Review

Th1 cytokines, true functional signatures for protective immunity against TB?

  • Cellular and Molecular Immunology volume 15, pages 206215 (2018)
  • doi:10.1038/cmi.2017.113
  • Download Citation
Received:
Revised:
Accepted:
Published:

Subjects

Abstract

The lack of an effective preventative vaccine against tuberculosis (TB) presents a great challenge to TB control. Since it takes an extremely long time to accurately determine the protective efficacy of TB vaccines, there is a great need to identify the surrogate signatures of protection to facilitate vaccine development. Unfortunately, antigen-specific Th1 cytokines that are currently used to evaluate the protective efficacy of the TB vaccine, do not align with the protection and failure of TB vaccine candidates in clinical trials. In this review, we discuss the limitation of current Th1 cytokines as surrogates of protection and address the potential elements that should be considered to finalize the true functional signatures of protective immunity against TB.

  • Subscribe to Cellular & Molecular Immunology for full access:

    $321

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    . Transfer of adoptive immunity to tuberculosis in mice. Infect Immunity 1975; 11: 1174–1181.

  2. 2.

    , . Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients. J Exp Med 1983; 158: 74–83.

  3. 3.

    . Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 2009; 27: 393–422.

  4. 4.

    . The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J Immunol 1987; 138: 293–298.

  5. 5.

    , , , , . The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med 2001; 193: 271–280.

  6. 6.

    , , , , , . CD4+ T cells contain early extrapulmonary tuberculosis (TB) dissemination and rapid TB progression and sustain multieffector functions of CD8+ T and CD3- lymphocytes: mechanisms of CD4+ T cell immunity. J Immunol 2014; 192: 2120–2132.

  7. 7.

    , . Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999; 340: 367–373.

  8. 8.

    , , , . Latent Mycobacterium tuberculosis infection. N Engl J Med 2015; 372: 2127–2135.

  9. 9.

    , , , , , . Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med 1993; 178: 2243–2247.

  10. 10.

    , , , . Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with mycobacterium tuberculosis. J Exp Med 1997; 186: 39–45.

  11. 11.

    , , , , , . An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med 1993; 178: 2249–2254.

  12. 12.

    , , , , , . Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc Natl Acad Sci USA 1997; 94: 5243–5248.

  13. 13.

    , , , , . Transient loss of resistance to pulmonary tuberculosis in p47(phox−/−) mice. Infect Immunity 2000; 68: 1231–1234.

  14. 14.

    , , , , , . The inducible nitric oxide synthase locus confers protection against aerogenic challenge of both clinical and laboratory strains of Mycobacterium tuberculosis in mice. Infect Immunity 2001; 69: 7711–7717.

  15. 15.

    , . Th1 and Th17 cells in tuberculosis: protection, pathology, and biomarkers. Mediat Inflamm 2015; 2015: 854507.

  16. 16.

    , , , , , et al. TCR repertoire, clonal dominance, and pulmonary trafficking of mycobacterium-specific CD4+ and CD8+ T effector cells in immunity against tuberculosis. J Immunol 2010; 185: 3940–3947.

  17. 17.

    , , , , , et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 1996; 335: 1941–1949.

  18. 18.

    , , , , , et al. Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis bacille calmette-guerin infection. J Infect Dis 2002; 185: 1468–1475.

  19. 19.

    , , , , . Missense mutation of the interleukin-12 receptor beta1 chain-encoding gene is associated with impaired immunity against Mycobacterium avium complex infection. Blood 2001; 97: 2688–2694.

  20. 20.

    , , , , , et al. Plasma granulysin levels and cellular interferon-gamma production correlate with curative host responses in tuberculosis, while plasma interferon-gamma levels correlate with tuberculosis disease activity in adults. Tuberculosis 2007; 87: 312–321.

  21. 21.

    , . Regulation of neutrophils by interferon-gamma limits lung inflammation during tuberculosis infection. J Exp Med 2011; 208: 2251–2262.

  22. 22.

    , . Tuberculosis vaccines—rethinking the current paradigm. Trends Immunol 2014; 35: 387–395.

  23. 23.

    , , , , , et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013; 381: 1021–1028.

