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Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae


Streptococcus pneumoniae is a major human pathogen that is involved in community-acquired pneumonia. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that activates immune responses against infection, invasion, injury, or inflammation. To study the role of TNF-α during S. pneumoniae infection, a murine pneumococcal pneumonia model was used. We intranasally infected C57BL/6J wild-type (WT) and TNF-α knockout (KO) mice with S. pneumoniae D39 serotype 2. In TNF-α KO mice, continuous and distinct loss of body weight, and low survival rates were observed. Bacterial counts in the lungs and blood of TNF-α KO mice were significantly higher than those in WT mice. Histopathological lesions in the spleen of TNF-α KO mice were more severe than those in WT mice. In TNF-α KO mice, severe depletion of white pulp was observed and the number of apoptotic cells was significantly increased. Interferon-gamma (IFN-γ), IL-12p70 and IL-10 levels in serum were significantly increased in TNF-α KO mice. TNF-α is clearly involved in the regulation of S. pneumoniae infections. Early death and low survival rates of TNF-α KO mice were likely caused by a combination of impaired bacterial clearance and damage to the spleen. Our findings suggest that TNF-α plays a critical role in protecting the host from systemic S. pneumoniae infection.


  1. 1.

    García-Suárez Mdel M, Cima-Cabal MD, Flórez N, García P, Cernuda-Cernuda R, Astudillo A, Vázquez F, De los Toyos JR, Méndez FJ. Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin. Infect Immun 2004; 72(8): 4534–4540.

    Article  Google Scholar 

  2. 2.

    O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, Lee E, Mulholland K, Levine OS, Cherian T; Hib and Pneumococcal Global Burden of Disease Study Team. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet 2009; 374(9693): 893–902.

    Article  Google Scholar 

  3. 3.

    Tracey KJ, Cerami A. Tumor necrosis factor, other cytokines and disease. Annu Rev Cell Biol 1993; 9: 317–343.

    CAS  Article  Google Scholar 

  4. 4.

    Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296(5573): 1634–1635.

    CAS  Article  Google Scholar 

  5. 5.

    Hatta M, Yamamoto N, Miyazato A, Ishii N, Nakamura K, Inden K, Aoyagi T, Kunishima H, Hirakata Y, Suzuki K, Kaku M, Kawakami K. Early production of tumor necrosis factor-alpha by Gr-1 cells and its role in the host defense to pneumococcal infection in lungs. FEMS Immunol Med Microbiol 2010; 58(2): 182–192.

    CAS  Article  Google Scholar 

  6. 6.

    Takashima K, Tateda K, Matsumoto T, Iizawa Y, Nakao M, Yamaguchi K. Role of tumor necrosis factor alpha in pathogenesis of pneumococcal pneumonia in mice. Infect Immun 1997; 65(1): 257–260.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Boelen A, Kwakkel J, Wieland CW, St Germain DL, Fliers E, Hernandez A. Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 2009; 150(4): 1984–1990.

    CAS  Article  Google Scholar 

  8. 8.

    Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, Schreiber R, Mak TW, Bloom BR. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2(6): 561–572.

    CAS  Article  Google Scholar 

  9. 9.

    Kerr AR, Irvine JJ, Search JJ, Gingles NA, Kadioglu A, Andrew PW, McPheat WL, Booth CG, Mitchell TJ. Role of inflammatory mediators in resistance and susceptibility to pneumococcal infection. Infect Immun 2002; 70(3): 1547–1557.

    CAS  Article  Google Scholar 

  10. 10.

    Baghai M, Osmon DR, Wolk DM, Wold LE, Haidukewych GJ, Matteson EL. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc 2001; 76(6): 653–656.

    CAS  Article  Google Scholar 

  11. 11.

    Ellerin T, Rubin RH, Weinblatt ME. Infections and anti-tumor necrosis factor alpha therapy. Arthritis Rheum 2003; 48(11): 3013–3022.

