Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mice, microbes and models of infection

Nature Reviews Genetics volume 4, pages 195–205 (2003)Cite this article

Key Points

  • The immune systems of mice and humans are similar and they can often be challenged with the same, or similar, pathogens.

  • Most mouse mutants with a defective immune system have a broad vulnerability to infection.

  • Forward genetic studies led to the discovery of genes determining resistance or susceptibility to bacterial infection (a recent example is the cloning of the Naip5/Birc1e gene).

  • Targeted gene knockout approaches have been successfully used to dissect the molecular pathways that are involved in host defence.

  • The complexities of bacterial gene expression during mammalian infection cannot be addressed by in vitro experiments alone. The concerted effort of host and pathogen gene-expression profiling by microarray technology and mouse genetics will be the method of choice for in vivo-induced gene analysis in the future.

  • For many human infectious diseases we do not have suitable animal models available; in the next few years it will be necessary to systematically develop new mouse models for infectious diseases.

Abstract

We urgently need animal models to study infectious disease. Mice are susceptible to a similar range of microbial infections as humans. Marked differences between inbred strains of mice in their response to pathogen infection can be exploited to analyse the genetic basis of infections. In addition, the genetic tools that are available in the laboratory mouse, and new techniques to monitor the expression of bacterial genes in vivo, make it the principal experimental animal model for studying mechanisms of infection and immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Toll-like receptor (TLR4) signalling.
Figure 2: The infected host — a complex and dynamic environment.
Figure 3: In vivo expression technology approaches.

Similar content being viewed by others

References

  1. Flajnik, M. F. Comparative analyses of immunoglobulin genes: surprises and portents. Nature Rev. Immunol. 2, 688–698 (2002).

    CAS  Google Scholar 

  2. Grüneberg, H. in The Genetics of the Mouse 421–434 (Martinus Nijhoff, The Hague, 1952).

    Google Scholar 

  3. Shultz, L. D. Immunological mutants of the mouse. Am. J. Anat. 191, 303–311 (1991).

    CAS  PubMed  Google Scholar 

  4. Plant, J. & Glynn, A. A. Locating salmonella resistance gene on mouse chromosome 1. Clin. Exp. Immunol. 37, 1–6 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Plant, J. E., Blackwell, J. M., O'Brien, A. D., Bradley, D. J. & Glynn, A. A. Are the Lsh and Ity disease resistance genes at one locus on mouse chromosome 1? Nature 297, 510–511 (1982).

    CAS  PubMed  Google Scholar 

  6. Bradley, D. J., Taylor, B. A., Blackwell, J., Evans, E. P. & Freeman, J. Regulation of Leishmania populations within the host. III. Mapping of the locus controlling susceptibility to visceral leishmaniasis in the mouse. Clin. Exp. Immunol. 37, 7–14 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Skamene, E. et al. Genetic regulation of resistance to intracellular pathogens. Nature 297, 506–509 (1982).

    CAS  PubMed  Google Scholar 

  8. Gros, P., Skamene, E. & Forget, A. Cellular mechanisms of genetically controlled host resistance to Mycobacterium bovis (BCG). J. Immunol. 131, 1966–1972 (1983).

    CAS  PubMed  Google Scholar 

  9. Schurr, E., Skamene, E., Forget, A. & Gros, P. Linkage analysis of the Bcg gene on mouse chromosome 1. Identification of a tightly linked marker. J. Immunol. 142, 4507–4513 (1989).

    CAS  PubMed  Google Scholar 

  10. Malo, D., Vidal, S. M., Hu, J., Skamene, E. & Gros, P. High-resolution linkage map in the vicinity of the host resistance locus Bcg. Genomics 16, 655–663 (1993).

    CAS  PubMed  Google Scholar 

  11. Malo, D., Vidal, S., Lieman, J. H., Ward, D. C. & Gros, P. Physical delineation of the minimal chromosomal segment encompassing the murine host resistance locus Bcg. Genomics 17, 667–675 (1993).

    CAS  PubMed  Google Scholar 

  12. Vidal, S. M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993). References 9–12 discuss the cloning of the first host-resistance gene Nramp1.

    CAS  PubMed  Google Scholar 

  13. Blackwell, J. M. et al. SLC11A1 (formerly NRAMP1) and disease resistance. Cell Microbiol. 3, 773–784 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vidal, S. et al. The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene. J. Exp. Med. 182, 655–666 (1995).

