Latent Tuberculosis Infection-associated Immunodiagnostic Test Responses as Biomarkers of Incipient Tuberculosis: Fruitful or Futile?
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ABSTRACT:
SUBMITTER: Dheda K
PROVIDER: S-EPMC7159435 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPrecise designation of high risk forms of latent Mycobacterium tuberculosis-M.tb infections (LTBI) is impossible. Delineation of high-risk LTBI can, however, allow for chemoprophylaxis and curtail majority cases of active tuberculosis (ATB). There is epidemiological evidence to support the view that LTBI in context of HIV-1 co-infection is high-risk for progression to ATB relative to LTBI among HIV-ve persons. We recently showed that assays of M.tb thymidylate kinase (TMKmt) antigen and host specific IgG can differentiate ATB from LTBI and or no TB (NTB, or healthy controls). In this study, we aimed to expose the differential levels of TMKmt Ag among HIV+ve co-infected LTBI relative to HIV-ve LTBI as a strategy to advance these assays for designating incipient LTBI.MethodsTMKmt host specific IgM and IgG detection Enzyme Immuno-Assays (EIA) were conducted on 40 TB exposed house-hold contacts (22 LTBI vs. 18 no TB (NTB) by QunatiFERON-TB GOLD®); and TMKmt Ag detection EIA done on 82 LTBI (46 HIV+ve vs 36 HIV-ve) and 9 NTB (American donors). Purified recombinant TMKmt protein was used as positive control for the Ag assays.ResultsIgM levels were found to be equally low across QuantiFERON-TB GOLD® prequalified NTB and TB exposed house-hold contacts. Higher TMKmt host specific IgG trends were found among TB house-hold contacts relative to NTB controls. TMKmt Ag levels among HIV+ve LTBI were 0.2676 ± 0.0197 (95% CI: 0.2279 to 0.3073) relative to 0.1069 ± 0.01628 (95% CI: 0.07385 to 0.14) for HIV-ve LTBI (supporting incipient nature of LTBI in context of HIV-1 co-infection). NTB had TMKmt Ag levels of 0.1013 ± 0.02505 (5% CI: 0.0421 to 0.1606) (intimating that some were indeed LTBI).ConclusionsTMKmt Ag levels represent a novel surrogate biomarker for high-risk LTBI, while host-specific IgG can be used to designate NTB from LTBI.
| S-EPMC5857104 | biostudies-literature
Project description:The association reaction between pairs of proteins proceeds through an encounter complex that develops into the final complex. Here, we combined Brownian dynamics simulations with experimental studies to analyze the structures of the encounter complexes along the association reaction between TEM1-beta-lactamase and its inhibitor, beta-lactamase-inhibitor protein. The encounter complex can be considered as an ensemble of short-lived low free-energy states that are stabilized primarily by electrostatic forces and desolvation. For the wild-type, the simulation showed two main encounter regions located outside the physical binding site. One of these regions was located near the experimentally determined transition state. To validate whether these encounters are fruitful or futile, we examined three groups of mutations that altered the encounter. The first group consisted of mutations that increased the experimental rate of association through electrostatic optimization. This resulted in an increase in the size of the encounter region located near the experimentally determined transition state, as well as a decrease in the energy of this region and an increase in the number of successful trajectories (i.e., encounters that develop into complex). A second group of mutations was specifically designed to either increase or decrease the size and energy of the second encounter complex, but either way it did not affect k(on). A third group of mutations consisted of residues that increased k(on) without significantly affecting the encounter complexes. These results indicate that the size and energy of the encounter regions are only two of several parameters that lead to fruitful association, and that electrostatic optimization is a major driving force in fast association.
| S-EPMC2712199 | biostudies-literature
Project description:Coexistent helminth infections are known to modulate T cell and cytokine responses in latent infection with Mycobacterium tuberculosis However, their role in modulating chemokine responses in latent tuberculosis (LTB) has not been explored. Because chemokines play a vital role in the protective immune responses in LTB, we postulated that coexistent helminth infection could modulate chemokine production in helminth-LTB coinfection. To test this, we measured the levels of a panel of CC and CXC chemokines at baseline and following mycobacterial Ag or mitogen stimulation in individuals with LTB with (Strongyloides stercoralis +LTB+) or without S. stercoralis (S. stercoralis -LTB+) infection and in individuals without both infections, healthy controls (HC). At baseline (in the absence of a stimulus), S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL9, CXCL10, and CXCL11 in comparison with S. stercoralis -LTB+ and/or HC individuals. Upon mycobacterial Ag stimulation, S. stercoralis +LTB+ individuals exhibited significantly diminished production of CCL1, CCL2, CCL4, CCL11, CXCL2, CXCL9, and CXCL10 in comparison with S. stercoralis -LTB+ and/or HC individuals. No differences were observed upon mitogen stimulation. Finally, after anthelmintic treatment, the baseline levels of CCL1, CCL2, CCL4, CCL11, and CXCL11 and mycobacterial Ag-stimulated levels of CCL1, CCL2, CCL11, CXCL2, and CXCL10 were significantly increased in S. stercoralis +LTB+ individuals. Thus, our data demonstrate that S. stercoralis +LTB+ individuals are associated with a compromised ability to express both CC and CXC chemokines and that this defect is at least partially reversible upon treatment. Hence, coexistent helminth infection induces downmodulation of chemokine responses in LTB individuals with likely potential effects on tuberculosis pathogenesis.