    CAS  Article  Google Scholar 

  12. 12.

    Schneeweiss S, Setoguchi S, Weinblatt ME, Katz JN, Avorn J, Sax PE, Levin R, Solomon DH. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007; 56(6): 1754–1764.

    CAS  Article  Google Scholar 

  13. 13.

    Houldsworth S, Andrew PW, Mitchell TJ. Pneumolysin stimulates production of tumor necrosis factor alpha and interleukin-1 beta by human mononuclear phagocytes. Infect Immun 1994; 62(4): 1501–1503.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rayner CF, Jackson AD, Rutman A, Dewar A, Mitchell TJ, Andrew PW, Cole PJ, Wilson R. Interaction of pneumolysin-sufficient and -deficient isogenic variants of Streptococcus pneumoniae with human respiratory mucosa. Infect Immun 1995; 63(2): 442–447.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Benton KA, Everson MP, Briles DE. A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. Infect Immun 1995; 63(2): 448–455.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Jones MR, Simms BT, Lupa MM, Kogan MS, Mizgerd JP. Lung NF-kappaB activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia. J Immunol 2005; 175(11): 7530–7535.

    CAS  Article  Google Scholar 

  17. 17.

    Kirby AC, Raynes JG, Kaye PM. The role played by tumor necrosis factor during localized and systemic infection with Streptococcus pneumoniae. J Infect Dis 2005; 191(9): 1538–1547.

    CAS  Article  Google Scholar 

  18. 18.

    Kadioglu A, Andrew PW. The innate immune response to pneumococcal lung infection: the untold story. Trends Immunol 2004; 25(3): 143–149.

    CAS  Article  Google Scholar 

  19. 19.

    Tinsley KW, Grayson MH, Swanson PE, Drewry AM, Chang KC, Karl IE, Hotchkiss RS. Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol 2003; 171(2): 909–914.

    CAS  Article  Google Scholar 

  20. 20.

    Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 2007; 96: 41–101.

    CAS  Article  Google Scholar 

  21. 21.

    Kaliñski P, Hilkens CM, Snijders A, Snijdewint FG, Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 1997; 159(1): 28–35.

    PubMed  Google Scholar 

  22. 22.

    Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol 2008; 180(9): 5771–5777.

    CAS  Article  Google Scholar 

  23. 23.

    Rubins JB, Pomeroy C. Role of gamma interferon in the pathogenesis of bacteremic pneumococcal pneumonia. Infect Immun 1997; 65(7): 2975–2977.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Puddu P, Fantuzzi L, Borghi P, Varano B, Rainaldi G, Guillemard E, Malorni W, Nicaise P, Wolf SF, Belardelli F, Gessani S. IL-12 induces IFN-gamma expression and secretion in mouse peritoneal macrophages. J Immunol 1997; 159(7): 3490–3497.

    CAS  PubMed  Google Scholar 

  25. 25.

    Karp CL, el-Safi SH, Wynn TA, Satti MM, Kordofani AM, Hashim FA, Hag-Ali M, Neva FA, Nutman TB, Sacks DL. In vivo cytokine profiles in patients with kala-azar. Marked elevation of both interleukin-10 and interferon-gamma. J Clin Invest 1993; 91(4): 1644–1648

    CAS  Article  Google Scholar 

  26. 26.

    Silva JS, Morrissey PJ, Grabstein KH, Mohler KM, Anderson D, Reed SG. Interleukin 10 and interferon gamma regulation of experimental Trypanosoma cruzi infection. J Exp Med 1992; 175(1): 169–174.

    CAS  Article  Google Scholar 

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This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2012R1A6A3A01019025 and 2012R1A1A2004577).

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Correspondence to Eui-Suk Jeong.

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Jeong, D., Seo, J., Heo, S. et al. Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae. Lab Anim Res 31, 78–85 (2015).

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  • Tumor necrosis factor-alpha knockout
  • Streptococcus pneumoniae
  • pneumonia