Gene expression profiles classifying clinical stages of tuberculosis and monitoring treatment responses in Ethiopian HIV-negative and HIV-positive cohorts


Autoři: Gebremedhin Gebremicael aff001;  Desta Kassa aff001;  Yodit Alemayehu aff001;  Atsbeha Gebreegziaxier aff001;  Yonas Kassahun aff003;  Debbie van Baarle aff004;  Tom H. M. Ottenhoff aff005;  Jacqueline M. Cliff aff002;  Mariëlle C. Haks aff005
Působiště autorů: HIV and TB Diseases Research Directorate, Ethiopian Public Health Institute (EPHI), Addis Ababa, Ethiopia aff001;  TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, England, United Kingdom aff002;  Armauer Hansen Research Institute, Addis Ababa, Ethiopia aff003;  Center for Immunology of Infectious Diseases and Vaccins (IIV), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands aff004;  Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226137

Souhrn

Background

Validation of previously identified candidate biomarkers and identification of additional candidate gene expression profiles to facilitate diagnosis of tuberculosis (TB) disease and monitoring treatment responses in the Ethiopian context is vital for improving TB control in the future.

Methods

Expression levels of 105 immune-related genes were determined in the blood of 80 HIV-negative study participants composed of 40 active TB cases, 20 latent TB infected individuals with positive tuberculin skin test (TST+), and 20 healthy controls with no Mycobacterium tuberculosis (Mtb) infection (TST-), using focused gene expression profiling by dual-color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification assay. Gene expression levels were also measured six months after anti-TB treatment (ATT) and follow-up in 38 TB patients.

Results

The expression of 15 host genes in TB patients could accurately discriminate between TB cases versus both TST+ and TST- controls at baseline and thus holds promise as biomarker signature to classify active TB disease versus latent TB infection in an Ethiopian setting. Interestingly, the expression levels of most genes that markedly discriminated between TB cases versus TST+ or TST- controls did not normalize following completion of ATT therapy at 6 months (except for PTPRCv1, FCGR1A, GZMB, CASP8 and GNLY) but had only fully normalized at the 18 months follow-up time point. Of note, network analysis comparing TB-associated host genes identified in the current HIV-negative TB cohort to TB-associated genes identified in our previously published Ethiopian HIV-positive TB cohort, revealed an over-representation of pattern recognition receptors including TLR2 and TLR4 in the HIV-positive cohort which was not seen in the HIV-negative cohort. Moreover, using ROC cutoff ≥ 0.80, FCGR1A was the only marker with classifying potential between TB infection and TB disease regardless of HIV status.

Conclusions

Our data indicate that complex gene expression signatures are required to measure blood transcriptomic responses during and after successful ATT to fully diagnose TB disease and characterise drug-induced relapse-free cure, combining genes which resolve completely during the 6-months treatment phase of therapy with genes that only fully return to normal levels during the post-treatment resolution phase.

Klíčová slova:

Blood – Gene expression – Immune response – Pattern recognition receptors – T cells – Tuberculosis – Tuberculosis diagnosis and management


Zdroje

1. Vitoria M, Granich R, Gilks CF, Gunneberg C, Hosseini M, Were W, et al. The global fight against HIV/AIDS, tuberculosis, and malaria: current status and future perspectives. Am J Clin Pathol2009 Jun;131(6):844–8. doi: 10.1309/AJCP5XHDB1PNAEYT 19461091

2. WHO. GLOBAL TUBERCULOSIS REPORT 2018. https://www.who.int/tb/publications/global_report/en/.

3. WHO. Global strategy and targets for tuberculosis prevention, care and control after 2015. <http://www.who.int/tb/post2015_TBstrategy.pdf>.

