Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1996 Aug;64(8):3288–3293. doi: 10.1128/iai.64.8.3288-3293.1996

Minimal requirements for murine resistance to infection with Francisella tularensis LVS.

K L Elkins 1, T R Rhinehart-Jones 1, S J Culkin 1, D Yee 1, R K Winegar 1
PMCID: PMC174220  PMID: 8757866

Abstract

Intraperitoneal or intravenous infection of mice with Francisella tularensis LVS is lethal, with an intraperitoneal 50% lethal dose (LD50) approaching a single bacterium. Intradermal (i.d.) LVS infection has a much higher LD50, about 10(6) bacteria in BALB/cByJ mice, and survival of i.d. infection leads to solid generation of immunity against lethal challenge. To define the minimal requirements for both initial and long-term survival of i.d. infection, we characterized the nature of i.d. LVS infection in lymphocyte-deficient BALB/cByJ.scid (scid) mice. scid mice infected i.d. with strain LVS survived for about 20 days and then died from overwhelming disseminated infection. However, scid mice treated with monoclonal antibodies to gamma interferon, tumor necrosis factor alpha, or neutrophils-granulocytes all died within 1 week of infection, indicating that these were essential for early control of infection. Studies using GKO (gamma interferon knockout) mice emphasized that gamma interferon is absolutely required for initial survival of i.d. LVS infection. scid mice could be reconstituted for long-term survival of i.d. LVS infection and clearance of bacteria by intravenous transfer of splenic lymphocytes or purified B220-/T+ lymphocytes but not nu/nu lymphocytes. T cells are therefore required for long-term clearance and survival of i.d. LVS infection; efforts to determine whether CD4+ T cells, CD8+ T cells, or both are involved are ongoing.