  24. 24.

    , , . The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 2015; 16: 57–63.

  25. 25.

    . T cells in mycobacterial infection and disease. Curr Opin Immunol 2009; 21: 378–384.

  26. 26.

    , , , , , et al. ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes. Proc Natl Acad Sci USA 2008; 105: 10961–10966.

  27. 27.

    , , , , , et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J Immunol 2007; 179: 2509–2519.

  28. 28.

    . Some clinical features of tuberculosis. 1. Incubation period. Acta tuberculosea Scandinavica 1950; 24: 311–346.

  29. 29.

    . The time-table of tuberculosis. Tubercle 1948; 29: 245–251.

  30. 30.

    , , , , . Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J Exp Med 2010; 207: 1409–1420.

  31. 31.

    , , , , , et al. Simultaneous immunization against tuberculosis. PLoS ONE 2011; 6: e27477.

  32. 32.

    , , , . Harnessing local and systemic immunity for vaccines against tuberculosis. Mucosal immunology 2014; 7: 20–26.

  33. 33.

    , , , . Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice. J Exp Med 2005; 201: 1915–1924.

  34. 34.

    , , , , , et al. Murine airway luminal antituberculosis memory CD8 T cells by mucosal immunization are maintained via antigen-driven in situ proliferation, independent of peripheral T cell recruitment. Am J Respir Crit Care Med 2010; 181: 862–872.

  35. 35.

    , , , , , et al. A key role for lung-resident memory lymphocytes in protective immune responses after BCG vaccination. Eur J Immunol 2010; 40: 2482–2492.

  36. 36.

    , , , , , et al. Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis. mBio 2016; 7: pii: e01686-16.

  37. 37.

    , , , , , . Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 2009; 10: 524–530.

  38. 38.

    . Resident memory T cells in human health and disease. Science translational medicine 2015; 7: 269rv261.

  39. 39.

    , , , , , et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 2007; 8: 369–377.

  40. 40.

    , , , , , et al. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 2010; 466: 973–977.

  41. 41.

    , , , , , et al. Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers. PLoS ONE 2013; 8: e70630.

  42. 42.

    , , , , , et al. Evaluation of antigen specific interleukin-1beta as a biomarker to detect cattle infected with Mycobacterium bovis. Tuberculosis 2017; 105: 53–59.

  43. 43.

    , , , , , et al. Reduced systemic and mycobacterial antigen-stimulated concentrations of IL-1beta and IL-18 in tuberculous lymphadenitis. Cytokine 2017; 90: 66–72.

  44. 44.

    , , , , , . Serum IL-1beta and IL-18 correlate with ESR and CRP in multidrug-resistant tuberculosis patients. J Med Res 2015; 29: 426–428.

  45. 45.

    , , , , , et al. Innate and adaptive interferons suppress IL-1alpha and IL-1beta production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Immunity 2011; 35: 1023–1034.

  46. 46.

    , , , , , et al. Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 2010; 184: 3326–3330.

  47. 47.

    , , , , , et al. IL-17 production of neutrophils enhances antibacteria ability but promotes arthritis development during mycobacterium tuberculosis infection. EBioMedicine 2017; 23: 88–99.

  48. 48.

    , , , . Mycobacterium bovis BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of gamma interferon. Infect Immunity 2010; 78: 4187–4194.

  49. 49.

    , , , , , . A novel nanoemulsion vaccine induces mucosal Interleukin-17 responses and confers protection upon Mycobacterium tuberculosis challenge in mice. Vaccine 2017; 35: 4983–4989.

  50. 50.

    , , , , , et al. Lactococcus lactis carrying a DNA vaccine coding for the ESAT-6 antigen increases IL-17 cytokine secretion and boosts the BCG vaccine immune response. J Appl Microbiol 2017; 122: 1657–1662.

  51. 51.

    , , , , , et al. Evaluation of Interleukin17and Interleukin 23 expression in patients with active and latent tuberculosis infection. Iran J Basic Med Sci 2016; 19: 844–850.

  52. 52.

