Gene Symbol: esxA
Description: ESAT-6 protein EsxA
Alias: esat-6
Species: Mycobacterium tuberculosis H37Rv
Products:     esxA

Top Publications

  1. Gallegos A, Pamer E, Glickman M. Delayed protection by ESAT-6-specific effector CD4+ T cells after airborne M. tuberculosis infection. J Exp Med. 2008;205:2359-68 pubmed publisher
    ..Our results demonstrate that pathogen-specific Th1 cells can provide protection against inhaled M. tuberculosis, but only after the first week of infection. ..
  2. Wang X, Barnes P, Dobos Elder K, Townsend J, Chung Y, Shams H, et al. ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells. J Immunol. 2009;182:3668-77 pubmed publisher
    ..We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70...
  3. Renshaw P, Lightbody K, Veverka V, Muskett F, Kelly G, Frenkiel T, et al. Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6. EMBO J. 2005;24:2491-8 pubmed
  4. Mishra B, Moura Alves P, Sonawane A, Hacohen N, Griffiths G, Moita L, et al. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cell Microbiol. 2010;12:1046-63 pubmed publisher
    ..In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT-6, and the subsequent IL-1beta response is regulated by a number of NLR/CARD proteins. ..
  5. Andersen P, Andersen A, Sørensen A, Nagai S. Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice. J Immunol. 1995;154:3359-72 pubmed
    ..ESAT-6 was biochemically purified, characterized, and the gene encoding the protein was cloned. ..
  6. Brodin P, Majlessi L, Marsollier L, de Jonge M, Bottai D, Demangel C, et al. Dissection of ESAT-6 system 1 of Mycobacterium tuberculosis and impact on immunogenicity and virulence. Infect Immun. 2006;74:88-98 pubmed
    ..The present study has allowed us to identify new aspects of the extRD1 region of M. tuberculosis and to explore its role in the pathogenesis of tuberculosis. ..
  7. Kinhikar A, Verma I, Chandra D, Singh K, Weldingh K, Andersen P, et al. Potential role for ESAT6 in dissemination of M. tuberculosis via human lung epithelial cells. Mol Microbiol. 2010;75:92-106 pubmed publisher
  8. Berthet F, Rasmussen P, Rosenkrands I, Andersen P, Gicquel B. A Mycobacterium tuberculosis operon encoding ESAT-6 and a novel low-molecular-mass culture filtrate protein (CFP-10). Microbiology. 1998;144 ( Pt 11):3195-203 pubmed
    ..These results show that the genes encoding CFP-10 and ESAT-6 are transcribed together in M. tuberculosis and that both code for small exported proteins. ..
  9. Brodin P, Rosenkrands I, Andersen P, Cole S, Brosch R. ESAT-6 proteins: protective antigens and virulence factors?. Trends Microbiol. 2004;12:500-8 pubmed
    ..Here, we discuss these findings and their implications for the development of new therapeutic and prophylactic interventions against tuberculosis. ..

More Information


  1. Pathak S, Basu S, Basu K, Banerjee A, Pathak S, Bhattacharyya A, et al. Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol. 2007;8:610-8 pubmed
  2. Kumar R, Halder P, Sahu S, Kumar M, Kumari M, Jana K, et al. Identification of a novel role of ESAT-6-dependent miR-155 induction during infection of macrophages with Mycobacterium tuberculosis. Cell Microbiol. 2012;14:1620-31 pubmed publisher
    ..Inhibition of miR-155 hindered survival of M.tb. in RAW264.7 and in murine BMDMs. Thus, our results offer new insights into the role of miRNAs in modulation of the host innate immune response by M.tb. for its own benefit. ..
  3. Sørensen A, Nagai S, Houen G, Andersen P, Andersen A. Purification and characterization of a low-molecular-mass T-cell antigen secreted by Mycobacterium tuberculosis. Infect Immun. 1995;63:1710-7 pubmed
    ..tuberculosis complex species. Among filtrates from mycobacteria not belonging to the M. tuberculosis complex, reactivity was observed in Mycobacterium kansasii, Mycobacterium szulgai, and Mycobacterium marinum. ..
  4. Derrick S, Morris S. The ESAT6 protein of Mycobacterium tuberculosis induces apoptosis of macrophages by activating caspase expression. Cell Microbiol. 2007;9:1547-55 pubmed
    ..Finally, experimental results using a cell impermeable fluorescent stain suggests that the formation of membrane pores may be a primary mechanism by which ESAT6 evokes an apoptotic response. ..