4. Parida SK, Kaufmann SH. The quest for biomarkers in tuberculosis. Drug Discov Today Feb;15(3–4):148–57.

5. Nahid P, Saukkonen J, Kenzie WRM, Johnson JL, Phillips PPJ, Andersen J, et al. Tuberculosis Biomarker and Surrogate Endpoint Research Roadmap. American Journal of Respiratory and Critical Care Medicine;184(8):972–9. doi: 10.1164/rccm.201105-0827WS 21737585

6. Walzl G, Ronacher K, Hanekom W, Scriba TJ, Zumla A. Immunological biomarkers of tuberculosis. Nat Rev Immunol May;11(5):343–54. doi: 10.1038/nri2960 21475309

7. Mehta PK, Raj A, Singh N, Khuller GK. Diagnosis of extrapulmonary tuberculosis by PCR. FEMS Immunol Med Microbiol Oct;66(1):20–36. doi: 10.1111/j.1574-695X.2012.00987.x 22574812

8. Parsons LM, Somoskovi A, Gutierrez C, Lee E, Paramasivan CN, Abimiku A, et al. Laboratory diagnosis of tuberculosis in resource-poor countries: challenges and opportunities. Clin Microbiol Rev Apr;24(2):314–50. doi: 10.1128/CMR.00059-10 21482728

9. Pai M, Denkinger CM, Kik SV, Rangaka MX, Zwerling A, Oxlade O, et al. Gamma interferon release assays for detection of Mycobacterium tuberculosis infection. Clin Microbiol Rev2014 Jan;27(1):3–20. doi: 10.1128/CMR.00034-13 24396134

10. Goletti D, Petruccioli E, Joosten SA, Ottenhoff THM. Tuberculosis Biomarkers: From Diagnosis to Protection. Infectious disease reports;8(2):6568–. doi: 10.4081/idr.2016.6568 27403267

11. Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature Aug 19;466(7309):973–7. doi: 10.1038/nature09247 20725040

12. Ottenhoff THM, Dass RH, Yang N, Zhang MM, Wong HEE, Sahiratmadja E, et al. Genome-Wide Expression Profiling Identifies Type 1 Interferon Response Pathways in Active Tuberculosis. PLoS ONE2012;7(9):e45839. doi: 10.1371/journal.pone.0045839 23029268

13. Maertzdorf J, Repsilber D, Parida SK, Stanley K, Roberts T, Black G, et al. Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun2011 Jan;12(1):15–22. doi: 10.1038/gene.2010.51 20861863

14. Lu C, Wu J, Wang H, Wang S, Diao N, Wang F, et al. Novel Biomarkers Distinguishing Active Tuberculosis from Latent Infection Identified by Gene Expression Profile of Peripheral Blood Mononuclear Cells. PLoS ONE2011;6(8):e24290. doi: 10.1371/journal.pone.0024290 21904626

15. Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, Krensky AM, et al. Messenger RNA Expression of IL-8, FOXP3, and IL-12β Differentiates Latent Tuberculosis Infection from Disease. Journal of immunology (Baltimore, Md: 1950)2007;178(6):3688–94.

16. Kaforou M, Wright VJ, Oni T, French N, Anderson ST, Bangani N, et al. Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study. PLOS Medicine;10(10):e1001538. doi: 10.1371/journal.pmed.1001538 24167453

17. Warsinske HC, Rao AM, Moreira FMF, Santos PCP, Liu AB, Scott M, et al. Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment ResponseProgression and Diagnosis of Tuberculosis, Disease Severity, and Treatment ResponseProgression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response. JAMA Network Open 2/12/2019;1(6):e183779–e.

18. Joosten SA, Goeman JJ, Sutherland JS, Opmeer L, de Boer KG, Jacobsen M, et al. Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay. Genes Immun2012;13.

19. Lalor MK, Floyd S, Gorak-Stolinska P, Ben-Smith A, Weir RE, Smith SG, et al. BCG vaccination induces different cytokine profiles following infant BCG vaccination in the UK and Malawi. The Journal of Infectious Diseases;204(7):1075–85. doi: 10.1093/infdis/jir515 21881123

20. Abera B, Alem A, Cherenet A, Kibret M. Immunological and hematological reference values for apparently healthy HIV-negative adults in Bahir Dar Town, Ethiopia. 20162016 2016-09-29;26(3).

21. Mihret A, Loxton AG, Bekele Y, Kaufmann SH, Kidd M, Haks MC, et al. Combination of gene expression patterns in whole blood discriminate between tuberculosis infection states. BMC Infectious Diseases. [journal article]. 2014 May 13;14(1):257.

