All Title Author
Keywords Abstract

PLOS ONE  2011 

Novel Biomarkers Distinguishing Active Tuberculosis from Latent Infection Identified by Gene Expression Profile of Peripheral Blood Mononuclear Cells

DOI: 10.1371/journal.pone.0024290

Full-Text   Cite this paper   Add to My Lib

Abstract:

Background Humans infected with Mycobacterium tuberculosis (MTB) can delete the pathogen or otherwise become latent infection or active disease. However, the factors influencing the pathogen clearance and disease progression from latent infection are poorly understood. This study attempted to use a genome-wide transcriptome approach to identify immune factors associated with MTB infection and novel biomarkers that can distinguish active disease from latent infection. Methodology/Principal Findings Using microarray analysis, we comprehensively determined the transcriptional difference in purified protein derivative (PPD) stimulated peripheral blood mononuclear cells (PBMCs) in 12 individuals divided into three groups: TB patients (TB), latent TB infection individuals (LTBI) and healthy controls (HC) (n = 4 per group). A transcriptional profiling of 506 differentially expressed genes could correctly group study individuals into three clusters. Moreover, 55- and 229-transcript signatures for tuberculosis infection (TB<BI) and active disease (TB) were identified, respectively. The validation study by quantitative real-time PCR (qPCR) performed in 83 individuals confirmed the expression patterns of 81% of the microarray identified genes. Decision tree analysis indicated that three genes of CXCL10, ATP10A and TLR6 could differentiate TB from LTBI subjects. Additional validation was performed to assess the diagnostic ability of the three biomarkers within 36 subjects, which yielded a sensitivity of 71% and specificity of 89%. Conclusions/Significance The transcription profiles of PBMCs induced by PPD identified distinctive gene expression patterns associated with different infectious status and provided new insights into human immune responses to MTB. Furthermore, this study indicated that a combination of CXCL10, ATP10A and TLR6 could be used as novel biomarkers for the discrimination of TB from LTBI.