  5. De Leon J, Jiang G, Ma Y, Rubin E, Fortune S, Sun J. Mycobacterium tuberculosis ESAT-6 exhibits a unique membrane-interacting activity that is not found in its ortholog from non-pathogenic Mycobacterium smegmatis. J Biol Chem. 2012;287:44184-91 pubmed publisher
    ..tuberculosis. ..
  6. Welin A, Eklund D, Stendahl O, Lerm M. Human macrophages infected with a high burden of ESAT-6-expressing M. tuberculosis undergo caspase-1- and cathepsin B-independent necrosis. PLoS ONE. 2011;6:e20302 pubmed publisher
    ..It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process...
  7. Shi J, Zhang H, Fang L, Xi Y, Zhou Y, Luo R, et al. A novel firefly luciferase biosensor enhances the detection of apoptosis induced by ESAT-6 family proteins of Mycobacterium tuberculosis. Biochem Biophys Res Commun. 2014;452:1046-53 pubmed publisher
    ..We screened ESAT-6 family proteins of Mycobacterium tuberculosis and found that esxA, esxT and esxL induced apoptosis...
  8. Kimuda S, Andia Biraro I, Egesa M, Bagaya B, Raynes J, Levin J, et al. Use of QuantiFERON®-TB Gold in-tube culture supernatants for measurement of antibody responses. PLoS ONE. 2017;12:e0188396 pubmed publisher
    ..tb specific cytokines. Further antibody and antibody/cytokine combinations need to be explored to achieve better diagnostic accuracy. ..
  9. Uvarova E, Belavin P, Permyakova N, Zagorskaya A, Nosareva O, Kakimzhanova A, et al. Oral Immunogenicity of plant-made Mycobacterium tuberculosis ESAT6 and CFP10. Biomed Res Int. 2013;2013:316304 pubmed publisher
    ..As has been shown, oral immunization of mice induces both the cell-mediated and humoral immunities. These data suggest that the proteins in question are appropriate as a candidate edible vaccine against tuberculosis. ..
  10. Singh G, Singh B, Trajkovic V, Sharma P. Mycobacterium tuberculosis 6 kDa early secreted antigenic target stimulates activation of J774 macrophages. Immunol Lett. 2005;98:180-8 pubmed
    ..1, MHC-II, and ICAM-1. Collectively, these data suggest that ESAT-6 might contribute to macrophage activation in tuberculosis. ..
  11. Volkman H, Pozos T, Zheng J, Davis J, Rawls J, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science. 2010;327:466-9 pubmed publisher
    ..Disruption of MMP9 function attenuated granuloma formation and bacterial growth. Thus, interception of epithelial MMP9 production could hold promise as a host-targeting tuberculosis therapy...
  12. Solans L, Aguilo N, Samper S, Pawlik A, Frigui W, Martin C, et al. A specific polymorphism in Mycobacterium tuberculosis H37Rv causes differential ESAT-6 expression and identifies WhiB6 as a novel ESX-1 component. Infect Immun. 2014;82:3446-56 pubmed publisher
  13. Zhou Z, Wang Z, Zhang L, Ren Y, Ma Z, Zhao N, et al. Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4/MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection. Biosci Rep. 2017;37: pubmed publisher
    ..ESAT6 may induce renal injury by promoting miR-155 expression through the TLR-4/MyD88 signaling pathway in MTB-infected mice. ..
  14. McLaughlin B, Chon J, MacGurn J, Carlsson F, Cheng T, Cox J, et al. A mycobacterium ESX-1-secreted virulence factor with unique requirements for export. PLoS Pathog. 2007;3:e105 pubmed
    ..The results establish EspB as a substrate of ESX-1 that is required for virulence and growth in macrophages and suggests that the contribution of ESX-1 to virulence may arise from the secretion of multiple independent substrates. ..
  15. Peng X, Jiang G, Liu W, Zhang Q, Qian W, Sun J. Characterization of differential pore-forming activities of ESAT-6 proteins from Mycobacterium tuberculosis and Mycobacterium smegmatis. FEBS Lett. 2016;590:509-19 pubmed publisher
    ..This study suggests I25-H26 as the pH-sensor essential for MsESAT-6 to fully acquire the activity, while multiple residues contributed to MtbESAT-6 PFA. ..