Full Text

The Full Text of this article is available as a PDF (215.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anthony L. S., Ghadirian E., Nestel F. P., Kongshavn P. A. The requirement for gamma interferon in resistance of mice to experimental tularemia. Microb Pathog. 1989 Dec;7(6):421–428. doi: 10.1016/0882-4010(89)90022-3. [DOI] [PubMed] [Google Scholar]
  2. Autenrieth I. B., Vogel U., Preger S., Heymer B., Heesemann J. Experimental Yersinia enterocolitica infection in euthymic and T-cell-deficient athymic nude C57BL/6 mice: comparison of time course, histomorphology, and immune response. Infect Immun. 1993 Jun;61(6):2585–2595. doi: 10.1128/iai.61.6.2585-2595.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baker C. N., Hollis D. G., Thornsberry C. Antimicrobial susceptibility testing of Francisella tularensis with a modified Mueller-Hinton broth. J Clin Microbiol. 1985 Aug;22(2):212–215. doi: 10.1128/jcm.22.2.212-215.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bancroft G. J., Schreiber R. D., Bosma G. C., Bosma M. J., Unanue E. R. A T cell-independent mechanism of macrophage activation by interferon-gamma. J Immunol. 1987 Aug 15;139(4):1104–1107. [PubMed] [Google Scholar]
  5. Bancroft G. J., Sheehan K. C., Schreiber R. D., Unanue E. R. Tumor necrosis factor is involved in the T cell-independent pathway of macrophage activation in scid mice. J Immunol. 1989 Jul 1;143(1):127–130. [PubMed] [Google Scholar]
  6. Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
  7. Cassatella M. A. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995 Jan;16(1):21–26. doi: 10.1016/0167-5699(95)80066-2. [DOI] [PubMed] [Google Scholar]
  8. Clark E. A., Ledbetter J. A. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425–428. doi: 10.1038/367425a0. [DOI] [PubMed] [Google Scholar]
  9. Conlan J. W., North R. J. Neutrophil-mediated dissolution of infected host cells as a defense strategy against a facultative intracellular bacterium. J Exp Med. 1991 Sep 1;174(3):741–744. doi: 10.1084/jem.174.3.741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Conlan J. W., North R. J. Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody. J Exp Med. 1994 Jan 1;179(1):259–268. doi: 10.1084/jem.179.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Conlan J. W., Sjöstedt A., North R. J. CD4+ and CD8+ T-cell-dependent and -independent host defense mechanisms can operate to control and resolve primary and secondary Francisella tularensis LVS infection in mice. Infect Immun. 1994 Dec;62(12):5603–5607. doi: 10.1128/iai.62.12.5603-5607.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Czuprynski C. J., Brown J. F. Effects of purified anti-Lyt-2 mAb treatment on murine listeriosis: comparative roles of Lyt-2+ and L3T4+ cells in resistance to primary and secondary infection, delayed-type hypersensitivity and adoptive transfer of resistance. Immunology. 1990 Sep;71(1):107–112. [PMC free article] [PubMed] [Google Scholar]
  13. Elkins K. L., Leiby D. A., Winegar R. K., Nacy C. A., Fortier A. H. Rapid generation of specific protective immunity to Francisella tularensis. Infect Immun. 1992 Nov;60(11):4571–4577. doi: 10.1128/iai.60.11.4571-4577.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Elkins K. L., Rhinehart-Jones T., Nacy C. A., Winegar R. K., Fortier A. H. T-cell-independent resistance to infection and generation of immunity to Francisella tularensis. Infect Immun. 1993 Mar;61(3):823–829. doi: 10.1128/iai.61.3.823-829.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Elkins K. L., Winegar R. K., Nacy C. A., Fortier A. H. Introduction of Francisella tularensis at skin sites induces resistance to infection and generation of protective immunity. Microb Pathog. 1992 Nov;13(5):417–421. doi: 10.1016/0882-4010(92)90085-3. [DOI] [PubMed] [Google Scholar]
  16. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fortier A. H., Slayter M. V., Ziemba R., Meltzer M. S., Nacy C. A. Live vaccine strain of Francisella tularensis: infection and immunity in mice. Infect Immun. 1991 Sep;59(9):2922–2928. doi: 10.1128/iai.59.9.2922-2928.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harty J. T., Schreiber R. D., Bevan M. J. CD8 T cells can protect against an intracellular bacterium in an interferon gamma-independent fashion. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11612–11616. doi: 10.1073/pnas.89.23.11612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Huang S., Hendriks W., Althage A., Hemmi S., Bluethmann H., Kamijo R., Vilcek J., Zinkernagel R. M., Aguet M. Immune response in mice that lack the interferon-gamma receptor. Science. 1993 Mar 19;259(5102):1742–1745. doi: 10.1126/science.8456301. [DOI] [PubMed] [Google Scholar]
  20. Hunter C. A., Abrams J. S., Beaman M. H., Remington J. S. Cytokine mRNA in the central nervous system of SCID mice infected with Toxoplasma gondii: importance of T-cell-independent regulation of resistance to T. gondii. Infect Immun. 1993 Oct;61(10):4038–4044. doi: 10.1128/iai.61.10.4038-4044.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Izzo A. A., North R. J. Evidence for an alpha/beta T cell-independent mechanism of resistance to mycobacteria. Bacillus-Calmette-Guerin causes progressive infection in severe combined immunodeficient mice, but not in nude mice or in mice depleted of CD4+ and CD8+ T cells. J Exp Med. 1992 Aug 1;176(2):581–586. doi: 10.1084/jem.176.2.581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kaufmann S. H. In vitro analysis of the cellular mechanisms involved in immunity to tuberculosis. Rev Infect Dis. 1989 Mar-Apr;11 (Suppl 2):S448–S454. doi: 10.1093/clinids/11.supplement_2.s448. [DOI] [PubMed] [Google Scholar]