    , , , . Evaluation of IL-2, IL-10, IL-17 and IP-10 as potent discriminative markers for active tuberculosis among pulmonary tuberculosis suspects. Tuberculosis 2016; 99: 100–108.

  53. 53.

    , , , , , et al. Genetic polymorphisms of IL-17A, IL-17F, TLR4 and miR-146a in association with the risk of pulmonary tuberculosis. Sci Rep 2016; 6: 28586.

  54. 54.

    , , , , , et al. Decreased IL-17 during treatment of sputum smear-positive pulmonary tuberculosis due to increased regulatory T cells and IL-10. J Transl Med 2016; 14: 179.

  55. 55.

    , , . Association analysis of interleukin-17 gene polymorphisms with the risk susceptibility to tuberculosis. Lung 2016; 194: 459–467.

  56. 56.

    , , , , , et al. Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection. PLoS Pathog 2014; 10: e1004099.

  57. 57.

    , , , , , et al. Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection. Mucosal Immunol 2017; 10: 1069–1081.

  58. 58.

    , , , , , et al. Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2015; 112: 5111–5116.

  59. 59.

    , , , , , et al. IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci Transl Med 2014; 6: 250ra114.

  60. 60.

    , , , , , et al. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci USA 2010; 107: 13402–13407.

  61. 61.

    , , , , . CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 2011; 186: 1598–1607.

  62. 62.

    , , . Anti-PD1 antibody treatment and the development of acute pulmonary tuberculosis. J Thorac Oncol 2016; 11: 2238–2240.

  63. 63.

    , , , , , et al. CD4 T cell-derived ifn-gamma plays a minimal role in control of pulmonary mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog 2016; 12: e1005667.

  64. 64.

    , , , , . Microarray analysis of Mycobacterium tuberculosis-infected monocytes reveals IL26 as a new candidate gene for tuberculosis susceptibility. Immunology 2015; 144: 291–301.

  65. 65.

    , , , , , et al. Interleukin-26 in antibacterial host defense of human lungs. Effects on neutrophil mobilization. Am J Respir Crit Care Med 2014; 190: 1022–1031.

  66. 66.

    , , , , , . Evidence for a role for interleukin-17, Th17 cells and iron homeostasis in protective immunity against tuberculosis in cynomolgus macaques. PLoS One 2014; 9: e88149.

  67. 67.

    , , , , , et al. Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice. Infect Immunity 2000; 68: 2962–2970.

  68. 68.

    , , , , , et al. Coadministration of interleukins 7 and 15 with bacille Calmette-Guerin mounts enduring T cell memory response against Mycobacterium tuberculosis. J Infect Dis 2010; 202: 480–489.

  69. 69.

    , , , , , et al. Aberrant plasma IL-7 and soluble IL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis. PLoS Pathog 2017; 13: e1006425.

  70. 70.

    , , , , , et al. Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue. Genes and immunity 2011; 12: 513–522.

  71. 71.

    , , , . Induction of Mycobacterium tuberculosis-specific primary and secondary T-cell responses in interleukin-15-deficient mice. Infect Immunity 2005; 73: 2910–2922.

  72. 72.

    , , , , , et al. Impaired protection against Mycobacterium bovis bacillus Calmette-Guerin infection in IL-15-deficient mice. J Immunol 2006; 176: 2496–2504.

  73. 73.

    , , , , . Overexpression of IL-15 in vivo enhances protection against Mycobacterium bovis bacillus Calmette-Guerin infection via augmentation of NK and T cytotoxic 1 responses. J Immunol 2001; 167: 946–956.

  74. 74.

    , , , . High IL-6 and low IL-15 levels mark the presence of TB infection: A preliminary study. Cytokine 2016; 81: 57–62.

  75. 75.

    , , , , . Vaccine for tuberculosis: up-regulation of IL-15 by Ag85A and not by ESAT-6. Tuberculosis 2011; 91: 136–139.

  76. 76.

    , , , , , et al. T Cell-Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection. J Immunol 2017; 199: 613–623.

  77. 77.

    , , , , , et al. In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J Immunol 2002; 169: 6343–6351.

  78. 78.