22. WHO. Tuberculosis, Leprosy and TB/HIV Prevention and Control Programme Manual Fourth Edition. 2008.

23. Geluk A, van Meijgaarden KE, Wilson L, Bobosha K, van der Ploeg-van Schip JJ, van den Eeden SJ, et al. Longitudinal immune responses and gene expression profiles in type 1 leprosy reactions. J Clin Immunol2014 Feb;34(2):245–55. doi: 10.1007/s10875-013-9979-x 24370984

24. Gebremicael G, Kassa D, Quinten E, Alemayehu Y, Gebreegziaxier A, Belay Y, et al. Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy. The Journal of Infectious Diseases;218(11):1833–46. doi: 10.1093/infdis/jiy404 29982697

25. Jenum S, Bakken R, Dhanasekaran S, Mukherjee A, Lodha R, Singh S, et al. BLR1 and FCGR1A transcripts in peripheral blood associate with the extent of intrathoracic tuberculosis in children and predict treatment outcome. Scientific Reports2016;6:38841. doi: 10.1038/srep38841 27941850

26. Yang Y, Li X, Cui W, Guan L, Shen F, Xu J, et al. Potential association of pulmonary tuberculosis with genetic polymorphisms of toll-like receptor 9 and interferon-gamma in a Chinese population. BMC Infectious Diseases. [journal article]. October 31;13(1):511.

27. Jacobsen M, Repsilber D, Gutschmidt A, Neher A, Feldmann K, Mollenkopf HJ, et al. Ras-Associated Small GTPase 33A, a Novel T Cell Factor, Is Down-Regulated in Patients with Tuberculosis. The Journal of Infectious Diseases2005;192(7):1211–8. doi: 10.1086/444428 16136464

28. Davis BK, Wen H, Ting JP. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol;29:707–35. doi: 10.1146/annurev-immunol-031210-101405 21219188

29. Inflammasomes and the Innate Immune Response Against Yersinia Pestis: A Dissertation. (2013). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 649. doi: 10.13028/M29W31 http://escholarship.umassmed.edu/gsbs_diss/649.

30. Sutherland JS, Loxton AG, Haks MC, Kassa D, Ambrose L, Lee JS, et al. Differential gene expression of activating Fcgamma receptor classifies active tuberculosis regardless of human immunodeficiency virus status or ethnicity. Clin Microbiol Infect Apr;20(4):O230–8.

31. Winslow GM, Cooper A, Reiley W, Chatterjee M, Woodland DL. Early T-cell responses in tuberculosis immunity. Immunological reviews2008;225: doi: 10.1111/j.600-065X.2008.00693.x

32. Zaidi S, Motabi I, Al-Shanqeeti A. Neural cell adhesion molecule (cluster of differentiation 56) in health and disease. Journal of Applied Hematology. [Review Article]. July 1, 2015;6(3):93–105.

33. Jiang H, Gong H, Zhang Q, Gu J, Liang L, Zhang J. Decreased expression of perforin in CD8 + T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment. Journal of Thoracic Disease;9(5):1353–60. doi: 10.21037/jtd.2017.05.74 28616288

34. Sahiratmadja E, Alisjahbana B, Buccheri S, Di Liberto D, de Boer T, Adnan I, et al. Plasma granulysin levels and cellular interferon-Î3 production correlate with curative host responses in tuberculosis, while plasma interferon-Î3 levels correlate with tuberculosis disease activity in adults. Tuberculosis2007;87(4):312–21. doi: 10.1016/j.tube.2007.01.002 17382591

35. Di Liberto D, Buccheri S, Caccamo N, Meraviglia S, Romano A, Di Carlo P, et al. Decreased serum granulysin levels in childhood tuberculosis which reverse after therapy. Tuberculosis (Edinb)2007 Jul;87(4):322–8.

36. Bloom CI, Graham CM, Berry MP, Wilkinson KA, Oni T, Rozakeas F, et al. Detectable changes in the blood transcriptome are present after two weeks of antituberculosis therapy. PloS one2012;7(10):e46191. doi: 10.1371/journal.pone.0046191 23056259

37. Jacobsen M, Mattow J, Repsilber D, Kaufmann SH. Novel strategies to identify biomarkers in tuberculosis. Biol Chem2008 May;389(5):487–95. doi: 10.1515/bc.2008.053 18953715