| S-EPMC6382527 | biostudies-literature
Project description:BackgroundThe challenges posed by Mycobacterium tuberculosis infection require the gradual removal of the pool of latent tuberculosis infection (LTBI). The current cell-immune-based diagnostic tests used to identify LTBI individuals have several irreversible drawbacks. In the present study, we attempted to identify novel diagnostic antigens for LTBI.MethodsA high-throughput glutathione S-transferase (GST)-fusion technology was used to express over 409 TB proteins and sera from LTBI and healthy individuals was used to interrogate these GST-TB fusion proteins.ResultsOf 409 TB proteins, sixty-three reacted seropositive and defined the immuno-ORFeome of latent M. tuberculosis. Within the immuno-ORFeome, the rare targets were predominantly latency-associated proteins and secreted proteins, while the preferentially recognized antigens tended to be transmembrane proteins. Six of novel highly-reactive antigens had the potential to distinguish LTBI from active TB and healthy individuals. A multiple-antigen combination set was selected through analysis of various combinations. A panel of 94 archived serum samples was used to validate the diagnostic performance of the multiple-antigen combination set, which had sensitivity of 66.1% (95% CI 52.9, 77.4) and specificity of 87.5% (95% CI 70.1, 95.1).ConclusionThese results provide experimental evidence of the immunogenicity of novel TB proteins that are suitable for the development of serodiagnostic tools for LTBI.
| S-EPMC5745629 | biostudies-literature
Project description:RationaleLatent tuberculosis infection (LTBI) test discordance is poorly understood.ObjectivesTo determine the frequency and predictors of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFT) discordance in the U.S.MethodsWe analyzed data from a representative sample of the U.S. population ages 6 years and older who participated in the 2011-2012 National Health and Nutrition Examination Survey. We determined prevalence estimates of test positivity, calculated test agreement and kappa statistics, and performed multivariable logistic regression to determine predictors of discordance.Measurements and main resultsLTBI prevalence among the U.S. born ranged from 0.6% to 2.8%, depending on how LTBI was defined, with test agreement 97.0% and kappa 0.27 (95% confidence interval, 0.18-0.36). Prevalence among the foreign born ranged from 9.1% to 20.3%, depending on how LTBI was defined, with test agreement 81.6% and kappa 0.38 (95% confidence interval, 0.33-0.44). TST(+)/QFT(-) discordance was associated with age, male sex, black race, Mexican-American ethnicity, previous TB exposure, and past LTBI treatment in U.S.-born participants, but only with higher lymphocyte count in foreign-born participants. TST(-)/QFT(+) discordance was associated with older age, previous TB exposure, and past LTBI treatment in U.S.-born participants and with older age, male sex, and past LTBI treatment in foreign-born participants.ConclusionsIn the largest population-based sample of concurrently performed TST and QFT tests in a low tuberculosis incidence population, prevalence estimates depended heavily on how LTBI was defined and test agreement was only fair. We identified several predictors of discordance warranting further study.
| S-EPMC5003328 | biostudies-literature
Project description:The study aimed to identify the potential biomarkers in pulmonary tuberculosis (TB) and TB latent infection based on bioinformatics analysis.The microarray data of GSE57736 were downloaded from Gene Expression Omnibus database. A total of 7 pulmonary TB and 8 latent infection samples were used to identify the differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was constructed by Cytoscape software. Then network-based neighborhood scoring analysis was performed to identify the important genes. Furthermore, the functional enrichment analysis, correlation analysis and logistic regression analysis for the identified important genes were performed.A total of 1084 DEGs were identified, including 565 down- and 519 up-regulated genes. The PPI network was constructed with 446 nodes and 768 edges. Down-regulated genes RIC8 guanine nucleotide exchange factor A (RIC8A), basic leucine zipper transcription factor, ATF-like (BATF) and microtubule associated monooxygenase, calponin LIM domain containing 1 (MICAL1) and up-regulated genes ATPase, Na+/K+ transporting, alpha 4 polypeptide (ATP1A4), histone cluster 1, H3c (HIST1H3C), histone cluster 2, H3d (HIST2H3D), histone cluster 1, H3e (HIST1H3E) and tyrosine kinase 2 (TYK2) were selected as important genes in network-based neighborhood scoring analysis. The functional enrichment analysis results showed that these important DEGs were mainly enriched in regulation of osteoblast differentiation and nucleoside triphosphate biosynthetic process. The gene pairs RIC8A-ATP1A4, HIST1H3C-HIST2H3D, HIST1H3E-BATF and MICAL1-TYK2 were identified with high positive correlations. Besides, these genes were selected as significant feature genes in logistic regression analysis.The genes such as RIC8A, ATP1A4, HIST1H3C, HIST2H3D, HIST1H3E, BATF, MICAL1 and TYK2 may be potential biomarkers in pulmonary TB or TB latent infection.