    CAS  PubMed  Google Scholar 

  15. Govoni, G. et al. The Bcg/Ity/Lsh locus: genetic transfer of resistance to infections in C57BL/6J mice transgenic for the Nramp1 Gly169 allele. Infect. Immun. 64, 2923–2929 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Casanova, J. L. & Abel, L. Genetic dissection of immunity to mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620 (2002).

    CAS  PubMed  Google Scholar 

  17. North, R. J., LaCourse, R., Ryan, L. & Gros, P. Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice. Infect. Immun. 67, 5811–5814 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kramnik, I., Dietrich, W. F., Demant, P. & Bloom, B. R. Genetic control of resistance to experimental infection with virulent Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 97, 8560–8565 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Molmeret, M. & Abu, K. Y. How does Legionella pneumophila exit the host cell? Trends Microbiol. 10, 258–260 (2002).

    CAS  PubMed  Google Scholar 

  20. Gao, L. Y. & Abu, K. Y. Apoptosis in macrophages and alveolar epithelial cells during early stages of infection by Legionella pneumophila and its role in cytopathogenicity. Infect. Immun. 67, 862–870 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao, L. Y. & Abu, K. Y. Activation of caspase 3 during Legionella pneumophila-induced apoptosis. Infect. Immun. 67, 4886–4894 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yoshida, S., Goto, Y., Mizuguchi, Y., Nomoto, K. & Skamene, E. Genetic control of natural resistance in mouse macrophages regulating intracellular Legionella pneumophila multiplication in vitro. Infect. Immun. 59, 428–432 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yamamoto, Y., Klein, T. W. & Friedman, H. Legionella pneumophila growth in macrophages from susceptible mice is genetically controlled. Proc. Soc. Exp. Biol. Med. 196, 405–409 (1991).

    CAS  PubMed  Google Scholar 

  24. Yamamoto, Y., Klein, T. W., Brown, K. & Friedman, H. Differential morphologic and metabolic alterations in permissive versus nonpermissive murine macrophages infected with Legionella pneumophila. Infect. Immun. 60, 3231–3237 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yamamoto, Y., Klein, T. W., Newton, C. A., Widen, R. & Friedman, H. Growth of Legionella pneumophila in thioglycolate-elicited peritoneal macrophages from A/J mice. Infect. Immun. 56, 370–375 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Diez, E., et al. Genetic and physical mapping of the mouse host resistance locus Lgn1. Mamm. Genome 8, 682–685 (1997).

    CAS  PubMed  Google Scholar 

  27. Growney, J. D. & Dietrich, W. F. High-resolution genetic and physical map of the Lgn1 interval in C57BL/6J implicates Naip2 or Naip5 in Legionella pneumophila pathogenesis. Genome Res. 10, 1158–1171 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Diez, E. et al. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nature Genet. 33, 55–60 (2003).

    CAS  PubMed  Google Scholar 

  29. Wright, E. K. et al. Naip5 affects host susceptibility to the intracellular pathogen Legionella pneumophila. Curr. Biol. 13, 27–36 (2003). References 28 and 29 provide clear evidence that Naip5 (Birc1e) is the gene associated with resistance to Legionella pneumophila in mice.

    CAS  PubMed  Google Scholar 

  30. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001). An excellent review that summarizes present concepts of Toll like receptors and innate immunity.

    CAS  Google Scholar 

  31. Hashimoto, C., Hudson, K. L. & Anderson, K. V. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52, 269–279 (1988).

    CAS  PubMed  Google Scholar 

  32. Lemaitre, B., Nicolas, E., Michnaut, L., Reichart, J. M. & Hoffman, J. A. The dorsoventral regulatory cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996). A landmark paper and a crucial demonstration of the immune function of Toll and of the regulatory gene cassette that establishes dorsoventral polarity in Drosophila.

    CAS  PubMed  Google Scholar 

  33. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997). This paper describes the first characterized mammalian Toll – human Tlr4.

    CAS  PubMed  Google Scholar 

  34. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    CAS  PubMed  Google Scholar 

  35. Qureshi, S. T. et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189, 615–625 (1999). References 34 and 35 describe the first indication of TLR4 function in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Heppner, G. & Weiss, D. A. High susceptibility of strain A mice to endotoxin and endotoxin-red blood cell mixtures. J. Bacteriol. 90, 696–703 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sultzer, B. M. Genetic control of leucocyte responses to endotoxin. Nature 219, 1253–1254 (1968).

