”

Section: Discussionmentioning

confidence: 99%

The Clinical Application Value of Cytokines in Treating Infectious Diseases

Shao

et al. 2014

PLoS ONE

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We performed a prospective study to evaluate the abilities of inflammatory cytokines to rule out the potential risk of sepsis and intracranial infection and to estimate the function of inflammatory cytokines in discriminating Gram-negative bacteria from Gram-positive ones through ROC analysis. During the course of the study, Levels of serum inflammatory cytokines were measured by flow cytometry at the onset of diseases of patients who suffered from sepsis or intracranial infection. A total of 299 cases of sepsis and 43 cases of intracranial infection were observed during the study. It is noticed that there is no difference of inflammatory cytokine levels between sepsis group and intracranial infection group. The area under ROC curve (AUC) of cytokines, such as IL-2, IL-6 and IL-10 were 0.901, 0.86, 0.888, respectively, which was employed to rule out the diseases of sepsis and intracranial infection. Through comparisons with the patients who were infected by Gram-positive bacteria or Gram-negative ones, it is estimated that IL-6 and IL-10 sharply elevated in patients with Gram-negative bacteria infection (median levels, pg/mL: IL-6: 116.6 vs. 25.4, P = 0.000; IL-10: 13.7 vs. 6.3, P = 0.000). Additionally, IL-2 significantly decreased when patients suffered from Gram-negative bacteria infection (median levels, pg/mL: IL-2: 2.2 vs. 2.7, P = 0.031). The AUCs for detecting cytokines, including IL-2, IL-10 and LOGREGR.Pred_IL-2+IL-10 were 0.581 (95% CI, 0.526 to 0.634), 0.661 (95% CI, 0.608 to 0.712) and 0.735 (95% CI, 0.685 to 0.782), respectively, which was used to evaluate the function of inflammatory cytokines in discriminating Gram-negative bacteria from Gram-positive ones infection. This paper indicates that IL-2, IL-6 and IL-10 are effective biomarkers to rule out sepsis and intracranial infection. Additionally, the combination of IL-2 and IL-10 is an effective biomarkers to diagnose whether patients afflicted by Gram-negative bacteria.

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“…Gram positive bacterial infections in young horses are common, and involved in a range of syndromes from reduced performance in young racing thoroughbreds to life-threatening sepsis in neonates [8,9]. Equine peripheral blood mononuclear cells (PBMC) stimulated with the TLR2/1 ligand Pam3CSK4 produce tumour necrosis factor-α (TNF-α), and LTA and PepG also stimulate release of TNF-α in equine whole blood assays [10,11]. These findings suggest TLR2 recognition of bacterial ligands is important in the horse, but do not provide clues regarding how ligands interact with the binding pockets of equine TLR2/1 and TLR2/6 heterodimers, which is important for targeting future therapeutics.…”

Section: Introductionmentioning

confidence: 99%

The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6

Irvine

Hopkins

Gangloff

et al. 2013

Vet Res

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TLR2 recognises bacterial lipopeptides and lipoteichoic acid, and forms heterodimers with TLR1 or TLR6. TLR2 is relatively well characterised in mice and humans, with published crystal structures of human TLR2/1/Pam3CSK4 and murine TLR2/6/Pam2CSK4. Equine TLR4 is activated by a different panel of ligands to human and murine TLR4, but less is known about species differences at TLR2. We therefore cloned equine TLR2, TLR1 and TLR6, which showed over 80% sequence identity with these receptors from other mammals, and performed a structure-function analysis. TLR2/1 and TLR2/6 from both horses and humans dose-dependently responded to lipoteichoic acid from Staphylococcus aureus, with no significant species difference in EC50 at either receptor pair. The EC50 of Pam2CSK4 was the same for equine and human TLR2/6, indicating amino acid differences between the two species' TLRs do not significantly affect ligand recognition. Species differences were seen between the responses to Pam2CSK4 and Pam3CSK4 at TLR2/1. Human TLR2/1, as expected, responded to Pam3CSK4 with greater potency and efficacy than Pam2CSK4. At equine TLR2/1, however, Pam3CSK4 was less potent than Pam2CSK4, with both ligands having similar efficacies. Molecular modelling indicates that the majority of non-conserved ligand-interacting residues are at the periphery of the TLR2 binding pocket and in the ligand peptide-interacting regions, which may cause subtle effects on ligand positioning. These results suggest that there are potentially important species differences in recognition of lipopeptides by TLR2/1, which may affect how the horse deals with bacterial infections.

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Pathogen associated molecular pattern motifs from Gram-positive and Gram-negative bacteria induce different inflammatory mediator profiles in equine blood

Cited by 27 publications

References 43 publications

Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

The Clinical Application Value of Cytokines in Treating Infectious Diseases

The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6

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