  16. Refai A, Haoues M, Othman H, Barbouche M, Moua P, Bondon A, et al. Two distinct conformational states of Mycobacterium tuberculosis virulent factor early secreted antigenic target 6 kDa are behind the discrepancy around its biological functions. FEBS J. 2015;282:4114-29 pubmed publisher
  17. Conrad W, Osman M, Shanahan J, Chu F, Takaki K, Cameron J, et al. Mycobacterial ESX-1 secretion system mediates host cell lysis through bacterium contact-dependent gross membrane disruptions. Proc Natl Acad Sci U S A. 2017;114:1371-1376 pubmed publisher
    ..ESX-1-mediated lysis is also morphologically distinct from the contact-dependent lysis of other bacterial secretion systems. Our findings suggest redirection of research to understand the mechanism of ESX-1-mediated lysis. ..
  18. Dong H, Jing W, Runpeng Z, Xuewei X, Min M, Ru C, et al. ESAT6 inhibits autophagy flux and promotes BCG proliferation through MTOR. Biochem Biophys Res Commun. 2016;477:195-201 pubmed publisher
    ..Furthermore, in both Raw264.7 and ACM cells, MTOR inhibition significantly suppressed the survival of BCG. In conclusion, our study highlights how ESAT6 blocks autophagy and promotes BCG survival in a way that activates MTOR. ..
  19. Yang H, Chen H, Liu Z, Ma H, Qin L, Jin R, et al. A novel B-cell epitope identified within Mycobacterium tuberculosis CFP10/ESAT-6 protein. PLoS ONE. 2013;8:e52848 pubmed publisher
    ..There was a B-cell epitope for CE and ESAT-6 protein in the position 40 to 62 of ESAT-6. E5 peptide may be useful in the serodiagnosis of tuberculosis, which need to be further confirmed by more sera samples...
  20. Anil Kumar V, Goyal R, Bansal R, Singh N, Sevalkar R, Kumar A, et al. EspR-dependent ESAT-6 Protein Secretion of Mycobacterium tuberculosis Requires the Presence of Virulence Regulator PhoP. J Biol Chem. 2016;291:19018-30 pubmed publisher
    ..tuberculosis Together, these results have significant implications on the mechanism of virulence regulation of M. tuberculosis. ..
  21. Grover A, Izzo A. BAT3 regulates Mycobacterium tuberculosis protein ESAT-6-mediated apoptosis of macrophages. PLoS ONE. 2012;7:e40836 pubmed publisher
    ..Taken together, the data suggest that BAT3 plays a role in the early immune response to M. tuberculosis infection and may be a key protein associated with the fate of antigen presenting cells during infection...
  22. Sreejit G, Ahmed A, Parveen N, Jha V, Valluri V, Ghosh S, et al. The ESAT-6 protein of Mycobacterium tuberculosis interacts with beta-2-microglobulin (β2M) affecting antigen presentation function of macrophage. PLoS Pathog. 2014;10:e1004446 pubmed publisher
    ..Identification of such novel interactions may help us in designing small molecule inhibitors as well as effective vaccine design against tuberculosis. ..
  23. Hasan Z, Jamil B, Ashraf M, Islam M, Yusuf M, Khan J, et al. ESAT6-induced IFNgamma and CXCL9 can differentiate severity of tuberculosis. PLoS ONE. 2009;4:e5158 pubmed publisher
    ..ESAT-induced CCL2 and CXCL9 were significantly associated in LNTB while correlation in response to LPS was only present in SevTB. ESAT6 induced IFNgamma and CXCL9 can differentiate between limited and severe TB infections...
  24. Samten B, Wang X, Barnes P. Mycobacterium tuberculosis ESX-1 system-secreted protein ESAT-6 but not CFP10 inhibits human T-cell immune responses. Tuberculosis (Edinb). 2009;89 Suppl 1:S74-6 pubmed publisher
    ..We conclude that ESAT-6 directly inhibits human T-cell responses by affecting TCR signaling pathways downstream of ZAP70...
  25. Ganguly N, Giang P, Basu S, Mir F, Siddiqui I, Sharma P. Mycobacterium tuberculosis 6-kDa early secreted antigenic target (ESAT-6) protein downregulates lipopolysaccharide induced c-myc expression by modulating the extracellular signal regulated kinases 1/2. BMC Immunol. 2007;8:24 pubmed
    ..This could be a mechanism by which secretory proteins of Mtb might modulate gene expression inside the macrophages. ..