References

[1]  Stop TB Partnership. WHO report 2008.
[2]  Global Tuberculosis Control. WHO report 2010.
[3]  Cardona P, Ruiz-Manzano J (2004) On the nature of Mycobacterium tuberculosis-latent bacilli. European Respiratory Journal 24: 1044.
[4]  van Pinxteren LAH, Cassidy JP, Smedegaard BHC, Agger EM, Andersen P (2000) Control of latent Mycobacterium tuberculosis infection is dependent on CD8 T cells. European journal of immunology 30: 3689–3698.
[5]  Jereb J, Etkind SC, Joglar OT, Moore M, Taylor Z (2003) Tuberculosis contact investigations: outcomes in selected areas of the United States, 1999. Int J Tuberc Lung Dis 7: S384–390.
[6]  Marks SM, Taylor Z, Qualls NL, Shrestha-Kuwahara RJ, Wilce MA, et al. (2000) Outcomes of contact investigations of infectious tuberculosis patients. Am J Respir Crit Care Med 162: 2033–2038.
[7]  Zhang S, Shao L, Mo L, Chen J, Wang F, et al. (2010) Evaluation of Gamma Interferon Release Assays Using Mycobacterium tuberculosis Antigens for Diagnosis of Latent and Active Tuberculosis in Mycobacterium bovis BCG-Vaccinated Populations. Clinical and Vaccine Immunology 17: 1985.
[8]  Cooper A (2009) Cell-mediated immune responses in tuberculosis. Annual review of immunology 27: 393–422.
[9]  Dheda K, Schwander SK, Zhu B, van Zyl-Smit RN, Zhang Y (2010) The immunology of tuberculosis: from bench to bedside. Respirology 15: 433–450.
[10]  Wilkinson KA, Wilkinson RJ (2010) Polyfunctional T cells in human tuberculosis. Eur J Immunol 40: 2139–2142.
[11]  Comas I, Gagneux S (2009) The past and future of tuberculosis research. PLoS Pathog 5: e1000600.
[12]  Marais B, Raviglione M, Donald P, Harries A, Kritski A, et al. (2010) Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action. The Lancet.
[13]  Altet-Gómez N, De Souza-Galvao M, Latorre I, Milà C, Jiménez M, et al. (2010) Diagnosing TB infection in children: analysis of discordances using in vitro tests and tuberculin skin test. European Respiratory Journal.
[14]  Adetifa IMO, Ota MOC, Jeffries DJ, Hammond A, Lugos MD, et al. (2010) Commercial interferon gamma release assays compared to the tuberculin skin test for diagnosis of latent Mycobacterium tuberculosis infection in childhood contacts in the Gambia. The Pediatric infectious disease journal 29: 439.
[15]  Chee CB, Barkham TM, Khinmar KW, Gan SH, Wang YT (2009) Quantitative T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens in active and latent tuberculosis. Eur J Clin Microbiol Infect Dis 28: 667–670.
[16]  Siawaya JFD, Ruhwald M, Eugen-Olsen J, Walzl G (2007) Correlates for disease progression and prognosis during concurrent HIV/TB infection. International journal of infectious diseases 11: 289–299.
[17]  Russell DG, Cardona PJ, Kim MJ, Allain S, Altare F (2009) Foamy macrophages and the progression of the human tuberculosis granuloma. Nat Immunol 10: 943–948.
[18]  Lawn SD, Wood R, Wilkinson RJ (2011) Changing concepts of “latent tuberculosis infection” in patients living with HIV infection. Clin Dev Immunol 2011.
[19]  Chegou N, Black G, Kidd M, Van Helden P, Walzl G (2009) Host markers in Quantiferon supernatants differentiate active TB from latent TB infection: preliminary report. BMC pulmonary medicine 9: 21.
[20]  Sutherland J, de Jong B, Jeffries D, Adetifa I, Ota M, et al. (2010) Production of TNF-alpha, IL-12 (p40) and IL-17 Can Discriminate between Active TB Disease and Latent Infection in a West African Cohort. PloS one 5: 465–473.
[21]  Wu B, Huang C, Kato-Maeda M, Hopewell P, Daley C, et al. (2007) Messenger RNA expression of IL-8, FOXP3, and IL-12beta differentiates latent tuberculosis infection from disease. The Journal of Immunology 178: 3688.
[22]  Berry M, Graham C, McNab F, Xu Z, Bloch S, et al. (2010) An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466: 973–977.
[23]  Maertzdorf J, Repsilber D, Parida SK, Stanley K, Roberts T, et al. (2010) Human gene expression profiles of susceptibility and resistance in tuberculosis. Genes Immun.
[24]  Mistry R, Cliff J, Clayton C, Beyers N, Mohamed Y, et al. (2007) Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis. The Journal of infectious diseases 195: 357–365.
[25]  Jacobsen M, Repsilber D, Gutschmidt A, Neher A, Feldmann K, et al. (2007) Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis. Journal of Molecular Medicine 85: 613–621.
[26]  Shao L, Zhang W, Zhang S, Chen CY, Jiang W, et al. (2008) Potent immune responses of Ag-specific Vgamma2Vdelta2+ T cells and CD8+ T cells associated with latent stage of Mycobacterium tuberculosis coinfection in HIV-1-infected humans. AIDS 22: 2241–2250.
[27]  Hao S, Baltimore D (2009) The stability of mRNA influences the temporal order of the induction of genes encoding inflammatory molecules. Nature immunology 10: 281–288.
