Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

Delemarre, Eveline M.; Hoorn, Laura van; Bossink, Aik; Drylewicz, Julia; Joosten, Simone A.; Ottenhoff, Tom H. M.; Akkerman, Onno W.; Goletti, Delia; Petruccioli, Elisa; Navarra, Assunta; Broek, Brigitte T.A. van den; Paardekooper, Sanne P. A.; Haeften, Ineke van; Koenderman, Leo; Lammers, Jan Willem J.; Thijsen, Steven; Hofland, Regina W.; Nierkens, Stefan

doi:10.3389/fimmu.2021.725447

Cited by 28 publications

(32 citation statements)

References 62 publications

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“…VEGFA, IL6, and IFN-gamma were identified in at least two other proteomic studies (29-33), while CD274 (also called PD-L1) was observed in several published transcriptional signatures. IP-10 (also called CXCL10), which was removed due to its high expression in severe viral LRT and sarcoidosis appears in several proteomic studies (30-33). The other markers were less common or identified in the current study.…”

Section: Resultsmentioning

confidence: 99%

“…VEGF was also included in a 4-protein signature (CCL1, CXCL10, ADA-2, VEGF) proposed by Delemarre et al (30), where they compared active TB to treated and untreated latent TB. The signature was validated in two separate patient cohorts with a sensitivity of 95% and a specificity of 90%.…”

Section: Discussionmentioning

confidence: 99%

“…We then compared the 12-marker signature with the other published gene signatures from the TBSignatureProfiler R package (28) and published protein signatures to investigate overlap between protein and transcriptional signatures with the proteins of our signature (Figure 5C). VEGFA, IL6, and IFN-gamma were identified in at least two other proteomic studies (29)(30)(31)(32)(33), while CD274 (also called PD-L1) was observed in several published transcriptional signatures. IP-10 (also called CXCL10), which was removed due to its high expression in severe viral LRT and sarcoidosis appears in several proteomic studies (30)(31)(32)(33).…”

Section: Identification Of a New 12-protein Signature For Active Tb D...mentioning

confidence: 98%

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A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis

Mousavian

Folkesson

Fröberg

et al. 2022

Preprint

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ObjectivesTuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis. Annually, an estimated 10 million people are diagnosed with active TB, and approximately 1.4 million dies of the disease. If left untreated, each person with active TB will infect 10 to 15 new individuals every year. Therefore, interrupting disease transmission by accurate early detection and diagnosis, paired with appropriate treatment is of major importance. In this study, we aimed to identify biomarkers associated with the development of active TB that can then be further developed for clinical testing.MethodsWe assessed the relative plasma concentration of 92 proteins associated with inflammation in individuals with active TB (n=19), latent TB (n=13), or healthy controls (n=10). We then constructed weighted protein co-expression networks to reveal correlations between protein expression profiles in all samples. After clustering the networks into four modules, we assessed their association with active TB.ResultsOne module consisting of 16 proteins was highly associated with active TB. We used multiple independent transcriptomic datasets from studies investigating respiratory infections and non-TB diseases. We then identified and removed genes encoding proteins within the module that were low expressed in active TB or associated with non-TB diseases, resulting in a 12-protein plasma signature associated with active TB.ConclusionWe identified a plasma protein signature that is highly enriched in patients with active TB but not in individuals with latent TB or healthy controls and that also had minimal cross-reactivity with common viral or bacterial lower respiratory tract infections.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of a New 12-protein Signature For Active Tb D...mentioning

confidence: 98%

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A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis

Mousavian

Folkesson

Fröberg

et al. 2022

Preprint

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“…The sensitivities achieved with these combinations are similar to those reported in a few other studies aiming to define combinations of biomarkers that provide diagnostic test accuracy consistent with WHO specifications for a rule-out test for aTB. These studies that were recently summarized ( 25 ), are based on combinations of various serum markers, mostly cytokines/chemokines ( 26 – 28 ), sometimes combined with antibodies against a TB antigen to raise the specificity for TB ( 29 ). We chose in our study to measure cytokines/chemokines released in response to mycobacterial antigens to increase the specificity for TB.…”