  26. Kumar K, Tharad M, Ganapathy S, Ram G, Narayan A, Khan J, et al. Phenylalanine-rich peptides potently bind ESAT6, a virulence determinant of Mycobacterium tuberculosis, and concurrently affect the pathogen's growth. PLoS ONE. 2009;4:e7615 pubmed publisher
  27. Van Lume D, De Souza J, Cabral M, Rego J, Balbino V, Saad M, et al. Immunological diagnosis of tuberculosis based on recombinant antigens ESAT-6 and CFP-10 in children from an endemic area in northeast Brazil. Scand J Immunol. 2010;72:460-8 pubmed publisher
    ..In conclusion, the ESAT-6 test may be the most appropriate for diagnosis of childhood TB, both LTBI and TB disease, when associated with epidemiological and clinical data, especially in endemic areas such as Brazil...
  28. Chen J, Zhang M, Rybniker J, Basterra L, Dhar N, Tischler A, et al. Phenotypic profiling of Mycobacterium tuberculosis EspA point mutants reveals that blockage of ESAT-6 and CFP-10 secretion in vitro does not always correlate with attenuation of virulence. J Bacteriol. 2013;195:5421-30 pubmed publisher
    ..However, our data also indicate for the first time that blockage of M. tuberculosis ESAT-6 and CFP-10 secretion in vitro and attenuation are mutually exclusive...
  29. Peng H, Wang X, Barnes P, Tang H, Townsend J, Samten B. The Mycobacterium tuberculosis early secreted antigenic target of 6 kDa inhibits T cell interferon-? production through the p38 mitogen-activated protein kinase pathway. J Biol Chem. 2011;286:24508-18 pubmed publisher
    ..Silencing of p38? MAPK with siRNA rendered T cells resistant to ESAT-6 inhibition of IFN-? production. Taken together, our results demonstrate that ESAT-6 inhibits T cell IFN-? production in a p38 MAPK-dependent manner...
  30. Francis R, Butler R, Stewart G. Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca2+ influx, necrosis and neutrophil extracellular trap formation. Cell Death Dis. 2014;5:e1474 pubmed publisher
  31. Yang S, Li F, Jia S, Zhang K, Jiang W, Shang Y, et al. Early secreted antigen ESAT-6 of Mycobacterium Tuberculosis promotes apoptosis of macrophages via targeting the microRNA155-SOCS1 interaction. Cell Physiol Biochem. 2015;35:1276-88 pubmed publisher
    ..ESAT-6 promotes apoptosis of macrophages via targeting the miRNA155-SOCS1 interaction. ..
  32. Xu X, Zhao R, Zhang R, Wu J, Hu D, Xing Y, et al. [ESAT-6 inhibits autophagy in macrophages and promotes the growth of BCG]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33:310-314 pubmed
    ..Moreover, the growth potential of BCG was strong in the three transfection groups. Conclusion ESAT6 can inhibit the autophagy and promote the growth of BCG in RAW264.7 cells. ..
  33. Ma Y, Keil V, Sun J. Characterization of Mycobacterium tuberculosis EsxA membrane insertion: roles of N- and C-terminal flexible arms and central helix-turn-helix motif. J Biol Chem. 2015;290:7314-22 pubmed publisher
    b>EsxA (ESAT-6), an important virulence factor of Mycobacterium tuberculosis, plays an essential role in phagosome rupture and bacterial cytosolic translocation within host macrophages...
  34. Murthy M, Kaliappan T, Raja A. Cytokine and chemokine responses to selected early secreted antigenic target-6 and culture filtrate protein-10 peptides in tuberculosis. J Interferon Cytokine Res. 2011;31:299-307 pubmed publisher
    ..Monocyte chemoattractant protein-1 positive monocytes increased in response to the peptides Esp1, Esp6, Cfp8, and Cfp9 in PTB. These peptides deserve attention for further immune studies. ..
  35. Kumar M, Sahu S, Kumar R, Subuddhi A, Maji R, Jana K, et al. MicroRNA let-7 modulates the immune response to Mycobacterium tuberculosis infection via control of A20, an inhibitor of the NF-κB pathway. Cell Host Microbe. 2015;17:345-356 pubmed publisher
    ..These results uncover a role for let-7f and its target A20 in regulating immune responses to Mtb and controlling bacterial burden. ..