  23. Ladel C. H., Daugelat S., Kaufmann S. H. Immune response to Mycobacterium bovis bacille Calmette Guérin infection in major histocompatibility complex class I- and II-deficient knock-out mice: contribution of CD4 and CD8 T cells to acquired resistance. Eur J Immunol. 1995 Feb;25(2):377–384. doi: 10.1002/eji.1830250211. [DOI] [PubMed] [Google Scholar]
  24. Ladel C. H., Flesch I. E., Arnoldi J., Kaufmann S. H. Studies with MHC-deficient knock-out mice reveal impact of both MHC I- and MHC II-dependent T cell responses on Listeria monocytogenes infection. J Immunol. 1994 Oct 1;153(7):3116–3122. [PubMed] [Google Scholar]
  25. Laskay T., Röllinghoff M., Solbach W. Natural killer cells participate in the early defense against Leishmania major infection in mice. Eur J Immunol. 1993 Sep;23(9):2237–2241. doi: 10.1002/eji.1830230928. [DOI] [PubMed] [Google Scholar]
  26. Leiby D. A., Fortier A. H., Crawford R. M., Schreiber R. D., Nacy C. A. In vivo modulation of the murine immune response to Francisella tularensis LVS by administration of anticytokine antibodies. Infect Immun. 1992 Jan;60(1):84–89. doi: 10.1128/iai.60.1.84-89.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mombaerts P., Arnoldi J., Russ F., Tonegawa S., Kaufmann S. H. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature. 1993 Sep 2;365(6441):53–56. doi: 10.1038/365053a0. [DOI] [PubMed] [Google Scholar]
  28. Nauciel C., Espinasse-Maes F. Role of gamma interferon and tumor necrosis factor alpha in resistance to Salmonella typhimurium infection. Infect Immun. 1992 Feb;60(2):450–454. doi: 10.1128/iai.60.2.450-454.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. O'Brien A. D., Metcalf E. S. Control of early Salmonella typhimurium growth in innately Salmonella-resistant mice does not require functional T lymphocytes. J Immunol. 1982 Oct;129(4):1349–1351. [PubMed] [Google Scholar]
  30. Orme I. M. The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. J Immunol. 1987 Jan 1;138(1):293–298. [PubMed] [Google Scholar]
  31. Pfeffer K., Matsuyama T., Kündig T. M., Wakeham A., Kishihara K., Shahinian A., Wiegmann K., Ohashi P. S., Krönke M., Mak T. W. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993 May 7;73(3):457–467. doi: 10.1016/0092-8674(93)90134-c. [DOI] [PubMed] [Google Scholar]
  32. Portnoy D. A. Innate immunity to a facultative intracellular bacterial pathogen. Curr Opin Immunol. 1992 Feb;4(1):20–24. doi: 10.1016/0952-7915(92)90118-x. [DOI] [PubMed] [Google Scholar]
  33. Reimann J., Rudolphi A., Claesson M. H. Selective reconstitution of T lymphocyte subsets in scid mice. Immunol Rev. 1991 Dec;124:75–95. doi: 10.1111/j.1600-065x.1991.tb00617.x. [DOI] [PubMed] [Google Scholar]
  34. Rhinehart-Jones T. R., Fortier A. H., Elkins K. L. Transfer of immunity against lethal murine Francisella infection by specific antibody depends on host gamma interferon and T cells. Infect Immun. 1994 Aug;62(8):3129–3137. doi: 10.1128/iai.62.8.3129-3137.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roberts A. D., Ordway D. J., Orme I. M. Listeria monocytogenes infection in beta 2 microglobulin-deficient mice. Infect Immun. 1993 Mar;61(3):1113–1116. doi: 10.1128/iai.61.3.1113-1116.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rothe J., Lesslauer W., Lötscher H., Lang Y., Koebel P., Köntgen F., Althage A., Zinkernagel R., Steinmetz M., Bluethmann H. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993 Aug 26;364(6440):798–802. doi: 10.1038/364798a0. [DOI] [PubMed] [Google Scholar]
  37. Sandström G., Löfgren S., Tärnvik A. A capsule-deficient mutant of Francisella tularensis LVS exhibits enhanced sensitivity to killing by serum but diminished sensitivity to killing by polymorphonuclear leukocytes. Infect Immun. 1988 May;56(5):1194–1202. doi: 10.1128/iai.56.5.1194-1202.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schreiber R. D., Hicks L. J., Celada A., Buchmeier N. A., Gray P. W. Monoclonal antibodies to murine gamma-interferon which differentially modulate macrophage activation and antiviral activity. J Immunol. 1985 Mar;134(3):1609–1618. [PubMed] [Google Scholar]
  39. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  40. Sjöstedt A., Conlan J. W., North R. J. Neutrophils are critical for host defense against primary infection with the facultative intracellular bacterium Francisella tularensis in mice and participate in defense against reinfection. Infect Immun. 1994 Jul;62(7):2779–2783. doi: 10.1128/iai.62.7.2779-2783.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tepper R. I., Coffman R. L., Leder P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science. 1992 Jul 24;257(5069):548–551. doi: 10.1126/science.1636093. [DOI] [PubMed] [Google Scholar]
  42. Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tärnvik A. Nature of protective immunity to Francisella tularensis. Rev Infect Dis. 1989 May-Jun;11(3):440–451. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES