Induction of indoleamine 2,3-dioxygenase by <i>Borrelia burgdorferi</i> in human immune cells correlates with pathogenic potential

Love, Andrea; Schwartz, Ira; Petzke, Mary M.

doi:10.1189/jlb.4a0714-339r

Cited by 15 publications

(15 citation statements)

References 82 publications

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“…1c and Supplementary Table S1 ). Since increased catabolism of tryptophan via IDO has been described in infectious diseases, including Lyme disease 17 – 22 , metabolites in this pathway were targeted for identification and quantitation. Xanthurenic acid, tryptophan, kynurenine, kynurenic acid, anthranilic acid, and quinolinic acid were confirmed based on their m/z and RT in pooled patient urine (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The alteration of tyrosine and phenylalanine metabolism has also been found to occur when fatigue, fever and/or loss of appetite occur 43 , 51 , 54 . The association between tryptophan catabolism and infectious diseases including LD 17 – 22 was of particular interest and led us to a directed evaluation of selected metabolites from this pathway (Fig. 3 ).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Urine Metabolites as Biomarkers of Early Lyme Disease

Pegalajar‐Jurado

Fitzgerald

Islam

et al. 2018

Sci Rep

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Metabolites detectible in human biofluids are attractive biomarkers for the diagnosis of early Lyme disease (ELD), a vector-borne infectious disease. Urine represents an easily obtained clinical sample that can be applied for diagnostic purposes. However, few studies have explored urine for biomarkers of ELD. In this study, metabolomics approaches were applied to evaluate small molecule metabolites in urine from patients with ELD (n = 14), infectious mononucleosis (n = 14) and healthy controls (n = 14). Metabolic biosignatures for ELD versus healthy controls and ELD versus infectious mononucleosis were generated using untargeted metabolomics. Pathway analyses and metabolite identification revealed the dysregulation of several metabolic processes in ELD as compared to healthy controls or mononucleosis, including metabolism of tryptophan. Linear discriminant analyses demonstrated that individual metabolic biosignatures can correctly discriminate ELD from the other patient groups with accuracies of 71 to 100%. These data provide proof-of-concept for use of urine metabolites as biomarkers for diagnostic classification of ELD.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of Urine Metabolites as Biomarkers of Early Lyme Disease

Pegalajar‐Jurado

Fitzgerald

Islam

et al. 2018

Sci Rep

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“…One proposed mechanism for type I IFN-mediated bacterial pathogenesis occurs via suppression of myeloid cells [ 59 ]. Indeed, we have demonstrated that B. burgdorferi B31-A3, an RST1 strain that readily disseminates in mice, induces significantly higher expression of both IFN-α [ 23 ] and indoleamine 2,3-dioxygenase [ 60 ], an enzyme with immunomodulatory functions in human myeloid and plasmacytoid dendritic cells [ 61 ], as compared to a mutant strain that is severely attenuated for infectivity. Expression of indoleamine 2,3-dioxygenase was found to be driven by the concerted actions of both B. burgdorferi -induced IFN-γ and type I IFN [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, we have demonstrated that B. burgdorferi B31-A3, an RST1 strain that readily disseminates in mice, induces significantly higher expression of both IFN-α [ 23 ] and indoleamine 2,3-dioxygenase [ 60 ], an enzyme with immunomodulatory functions in human myeloid and plasmacytoid dendritic cells [ 61 ], as compared to a mutant strain that is severely attenuated for infectivity. Expression of indoleamine 2,3-dioxygenase was found to be driven by the concerted actions of both B. burgdorferi -induced IFN-γ and type I IFN [ 60 ]. The expression of type I IFN and IFN-responsive genes in mouse skin may therefore comprise a fingerprint of activated suppressor dendritic cells, which potentially could be manipulated by the spirochete in order to promote pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Borrelia burgdorferi induces a type I interferon response during early stages of disseminated infection in mice

et al. 2016

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BackgroundLyme borrelia genotypes differ in their capacity to cause disseminated disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia burgdorferi strains with different capacities for causing disseminated disease in the blood of C3H/HeJ mice during early infection.ResultsB. burgdorferi B515, a clinical isolate that causes disseminated infection in mice, differentially regulated 236 transcripts (P < 0.05 by ANOVA, with fold change of at least 2). The 216 significantly induced transcripts included interferon (IFN)-responsive genes and genes involved in immunity and inflammation. In contrast, B. burgdorferi B331, a clinical isolate that causes transient skin infection but does not disseminate in C3H/HeJ mice, stimulated changes in only a few genes (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by quantitative RT-PCR in mouse skin biopsies collected from the site of infection 24 h after inoculation with B. burgdorferi. The mean values for transcripts of Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2 were found to be significantly increased in B. burgdorferi strain B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B. burgdorferi strain B331 or B31-4, a mutant that is unable to disseminate.ConclusionsThese results establish a positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction in a murine model of Lyme disease.

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“…Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus and the anterior midcingulate cortex compared to controls 95. Quinolinic acid in cerebrospinal fluid is increased in a number of chronic infections including B. burgdorferi infections and correlates with “symptom severity” and “pathological potential” 96,97…”

Section: Introductionmentioning

confidence: 99%

Suicide and Lyme and associated diseases

Bransfield¹

2017

NDT

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PurposeThe aim of this paper is to investigate the association between suicide and Lyme and associated diseases (LAD). No journal article has previously performed a comprehensive assessment of this subject.IntroductionMultiple case reports and other references demonstrate a causal association between suicidal risk and LAD. Suicide risk is greater in outdoor workers and veterans, both with greater LAD exposure. Multiple studies demonstrate many infections and the associated proinflammatory cytokines, inflammatory-mediated metabolic changes, and quinolinic acid and glutamate changes alter neural circuits which increase suicidality. A similar pathophysiology occurs in LAD.MethodA retrospective chart review and epidemiological calculations were performed.ResultsLAD contributed to suicidality, and sometimes homicidality, in individuals who were not suicidal before infection. A higher level of risk to self and others is associated with multiple symptoms developing after acquiring LAD, in particular, explosive anger, intrusive images, sudden mood swings, paranoia, dissociative episodes, hallucinations, disinhibition, panic disorder, rapid cycling bipolar, depersonalization, social anxiety disorder, substance abuse, hypervigilance, generalized anxiety disorder, genital–urinary symptoms, chronic pain, anhedonia, depression, low frustration tolerance, and posttraumatic stress disorder. Negative attitudes about LAD from family, friends, doctors, and the health care system may also contribute to suicide risk. By indirect calculations, it is estimated there are possibly over 1,200 LAD suicides in the US per year.ConclusionSuicidality seen in LAD contributes to causing a significant number of previously unexplained suicides and is associated with immune-mediated and metabolic changes resulting in psychiatric and other symptoms which are possibly intensified by negative attitudes about LAD from others. Some LAD suicides are associated with being overwhelmed by multiple debilitating symptoms, and others are impulsive, bizarre, and unpredictable. Greater understanding and a direct method of acquiring LAD suicide statistics is needed. It is suggested that medical examiners, the Centers for Disease Control and Prevention, and other epidemiological organizations proactively evaluate the association between LAD and suicide.

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Induction of indoleamine 2,3-dioxygenase by Borrelia burgdorferi in human immune cells correlates with pathogenic potential

Cited by 15 publications

References 82 publications

Identification of Urine Metabolites as Biomarkers of Early Lyme Disease

Identification of Urine Metabolites as Biomarkers of Early Lyme Disease

Borrelia burgdorferi induces a type I interferon response during early stages of disseminated infection in mice

Suicide and Lyme and associated diseases

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