Skip to main content

Advertisement

SpringerLink
Log in

Differential Immune Responses and Protective Effects in Avirulent Mycobacterial Strains Vaccinated BALB/c Mice

  • Published:
Current Microbiology Aims and scope Submit manuscript

Abstract

Screening live mycobacterial vaccine candidates is the important strategy to develop new vaccines against adult tuberculosis (TB). In this study, the immunogenicity and protective efficacy of several avirulent mycobacterial strains including Mycobacterium smegmatis, M. vaccae, M. terrae, M. phlei, M. trivial, and M. tuberculosis H37Ra were compared with M. bovis BCG in BALB/c mice. Our results demonstrated that differential immune responses were induced in different mycobacterial species vaccinated mice. As BCG-vaccinated mice did, M. terrae immunization resulted in Th1-type responses in the lung, as well as splenocytes secreting IFN-γ against a highly conserved mycobacterial antigen Ag85A. M. smegmatis also induced the same splenocytes secreting IFN-γ as BCG and M. terrae did. In addition, M. terrae and M. smegmatis-immunized mice predominantly increased expression of IL-10 and TGF-β in the lung. Most importantly, mice vaccinated with H37Ra and M. vaccae could provide the same protection in the lung against virulent M. tuberculosis challenge as BCG. The result may have important implications in developing adult TB vaccine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Alsaadi AI, Smith DW (1973) The fate of virulent and attenuated mycobacteria in guinea pigs infected by the respiratory route. Am Rev Respir Dis 107:1041–1046

    CAS  PubMed  Google Scholar 

  2. Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbos TC, Cumano A, Bandeira A (2001) CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166:3008–3018

    Article  CAS  PubMed  Google Scholar 

  3. Anonymous (2013) Global tuberculosis report. World Health Organization, Geneva

    Google Scholar 

  4. Brandt L, Feino CJ, Weinreich OA, Chilima B, Hirsch P, Appelberg R, Andersen P (2002) Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacteria block multiplication of BCG and induction of protective immunity to tuberculosis. Infect Immun 70:672–678

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Cooper AM (2009) Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 27:393–422

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Elias D, Britton S, Aseffa A, Engers H, Akuffo H (2008) Poor immunogenicity of BCG in helminth infected population is associated with increased in vitro TGF-beta production. Vaccine 26:3897–3902

    Article  CAS  PubMed  Google Scholar 

  7. Falkinham JO 3rd (2009) Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment. J Appl Microbiol 107:356–367

    Article  CAS  PubMed  Google Scholar 

  8. Fine PE (1995) Variation in protection by BCG: implications of and for heterologous immunity. Lancet 346:1339–1345

    Article  CAS  PubMed  Google Scholar 

  9. Gonzalo Asensio J, Maia C, Ferrer NL, Barilone N, Laval F, Soto CY, Winter N, Daffé M, Gicquel B, Martín C, Jackson M (2006) The virulence-associated two-component PhoP-PhoR system controls the biosynthesis of polyketide-derived lipids in Mycobacterium tuberculosis. J Biol Chem 281:1313–1316

    Article  PubMed  Google Scholar 

  10. Harboe M, Mshana RN, Closs O, Kronvall G, Axelsen NH (1979) Cross-reactions between mycobacteria. II. Crossed immunoelectrophoretic analysis of soluble antigens of BCG and comparison with other mycobacteria. Scand J Immunol 9:115–124

    Article  CAS  PubMed  Google Scholar 

  11. Hattikudur S, Kamat RS (1985) Polymorphism of a mycobacterial antigen participating in cell-mediated immunity. J Med Microbiol 19:69–75

    Article  CAS  PubMed  Google Scholar 

  12. Ho YS, Adroub SA, Abadi M, Al Alwan B, Alkhateeb R, Gao G, Ragab A, Ali S, van Soolingen D, Bitter W, Pain A, Abdallah AM (2012) Complete genome sequence of Mycobacterium vaccae type strain ATCC 25954. J Bacteriol 194:6339–6340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hougardy JM, Place S, Hildebrand M, Drowart A, Debrie AS, Locht C, Mascart F (2007) Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med 176:409–416