    , , , , , . IL-10 inhibits mature fibrotic granuloma formation during Mycobacterium tuberculosis infection. J Immunol 2013; 190: 2778–2790.

  79. 79.

    , , , , , et al. Interleukin-10 promotes Mycobacterium tuberculosis disease progression in CBA/J mice. J Immunol 2008; 181: 5545–5550.

  80. 80.

    , , , , , . Cytokine production at the site of disease in human tuberculosis. Infect Immunity 1993; 61: 3482–3489.

  81. 81.

    , , , , , et al. The Mycobacterium tuberculosis complex-restricted gene cfp32 encodes an expressed protein that is detectable in tuberculosis patients and is positively correlated with pulmonary interleukin-10. Infect Immunity 2003; 71: 6871–6883.

  82. 82.

    , , , , , et al. Tuberculosis is associated with a down-modulatory lung immune response that impairs Th1-type immunity. J Immunol 2009; 183: 718–731.

  83. 83.

    , , , , , et al. Down-modulation of lung immune responses by interleukin-10 and transforming growth factor beta (TGF-beta) and analysis of TGF-beta receptors I and II in active tuberculosis. Infect Immunity 2004; 72: 2628–2634.

  84. 84.

    , , , , , et al. IL-23-dependent IL-17 drives Th1-cell responses following Mycobacterium bovis BCG vaccination. Eur J Immunol 2012; 42: 364–373.

  85. 85.

    , , , , , et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. J Immunol 2005; 175: 788–795.

  86. 86.

    , , , , , . A gamma interferon independent mechanism of CD4 T cell mediated control of M. tuberculosis infection in vivo. PLoS Pathog 2011; 7: e1002052.

  87. 87.

    , , , , , et al. Reduced Th17 response in patients with tuberculosis correlates with IL-6R expression on CD4+ T Cells. Am J Respir Crit Care Med 2010; 181: 734–742.

  88. 88.

    , , , , , . In search of a new paradigm for protective immunity to TB. Nat Reviews Microbiol 2014; 12: 289–299.

  89. 89.

    , , , . Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon gamma-producing T cells from apoptosis in patients with pulmonary tuberculosis. J Infect Dis 2013; 208: 603–615.

  90. 90.

    , , , , , et al. Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol 2008; 181: 116–125.

  91. 91.

    , , , , , et al. Annual risk of tuberculosis infection in rural China: a population-based prospective study. Eur Respir J 2016; 48: 168–178.

  92. 92.

    , , , , , et al. Highly multiplexed proteomic analysis of quantiferon supernatants to identify biomarkers of latent tuberculosis infection. J Clin Microbiol 2017; 55: 391–402.

  93. 93.

    , , , , , et al. Discriminating active from latent tuberculosis in patients presenting to community clinics. PLoS ONE 2012; 7: e38080.

  94. 94.

    , , , , , et al. Decreased serum 5-oxoproline in TB patients is associated with pathological damage of the lung. Clin Chim Acta 2013; 423: 5–9.

  95. 95.

    , , , , , et al. Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS ONE 2012; 7: e40221.

  96. 96.

    , , , , , et al. Cytokine gene expression profile of circulating CD4+ T cells in active pulmonary tuberculosis. Chest 1997; 111: 606–611.

  97. 97.

    , , , , , . Protective CD4 T cells targeting cryptic epitopes of Mycobacterium tuberculosis resist infection-driven terminal differentiation. J Immunol 2014; 192: 3247–3258.

  98. 98.

    , , , , . Quality and vaccine efficacy of CD4+ T cell responses directed to dominant and subdominant epitopes in ESAT-6 from Mycobacterium tuberculosis. J Immunol 2009; 183: 2659–2668.

  99. 99.

    , , . T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 2008; 8: 247–258.

  100. 100.

    , , , , , et al. Dominant TNF-alpha+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease. Nat Med 2011; 17: 372–376.

  101. 101.

    , , , , , et al. Differentiation of antigen-specific T cells with limited functional capacity during Mycobacterium tuberculosis infection. Infect Immunity 2014; 82: 132–139.

  102. 102.

    , , , , , et al. IFNgamma/TNFalpha specific-cells and effector memory phenotype associate with active tuberculosis. J Infect 2013; 66: 475–486.