Section: Discussionmentioning

confidence: 99%

Immuno-Diagnosis of Active Tuberculosis by a Combination of Cytokines/Chemokines Induced by Two Stage-Specific Mycobacterial Antigens: A Pilot Study in a Low TB Incidence Country

et al. 2022

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Active tuberculosis (aTB) remains a major killer from infectious disease, partially due to delayed diagnosis and hence treatment. Classical microbiological methods are slow and lack sensitivity, molecular techniques are costly and often unavailable. Moreover, available immuno-diagnostic tests lack sensitivity and do not differentiate between aTB and latent TB infection (LTBI). Here, we evaluated the performance of the combined measurement of different chemokines/cytokines induced by two different stage-specific mycobacterial antigens, Early-secreted-antigenic target-6 (ESAT-6) and Heparin-binding-haemagglutinin (HBHA), after a short in vitro incubation of either peripheral blood mononuclear cells (PBMC) or whole blood (WB). Blood samples were collected from a training cohort comprising 22 aTB patients, 22 LTBI subjects and 17 non-infected controls. The concentrations of 13 cytokines were measured in the supernatants. Random forest analysis identified the best markers to differentiate M. tuberculosis-infected from non-infected subjects, and the most appropriate markers to differentiate aTB from LTBI. Logistic regression defined predictive abilities of selected combinations of cytokines, first on the training and then on a validation cohort (17 aTB, 27 LTBI, 25 controls). Combining HBHA- and ESAT-6-induced IFN-γ concentrations produced by PBMC was optimal to differentiate infected from non-infected individuals in the training cohort (100% correct classification), but 2/16 (13%) patients with aTB were misclassified in the validation cohort. ESAT-6-induced-IP-10 combined with HBHA-induced-IFN-γ concentrations was selected to differentiate aTB from LTBI, and correctly classified 82%/77% of infected subjects as aTB or LTBI in the training/validation cohorts, respectively. Results obtained on WB also selected ESAT-6- and HBHA-induced IFN-γ concentrations to provided discrimination between infected and non-infected subjects (89%/90% correct classification in the training/validation cohorts). Further identification of aTB patients among infected subjects was best achieved by combining ESAT-6-induced IP-10 with HBHA-induced IL-2 and GM-CSF. Among infected subjects, 90%/93% of the aTB patients were correctly identified in the training/validation cohorts. We therefore propose a two steps strategy performed on 1 mL WB for a rapid identification of patients with aTB. After elimination of most non-infected subjects by combining ESAT-6 and HBHA-induced IFN-γ, the combination of IP-10, IL-2 and GM-CSF released by either ESAT-6 or HBHA correctly identifies most patients with aTB.

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“…ADA2 is highly expressed in myeloid cells and produced by activated monocytes, macrophages, and DC in the sites of inflammation and TME [81]. Besides, ADA2 is secreted by monocytes during differentiation into macrophages or DC, and its secretion is regulated by interferon (IFN)-γ. Immune-inflammatory diseases such as systemic lupus erythematosis, rheumatoid arthritis, Chrone's diseases, tuberculosis, and HIV infection, are associated with an enhancement in the activity of ADA2, which can be used as a biomarker of the disease and response to treatment, especially in patients with tuberculosis [82][83][84][85]. It is reported that ADA2 can act as a growth factor [86].…”

Section: The Biological Significance Of Adenosine Deaminasementioning

confidence: 99%

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

et al. 2022

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The immunosuppressive effect of adenosine in the microenvironment of a tumor is well established. Presently, researchers are developing approaches in immune therapy that target inhibition of adenosine or its signaling such as CD39 or CD73 inhibiting antibodies or adenosine A2A receptor antagonists. However, numerous enzymatic pathways that control ATP-adenosine balance, as well as understudied intracellular adenosine regulation, can prevent successful immunotherapy. This review contains the latest data on two adenosine-lowering enzymes: adenosine kinase (ADK) and adenosine deaminase (ADA). ADK deletes adenosine by its phosphorylation into 5′-adenosine monophosphate. Recent studies have revealed an association between a long nuclear ADK isoform and an increase in global DNA methylation, which explains epigenetic receptor-independent role of adenosine. ADA regulates the level of adenosine by converting it to inosine. The changes in the activity of ADA are detected in patients with various cancer types. The article focuses on the biological significance of these enzymes and their roles in the development of cancer. Perspectives of future studies on these enzymes in therapy for cancer are discussed.

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Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

Cited by 28 publications

References 62 publications

A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis

A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis

Immuno-Diagnosis of Active Tuberculosis by a Combination of Cytokines/Chemokines Induced by Two Stage-Specific Mycobacterial Antigens: A Pilot Study in a Low TB Incidence Country

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

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