[28]  Thuong NT, Dunstan SJ, Chau TT, Thorsson V, Simmons CP, et al. (2008) Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. PLoS Pathog 4: e1000229.
[29]  Harari A, Rozot V, Enders FB, Perreau M, Stalder JM, et al. (2011) Dominant TNF-alpha(+) Mycobacterium tuberculosis-specific CD4(+) T cell responses discriminate between latent infection and active disease. Nat Med 17: 372–376.
[30]  Meguro M, Kashiwagi A, Mitsuya K, Nakao M, Kondo I, et al. (2001) A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome. Nature genetics 28: 19–20.
[31]  Herzing L, Kim S, Cook E, Ledbetter D (2001) The human aminophospholipid-transporting ATPase gene ATP10C maps adjacent to UBE3A and exhibits similar imprinted expression. The American Journal of Human Genetics 68: 1501–1505.
[32]  Dhar MS, Sommardahl CS, Kirkland T, Nelson S, Donnell R, et al. (2004) Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes. The Journal of nutrition 134: 799.
[33]  Booth V, Keizer DW, Kamphuis MB, Clark-Lewis I, Sykes BD (2002) The CXCR3 binding chemokine IP-10/CXCL10: structure and receptor interactions. Biochemistry 41: 10418–10425.
[34]  Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, et al. (1998) Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J Biol Chem 273: 18288–18291.
[35]  Farber JM (1997) Mig and IP-10: CXC chemokines that target lymphocytes. Journal of leukocyte biology 61: 246.
[36]  Azzurri A, Sow O, Amedei A, Bah B, Diallo S, et al. (2005) IFN-[gamma]-inducible protein 10 and pentraxin 3 plasma levels are tools for monitoring inflammation and disease activity in Mycobacterium tuberculosis infection. Microbes and Infection 7: 1–8.
[37]  Ruhwald M, Bodmer T, Maier C, Jepsen M, Haaland M, et al. (2008) Evaluating the potential of IP-10 and MCP-2 as biomarkers for the diagnosis of tuberculosis. European Respiratory Journal 32: 1607.
[38]  Lighter J, Rigaud M, Huie M, Peng CH, Pollack H (2009) Chemokine IP-10: an adjunct marker for latent tuberculosis infection in children. Int J Tuberc Lung Dis 13: 731–736.
[39]  Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, et al. (2007) Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PloS one 2: 1318.
[40]  Chang JS, Huggett JF, Dheda K, Kim LU, Zumla A, et al. (2006) Myobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. The Journal of Immunology 176: 3010.
[41]  Bulut Y, Faure E, Thomas L, Equils O, Arditi M (2001) Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J Immunol 167: 987–994.
[42]  Pasare C, Medzhitov R (2005) Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol 560: 11–18.
[43]  Muraguchi A, Kehrl JH, Longo DL, Volkman DJ, Smith KA, et al. (1985) Interleukin 2 receptors on human B cells. Implications for the role of interleukin 2 in human B cell function. J Exp Med 161: 181–197.
[44]  Uchiyama T, Hori T, Tsudo M, Wano Y, Umadome H, et al. (1985) Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. J Clin Invest 76: 446–453.
[45]  Stern JB, Smith KA (1986) Interleukin-2 induction of T-cell G1 progression and c-myb expression. Science 233: 203–206.
[46]  Beadling C, Johnson KW, Smith KA (1993) Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci U S A 90: 2719–2723.
[47]  Beadling C, Smith KA (2002) DNA array analysis of interleukin-2-regulated immediate/early genes. Med Immunol 1: 2.
[48]  Marin ND, París SC, Vélez VM, Rojas CA, Rojas M, et al. (2010) Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis 90: 252–261.
[49]  Li L, Wu CY (2008) CD4+ CD25+ Treg cells inhibit human memory gammadelta T cells to produce IFN-gamma in response to M tuberculosis antigen ESAT-6. Blood 111: 5629–5636.
[50]  Chen J, Su X, Zhang Y, Wang S, Shao L, et al. (2009) Novel recombinant RD2- and RD11-encoded Mycobacterium tuberculosis antigens are potential candidates for diagnosis of tuberculosis infections in BCG-vaccinated individuals. Microbes Infect 11: 876–885.
[51]  Meyerson M HD (2005) Microarray Approaches to Gene Expression Analysis; Tsongalis G, Coleman W, eds. TotowaNJ: Humana Press.121–148.
[52]  Huang J, Zheng D, Qin F, Cheng N, Chen H, et al. (2010) Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling. The Journal of clinical investigation 120: 223.
[53]  Chen X, Li J, Hu W, Yang S, Gong Y (2010) Differential gene expression of human keratinocyte HaCaT cells induced by fibroblast growth factor 10 treatment. Mol Cell Biochem 342: 71–85.
[54]  Livak K, Schmittgen T (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta] CT method. Methods 25: 402–408.
[55]  Yuen MF, Fong DYT, Wong DKH, Yuen JCH, Fung J, et al. (2007) Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology 46: 1695–1703.

Full-Text

comments powered by Disqus

Contact Us

service@oalib.com

QQ:3279437679

微信:OALib Journal