  103. 103.

    , , , , , et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011; 187: 2222–2232.

  104. 104.

    , , , , , et al. Multifunctional CD4 T cell responses in patients with active tuberculosis. Sci Rep 2012; 2: 216.

  105. 105.

    , , , , . Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease. Eur J Immunol 2009; 39: 723–729.

  106. 106.

    , , , , , et al. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol 2010; 40: 2211–2220.

  107. 107.

    , , , , , . Polyfunctional responses by human T cells result from sequential release of cytokines. Proc Natl Acad Sci USA 2012; 109: 1607–1612.

  108. 108.

    , . Transcription factor interplay in T helper cell differentiation. Brief Funct Genomics 2013; 12: 499–511.

  109. 109.

    , , , , , et al. IL-17 and IFN-gamma expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease. J Leukoc Biol 2012; 91: 991–1002.

  110. 110.

    , , , , , et al. Transcriptional profile of tuberculosis antigen-specific T cells reveals novel multifunctional features. J Immunol 2014; 193: 2931–2940.

  111. 111.

    , , , , , et al. Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset. PLoS Pathog 2013; 9: e1003130.

  112. 112.

    , , , , , et al. T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science 2015; 347: 400–406.

  113. 113.

    , , , , , et al. A functional role for antibodies in tuberculosis. Cell 2016; 167: 433–443 e414.

  114. 114.

    , , . Antibody bound to the surface antigen MPB83 of Mycobacterium bovis enhances survival against high dose and low dose challenge. FEMS Immunol Med Microbiology 2004; 41: 93–100.

  115. 115.

    , , , , , . A mycobacterial lipoarabinomannan specific monoclonal antibody and its F(ab') fragment prolong survival of mice infected with Mycobacterium tuberculosis. Clin Exp Immunol 2004; 138: 30–38.

  116. 116.

    , , , , , et al. Induction of a protective response with an IgA monoclonal antibody against Mycobacterium tuberculosis 16kDa protein in a model of progressive pulmonary infection. Int J Med Microbiol 2009; 299: 447–452.

  117. 117.

    , , , , , et al. Passive protection with immunoglobulin A antibodies against tuberculous early infection of the lungs. Immunology 2004; 111: 328–333.

  118. 118.

    , , , , , et al. Therapeutic efficacy of high-dose intravenous immunoglobulin in Mycobacterium tuberculosis infection in mice. Infect Immunity 2005; 73: 6101–6109.

  119. 119.

    , , , , , et al. Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice. Microbes Infect 2006; 8: 1252–1259.

  120. 120.

    , , , , , et al. The effect of the administration of human gamma globulins in a model of BCG infection in mice. Tuberculosis 2006; 86: 268–272.

  121. 121.

    , , , , , et al. Human isotype-dependent inhibitory antibody responses against Mycobacterium tuberculosis. EMBO Mol Med 2016; 8: 1325–1339.

  122. 122.

    , , , , , et al. Latently and uninfected healthcare workers exposed to TB make protective antibodies against Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2017; 114: 5023–5028.

Download references

Acknowledgements

This study was supported by Thirteenth-Fifth Mega-Scientific Projects (2017ZX10103004); National Natural Science Foundation of China (81501714, 81525016, 81471913); National Key R&D Program of China (2016YFE0106900); Natural Science Foundation of Guangdong (2014A030313789); Shenzhen Scientific and Technological Project (JCYJ20170307095003051, JCYJ20170412151620658 and JSGG20140701164 558078); and Sanming Project of Medicine in Shenzhen (GCZX2015043015340 574, ZDSYS201504301534057).

Author information

Affiliations

  1. Department of Microbiology, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China

    • Gucheng Zeng
  2. Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Guangdong Medical University, Shenzhen, Guangdong 518112, China

    • Guoliang Zhang
  3. Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China

    • Xinchun Chen

Authors

  1. Search for Gucheng Zeng in:

  2. Search for Guoliang Zhang in:

  3. Search for Xinchun Chen in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to Gucheng Zeng or Guoliang Zhang or Xinchun Chen.