    Article  CAS  PubMed  Google Scholar 

  14. Howard CJ, Kwong LS, Villarreal-Ramos B, Sopp P, Hope JC (2002) Exposure to Mycobacterium avium primes the immune system of calves for vaccination with Mycobacterium bovis BCG. Clin Exp Immunol 130:190–195

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kamala T, Paramasivan CN, Herbert D, Venkatesan P, Prabhakar R (1996) Immune response & modulation of immune response induced in the guinea-pigs by Mycobacterium avium complex (MAC) & M. fortuitum complex isolates from different sources in the south Indian BCG trial area. Indian J Med Res 103:201–211

    CAS  PubMed  Google Scholar 

  16. Howard ST, Byrd TF (2000) The rapidly growing mycobacteria: saprophytes and parasites. Microb Infect 2:1845–1853

    Article  CAS  Google Scholar 

  17. Larson CL, Wicht WC (1964) Infection of mice with Mycobacterium tuberculosis, strain H37Ra. Am Rev Respir Dis 90:742–748

    CAS  PubMed  Google Scholar 

  18. Li L, Lao SH, Wu CY (2007) Increased frequency of CD4 (+) CD25 (high) Treg cells inhibit BCG-specific induction of IFN-gamma by CD4 (+) T cells from TB patients. Tuberculosis (Edinb) 87:526–534

    Article  CAS  Google Scholar 

  19. Lozes E, Denis O, Drowart A, Jurion F, Palfliet K, Vanonckelen A, De Bruyn J, De Cock M, Van Vooren JP, Huygen K (1997) Cross-reactive immune responses against Mycobacterium bovis BCG in mice infected with non-tuberculous mycobacteria belonging to the MAIS-Group. Scand J Immunol 46:16–26

    Article  CAS  PubMed  Google Scholar 

  20. Luo Y (2001) The immunotherapeutic effect of Mycobacterium vaccae vaccine on initially treated pulmonary tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 24:43–47 (in Chinese)

    CAS  PubMed  Google Scholar 

  21. Martin C, Williams A, Hernandez-Pando R, Cardona PJ, Gormley E, Bordat Y, Soto CY, Clark SO, Hatch GJ, Aguilar D, Ausina V, Gicquel B (2006) The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis in mice and guinea pigs. Vaccine 24:3408–3419

    Article  CAS  PubMed  Google Scholar 

  22. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W (2004) TGF-beta 1 plays an important role in the mechanism of CD4+ CD25+ regulatory T cell activity in both humans and mice. J Immunol 172:834–842

    Article  CAS  PubMed  Google Scholar 

  23. Orme IM, Collins FM (1983) Infection with Mycobacterium kansasii and efficacy of vaccination against tuberculosis. Immunology 50:581–586

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Orme IM, Collins FM (1984) Efficacy of Mycobacterium bovis BCG vaccination in mice undergoing prior pulmonary infection with atypical mycobacteria. Infect Immun 44:28–32

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Palmer C, Long M (1966) Effects of infection with atypical mycobacteria on BCG vaccination and tuberculosis. Am Rev Respir Dis 94:553–568

    CAS  PubMed  Google Scholar 

  26. Pérez E, Samper S, Bordas Y, Guilhot C, Gicquel B, Martín C (2001) An essential role for phoP in Mycobacterium tuberculosis virulence. Mol Microbiol 41:179–187

    Article  PubMed  Google Scholar 

  27. Primm TP, Lucero CA, Falkinham JO 3rd (2004) Health impacts of environmental mycobacteria. Clin Microbiol Rev 17:98–106

    Article  PubMed Central  PubMed  Google Scholar 

  28. Schwander S, Dheda K (2011) Human lung immunity against Mycobacterium tuberculosis: insights into pathogenesis and protection. Am J Respir Crit Care Med 183:696–707

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Skinner MA, Yuan S, Prestidge R, Chuk D, Watson JD, Tan PL (1997) Immunization with heat-killed Mycobacterium vaccae stimulates CD8+ cytotoxic T cells specific for macrophages infected with Mycobacterium tuberculosis. Infect Immun 65:4525–4530