    CAS  PubMed  Google Scholar 

  38. Watson, J. & Riblet, R. Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic response to lipopolysaccharides. J. Exp. Med. 140, 1147–1161 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Malo, D. et al. Haplotype mapping and sequence analysis of the mouse Nramp gene predict susceptibility to infection with intracellular parasites. Genomics 23, 51–61 (1994).

    CAS  PubMed  Google Scholar 

  40. Wright, S. D., Ramos, R. A., Tobias, P. S., Ulevitch, R. J. & Mathison, J. C. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249, 1431–1433 (1990).

    CAS  PubMed  Google Scholar 

  41. Haziot, A. et al. Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity 4, 407–414 (1996).

    CAS  PubMed  Google Scholar 

  42. Shimazu, R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Schromm, A. B. et al. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J. Exp. Med. 194, 79–88 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lien, E. et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J. Clin. Invest 105, 497–504 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Poltorak, A., Ricciardi-Castagnoli, P., Citterio, S. & Beutler, B. Physical contact between lipopolysaccharide and toll-like receptor 4 revealed by genetic complementation. Proc. Natl Acad. Sci. USA 97, 2163–2167 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. da Silva, C. J., Soldau, K., Christen, U., Tobias, P. S. & Ulevitch, R. J. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J. Biol. Chem. 276, 21129–21135 (2001).

    Google Scholar 

  47. Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNF α-deficient mice: a critical requirement for TNF-α in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996).

    CAS  PubMed  Google Scholar 

  48. Flynn, J. L. et al. Tumor necrosis factor-α is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2, 561–572 (1995).

    CAS  PubMed  Google Scholar 

  49. Netea, M. G. et al. Lethal Escherichia coli and Salmonella typhimurium endotoxemia is mediated through different pathways. Eur. J. Immunol. 31, 2529–2538 (2001).

    CAS  PubMed  Google Scholar 

  50. Kamradt, A. E., Greiner, M., Ghiara, P. & Kaufmann, S. H. Helicobacter pylori infection in wild-type and cytokine-deficient C57BL/6 and BALB/c mouse mutants. Microbes Infect. 2, 593–597 (2000).

    CAS  PubMed  Google Scholar 

  51. Yamada, H., Mizumo, S., Horai, R., Iwakura, Y. & Sugawara, I. Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice. Lab. Invest. 80, 759–767 (2000).

    CAS  PubMed  Google Scholar 

  52. Hultgren, O. H., Svensson, L. & Tarkowski, A. Critical role of signaling through IL-1 receptor for development of arthritis and sepsis during Staphylococcus aureus infection. J. Immunol. 168, 5207–5212 (2002).

    CAS  PubMed  Google Scholar 

  53. Shinozawa, Y. et al. Role of interferon-γ in inflammatory responses in murine respiratory infection with Legionella pneumophila. J. Med. Microbiol. 51, 225–230 (2002).

    CAS  PubMed  Google Scholar 

  54. Reznikov, L. L. et al. Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: role of interleukin 1β. Biol. Reprod. 60, 1231–1238 (1999).

    CAS  PubMed  Google Scholar 

  55. Zheng, H. et al. Resistance to fever induction and impaired acute-phase response in interleukin-1 β-deficient mice. Immunity 3, 9–19 (1995).

    CAS  PubMed  Google Scholar 

  56. Dai, W. J., Kohler, G. & Brombacher, F. Both innate and acquired immunity to Listeria monocytogenes infection are increased in IL-10-deficient mice. J. Immunol. 158, 2259–2267 (1997).

    CAS  PubMed  Google Scholar 

  57. Brombacher, F. et al. IL-12 is dispensable for innate and adaptive immunity against low doses of Listeria monocytogenes. Int. Immunol. 11, 325–332 (1999).

    CAS  PubMed  Google Scholar 

  58. Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).

    CAS  PubMed  Google Scholar 

  59. Ladel, C. H. et al. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect. Immun. 65, 4843–4849 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. van Der, P. T. et al. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J. Infect. Dis. 176, 439–444 (1997).

    Google Scholar 

  61. Sugawara, I., Yamada, H., Mizuno, S. & Iwakura, Y. IL-4 is required for defense against mycobacterial infection. Microbiol. Immunol. 44, 971–979 (2000).