  36. Yin Y, Li H, Wu S, Dong D, Zhang J, Fu L, et al. Hepatitis B virus core particles displaying Mycobacterium tuberculosis antigen ESAT-6 enhance ESAT-6-specific immune responses. Vaccine. 2011;29:5645-51 pubmed publisher
    ..These data demonstrate the feasibility of HBc particles serving as an efficient immune carrier for ESAT-6 and suggest that HE6 has potential for use in a tuberculosis subunit vaccine...
  37. Yabaji S, Mishra A, Chatterjee A, Dubey R, Srivastava K, Srivastava K. Peroxiredoxin-1 of macrophage is critical for mycobacterial infection and is controlled by early secretory antigenic target protein through the activation of p38 MAPK. Biochem Biophys Res Commun. 2017;494:433-439 pubmed publisher
    ..The intermediate mechanisms involve the increased Prdx-1 production in macrophages through the activation of p38 and NRF-2 dependent signaling...
  38. Salman A, Rosenkrands I, Andersen P, Abdel Ghaffar A. Assessment of T cell response to novel Mycobacterium tuberculosis synthetic overlapping peptides mixtures (Rv2659 and Rv2660) and ESAT-6 in Egyptian patients. Egypt J Immunol. 2014;21:75-83 pubmed
    ..In conclusion, the ESAT-6 pepmix is recognized in a greater proportion of TB patients compared to Rv2659 and Rv2660, and levels of IFN-γ in response to ESAT-6 are higher than the levels observed in response to Rv2659 and Rv2660. ..
  39. Callahan B, Nguyen K, Collins A, Valdes K, Caplow M, Crossman D, et al. Conservation of structure and protein-protein interactions mediated by the secreted mycobacterial proteins EsxA, EsxB, and EspA. J Bacteriol. 2010;192:326-35 pubmed publisher
    Mycobacterium tuberculosis EsxA and EsxB proteins are founding members of the WXG100 (WXG) protein family, characterized by their small size (approximately 100 amino acids) and conserved WXG amino acid motif. M...
  40. Masood K, Hussain R, Rao N, Rottenberg M, Salahuddin N, Irfan M, et al. Differential Early Secreted Antigen Target (ESAT) 6 kDa-induced IFN-? and SOCS1 expression distinguishes latent and active tuberculosis. J Infect Dev Ctries. 2014;8:59-66 pubmed publisher
    ..A decreasing IFN-? /SOCS1 ratio may leads to reduced Th1 immunity which contributes to inability of the host to control clinical disease. ..
  41. Davila J, Zhang L, Marrs C, Durmaz R, Yang Z. Assessment of the genetic diversity of Mycobacterium tuberculosis esxA, esxH, and fbpB genes among clinical isolates and its implication for the future immunization by new tuberculosis subunit vaccines Ag85B-ESAT-6 and Ag85B-TB10.4. J Biomed Biotechnol. 2010;2010:208371 pubmed publisher
    ..tuberculosis strains may compromise vaccine efficacy. In this study, we sequenced the esxA, esxH, and fbpB genes of M. tuberculosis encoding ESAT-6, TB10...
  42. Brilha S, Sathyamoorthy T, Stuttaford L, Walker N, Wilkinson R, Singh S, et al. Early Secretory Antigenic Target-6 Drives Matrix Metalloproteinase-10 Gene Expression and Secretion in Tuberculosis. Am J Respir Cell Mol Biol. 2017;56:223-232 pubmed publisher
    ..In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction. ..
  43. Kupz A, Zedler U, Stäber M, Perdomo C, Dorhoi A, Brosch R, et al. ESAT-6-dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo. J Clin Invest. 2016;126:2109-22 pubmed publisher
    ..Our findings provide a comprehensive mechanistic framework for antigen-independent IFN-? secretion in response to Mtb with critical implications for future intervention strategies against TB. ..
  44. Yi N, Jung B, Wang X, Vankayalapati R, Samten B. The early secreted antigenic target of 6 kD of Mycobacterium tuberculosis inhibits the proliferation and differentiation of human peripheral blood CD34+ cells. Tuberculosis (Edinb). 2016;101S:S28-S34 pubmed publisher
    ..We conclude that ESAT-6, an essential virulence factor of Mtb, may contribute to the abnormal hematopoiesis of tuberculosis patients by inhibiting the proliferation and differentiation of hematopoietic cells via apoptosis. ..