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Sweeney KA, Dao DN, Goldberg MF, Hsu T, Venkataswamy MM, Henao-Tamayo M, Ordway D, Sellers RS, Jain P, Chen B, Chen M, Kim J, Lukose R, Chan J, Orme IM, Porcelli SA, Jacobs WR Jr (2011) A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis. Nat Med 17:1261–1268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Tortoli E (2006) The new mycobacteria: an update. FEMS Immunol Med Microbiol 48:159–178

    Article  CAS  PubMed  Google Scholar 

  32. Tortoli E (2009) Clinical manifestations of nontuberculous mycobacteria infections. Clin Microbiol Infect 15:906–910

    Article  CAS  PubMed  Google Scholar 

  33. Walters SB, Dubnau E, Kolesnikova I, Laval F, Daffe M, Smith I (2006) The Mycobacterium tuberculosis PhoPR two-component system regulates genes essential for virulence and complex lipid biosynthesis. Mol Microbiol 60:312–330

    Article  CAS  PubMed  Google Scholar 

  34. Wammes LJ, Hamid F, Wiria AE, de Gier B, Sartono E, Maizels RM, Luty AJ, Fillié Y, Brice GT, Supali T, Smits HH, Yazdanbakhsh M (2010) Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum. Eur J Immunol 40:437–442

    Article  CAS  PubMed  Google Scholar 

  35. Wang C, Chen Z, Fu R, Zhang Y, Chen L, Huang L, Li J, Shi C, Fan X (2011) A DNA vaccine expressing CFP21 and MPT64 fusion protein enhances BCG-induced protective immunity against Mycobacterium tuberculosis infection in mice. Med Microbiol Immunol 200:165–175

    Article  CAS  PubMed  Google Scholar 

  36. Young SL, Slobbe L, Wilson R, Buddle BM, de Lisle GW, Buchan GS (2007) Environmental strains of Mycobacterium avium interfere with immune responses associated with Mycobacterium bovis BCG vaccination. Infect Immun 75:2833–2840

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Zheng H, Lu L, Wang B, Pu S, Zhang X, Zhu G, Shi W, Zhang L, Wang H, Wang S, Zhao G, Zhang Y (2008) Genetic basis of virulence attenuation revealed by comparative genomic analysis of Mycobacterium tuberculosis strain H37Ra versus H37Rv. PLoS ONE 3:e2375

    Article  PubMed Central  PubMed  Google Scholar 

  38. Zumla A, Grange J (2002) Infection and disease caused by environmental mycobacteria. Curr Opin Pulm Med 8:166–172

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by a grant of the Key Project Specialized for Infectious Diseases of the Chinese Ministry of Health (2012ZX10003008-005).

Author information

Author notes

    Authors and Affiliations

    1. Department of Medical Laboratory, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, People’s Republic of China

      Laicheng Liu

    2. Department of Pathogen Biology, School of Preclinical Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, People’s Republic of China

      Ruiling Fu, Xuefeng Yuan, Chunwei Shi, Zhao Ma, Xiaoming Zhang, Weiyan Qin & Xionglin Fan

    3. The Third People’s Hospital of Chongqing City, Clinical Laboratory Center of Chongqing, Chongqing, 400014, People’s Republic of China

      Shuling Wang

    4. Department of Clinical Immunology, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

      Xianyu Lu

    Authors
    1. Laicheng Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ruiling Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Xuefeng Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Chunwei Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Shuling Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xianyu Lu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Zhao Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Xiaoming Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Weiyan Qin
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xionglin Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Xianyu Lu or Xionglin Fan.

    Additional information

    Laicheng Liu, Ruiling Fu, and Xuefeng Yuan contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Liu, L., Fu, R., Yuan, X. et al. Differential Immune Responses and Protective Effects in Avirulent Mycobacterial Strains Vaccinated BALB/c Mice. Curr Microbiol 71, 129–135 (2015). https://doi.org/10.1007/s00284-015-0837-3

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00284-015-0837-3

    Keywords

    Search

    Navigation