38. Maertzdorf J, Ota M, Repsilber D, Mollenkopf HJ, Weiner J, Hill PC, et al. Functional correlations of pathogenesis-driven gene expression signatures in tuberculosis. PloS one2011;6(10):e26938. doi: 10.1371/journal.pone.0026938 22046420

39. Chang J-S, Huggett JF, Dheda K, Kim LU, Zumla A, Rook GAW. Myobacterium tuberculosis Induces Selective Up-Regulation of TLRs in the Mononuclear Leukocytes of Patients with Active Pulmonary Tuberculosis. The Journal of Immunology2006;176(5):3010–8. doi: 10.4049/jimmunol.176.5.3010 16493059

40. van der Poel CE, Spaapen RM, van de Winkel JG, Leusen JH. Functional characteristics of the high affinity IgG receptor, FcgammaRI. J Immunol2011 Mar 1;186(5):2699–704. doi: 10.4049/jimmunol.1003526 21325219

41. Fenhalls G, Squires GR, Stevens-Muller L, Bezuidenhout J, Amphlett G, Duncan K, et al. Associations between toll-like receptors and interleukin-4 in the lungs of patients with tuberculosis. Am J Respir Cell Mol Biol2003 Jul;29(1):28–38. doi: 10.1165/rcmb.2002-0163OC 12600829

42. Sutherland JS, Hill PC, Adetifa IM, de Jong BC, Donkor S, Joosten SA, et al. Identification of probable early-onset biomarkers for tuberculosis disease progression. PloS one2011;6(9):e25230. doi: 10.1371/journal.pone.0025230 21966464

43. Wassie L, Demissie A, Aseffa A, Abebe M, Yamuah L, Tilahun H, et al. Ex vivo cytokine mRNA levels correlate with changing clinical status of ethiopian TB patients and their contacts over time. PloS one2008;3(1):e1522. doi: 10.1371/journal.pone.0001522 18231607

44. Cliff JM, Lee JS, Constantinou N, Cho JE, Clark TG, Ronacher K, et al. Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response. J Infect Dis2013 Jan 01;207(1):18–29. doi: 10.1093/infdis/jis499 22872737

45. Bloom CI, Graham CM, Berry MPR, Wilkinson KA, Oni T, Rozakeas F, et al. Detectable Changes in The Blood Transcriptome Are Present after Two Weeks of Antituberculosis Therapy. PLoS One;7(10):e46191. doi: 10.1371/journal.pone.0046191 23056259

46. Thompson EG, Du Y, Malherbe ST, Shankar S, Braun J, Valvo J, et al. Host blood RNA signatures predict the outcome of tuberculosis treatment. Tuberculosis (Edinb) Dec;107:48–58.

47. Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature2010 Aug 19;466(7309):973–7. doi: 10.1038/nature09247 20725040

48. Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, et al. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nature medicine;22(10):1094–100. doi: 10.1038/nm.4177 27595324

49. Sanchez MD, Garcia Y, Montes C, Paris SC, Rojas M, Barrera LF, et al. Functional and phenotypic changes in monocytes from patients with tuberculosis are reversed with treatment. Microbes Infect2006 Aug;8(9–10):2492–500. doi: 10.1016/j.micinf.2006.06.005 16872859

50. Hernández JC, Arteaga J, Paul Sp, Kumar A, Latz E, Urcuqui-Inchima S. Up-regulation of TLR2 and TLR4 in dendritic cells in response to HIV type 1 and coinfection with opportunistic pathogens. AIDS research and human retroviruses;27(10):1099–109. doi: 10.1089/AID.2010.0302 21406030

51. Garand M, Goodier M, Owolabi O, Donkor S, Kampmann B, Sutherland JS. Functional and Phenotypic Changes of Natural Killer Cells in Whole Blood during Mycobacterium tuberculosis Infection and Disease. Front Immunol;9:257. doi: 10.3389/fimmu.2018.00257 29520269

52. Bauer AL, Hogue IB, Marino S, Kirschner DE. The Effects of HIV-1 Infection on Latent Tuberculosis. Mathematical Modelling of Natural Phenomena2008;3(7):229–66.

53. Sullivan ZA, Wong EB, Ndung'u T, Kasprowicz VO, Bishai WR. Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV. EBioMedicine Apr 1;2(4):334–40. doi: 10.1016/j.ebiom.2015.03.005 26114158


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