| S-EPMC5031349 | biostudies-literature
Project description:BackgroundInterferon gamma release assays (IGRAs) are widely used to determine latent tuberculosis infection status. However, its pregnancy-affected performance and cost-expensive nature warrants for different alternatives for pregnant women. This study aims to evaluate the diagnostic performance of several alternative cytokines, including interleukin 2 (IL-2), interleukin 10 (IL-10), and interferon gamma-induced protein 10 (IP-10) to identify latent tuberculosis status in pregnant women.Materials and methods123 pregnant womens were recruited for this study. The IGRA status was determined by using QuantiFERON Gold In-Tube. Meanwhile, we measured the level IL-2, IL-10, and IP-10 by using sandwich-microELISA method. We performed normality and comparison test by SPSS. In addition, receiver-operator characteristic (ROC) analyses and the optimal cutoff scores were identified using the EasyROC webtool.ResultsWe showed that IL-2, IL-10, and IP-10 were able to discriminate between IGRA-negative and IGRA-positive pregnant women. Moreover, IP-10 showed the highest discriminatory and diagnostic performance when compared to IL-2 and IL-10 with area under the curve (AUC) of 0.96 and cutoff point of 649.65 pg/mL.ConclusionsOur study showed that IP-10 can be considered as a promising alternative biomarker for IGRAs to diagnose LTBI in pregnant women.
| S-EPMC9269918 | biostudies-literature
Project description:A proteomic analysis was performed to screen the potential latent tuberculosis infection (LTBI) biomarkers. A training set of spectra was used to generate diagnostic models, and a blind testing set was used to determine the accuracy of the models. Candidate peptides were identified using nano-liquid chromatography-electrospray ionization-tandem mass spectrometry. Based on the training set results, 3 diagnostic models recognized LTBI subjects with good cross-validation accuracy. In the blind testing set, LTBI subjects could be identified with sensitivities and specificities of 85.20% to 88.90% and 85.7% to 100%, respectively. Additionally, 14 potential LTBI biomarkers were identified, and all proteins were identified for the first time through proteomics in the plasma of healthy, latently infected individuals. In all, proteomic pattern analyses can increase the accuracy of LTBI diagnosis, and the data presented here provide novel insights into potential mechanisms involved in LTBI.
| S-EPMC7127109 | biostudies-literature
Project description:The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-γ), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B (P <0.00001). In addition, antigen stimulation increased the expression of heparin-binding EGF-like growth factor (HB-EGF) and activin AB in LTBI samples. In nil tubes, LIGHT was the most significant marker (P <0.0001) and was elevated in LTBI subjects. Other prominent markers in nonstimulated QFT-GIT supernatants were the complement-3 components C3b, iC3b, and C3d, which were upregulated in LTBI and markedly decreased upon stimulation. We found known and novel proteins that warrant further studies for developing improved tests for LTBI, for predicting progression to active disease, and for discriminating LTBI from active TB.
| S-EPMC5277508 | biostudies-literature
Project description:BackgroundLack of a gold standard for latent TB infection has precluded direct measurement of test characteristics of the tuberculin skin test and interferon-γ release assays (QuantiFERON Gold In-Tube and T-SPOT.TB).ObjectiveWe estimated test sensitivity/specificity and latent TB infection prevalence in a prospective, US-based cohort of 10 740 participants at high risk for latent infection.MethodsBayesian latent class analysis was used to estimate test sensitivity/specificity and latent TB infection prevalence among subgroups based on age, foreign birth outside the USA and HIV infection.ResultsLatent TB infection prevalence varied from 4.0% among foreign-born, HIV-seronegative persons aged <5 years to 34.0% among foreign-born, HIV-seronegative persons aged ≥5 years. Test sensitivity ranged from 45.8% for the T-SPOT.TB among foreign-born, HIV-seropositive persons aged ≥5 years to 80.7% for the tuberculin skin test among foreign-born, HIV-seronegative persons aged ≥5 years. The skin test was less specific than either interferon-γ release assay, particularly among foreign-born populations (eg, the skin test had 70.0% specificity among foreign-born, HIV-seronegative persons aged ≥5 years vs 98.5% and 99.3% specificity for the QuantiFERON and T-SPOT.TB, respectively). The tuberculin skin test's positive predictive value ranged from 10.0% among foreign-born children aged <5 years to 69.2% among foreign-born, HIV-seropositive persons aged ≥5 years; the positive predictive values of the QuantiFERON (41.4%) and T-SPOT.TB (77.5%) were also low among US-born, HIV-seropositive persons aged ≥5 years.ConclusionsThese data reinforce guidelines preferring interferon-γ release assays for foreign-born populations and recommending against screening populations at low risk for latent TB infection.Trial registration numberNCT01622140.
| S-EPMC6494673 | biostudies-literature