    CAS  PubMed  Google Scholar 

  62. McKenzie, G. J. et al. Impaired development of Th2 cells in IL-13-deficient mice. Immunity 9, 423–432 (1998).

    CAS  PubMed  Google Scholar 

  63. Matthews, D. J. et al. IL-13 is a susceptibility factor for Leishmania major infection. J. Immunol. 164, 1458–1462 (2000).

    CAS  PubMed  Google Scholar 

  64. Hess, J., Ladel, C., Miko, D. & Kaufmann, S. H. Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-α-β cells and IFN-γ in bacterial clearance independent of intracellular location. J. Immunol. 156, 3321–3326 (1996).

    CAS  PubMed  Google Scholar 

  65. Harty, J. T. & Bevan, M. J. Specific immunity to Listeria monocytogenes in the absence of IFN-γ. Immunity 3, 109–117 (1995).

    CAS  PubMed  Google Scholar 

  66. Flynn, J. L. et al. An essential role for interferon-γ in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178, 2249–2254 (1993).

    CAS  PubMed  Google Scholar 

  67. Wille, U., Villegas, E. N., Striepen, B., Roos, D. S. & Hunter, C. A. Interleukin-10 does not contribute to the pathogenesis of a virulent strain of Toxoplasma gondii. Parasite Immunol. 23, 291–296 (2001).

    CAS  PubMed  Google Scholar 

  68. Cooper, A. M. et al. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immunol. 168, 1322–1327 (2002).

    CAS  PubMed  Google Scholar 

  69. Kinjo, Y. et al. Contribution of IL-18 to Th1 response and host defense against infection by Mycobacterium tuberculosis: a comparative study with IL-12p40. J. Immunol. 169, 323–329 (2002).

    CAS  PubMed  Google Scholar 

  70. Wei, X. Q. et al. Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice. J. Immunol. 163, 2821–2828 (1999).

    CAS  PubMed  Google Scholar 

  71. Jacobs, M., Brown, N., Allie, N., Gulert, R. & Ryffel, B. Increased resistance to mycobacterial infection in the absence of interleukin-10. Immunology 100, 494–501 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Shanahan, F. Immunology: therapeutic manipulation of gut flora. Science 289, 1311–1312 (2000).

    CAS  PubMed  Google Scholar 

  73. Steidler, L. et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289, 1352–1355 (2000). A paper that provides a new concept for mucosal immune modulation in mice by in situ delivery of cytokines using genetically engineered Lactococcus lactis.

    CAS  PubMed  Google Scholar 

  74. Strober, W., Fuss, I. J. & Blumberg, R. S. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20, 495–549 (2002). A review that provides a broad overview of mucosal models of inflammation mainly in mice.

    CAS  PubMed  Google Scholar 

  75. Lengeling, A., Pfeffer, K. & Balling, R. The battle of two genomes: genetics of bacterial host/pathogen interactions in mice. Mamm. Genome 12, 261–271 (2001).

    CAS  PubMed  Google Scholar 

  76. Jouanguy, E. et al. Interferon-γ-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N. Engl. J. Med. 335, 1956–1961 (1996).

    CAS  PubMed  Google Scholar 

  77. Newport, M. J. et al. A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection. N. Engl. J. Med. 335, 1941–1949 (1996).

    CAS  PubMed  Google Scholar 

  78. Tracey, K. J. & Abraham, E. From mouse to man: or what have we learned about cytokine-based anti-inflammatory therapies? Shock 11, 224–225 (1999).

    CAS  PubMed  Google Scholar 

  79. Ehlers, S., Kutsch, S., Ehlers, E. M., Benini, J. & Pfeffer, K. Lethal granuloma disintegration in mycobacteria-infected TNFRp55−/− mice is dependent on T cells and IL-12. J. Immunol. 165, 483–492 (2000). Demonstration that lethal granuloma disintegration in mycobacteria-infected Tnfrp55−/− mice is T cell and IL–12 dependent.

    CAS  PubMed  Google Scholar 

  80. Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    CAS  PubMed  Google Scholar 

  81. Rothe, J. et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364, 798–802 (1993). References 80 and 81 are landmark papers showing the impact of knockout mice for the study of infectious disease.

    CAS  PubMed  Google Scholar 

  82. Chan, F. K. et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288, 2351–2354 (2000).

    CAS  PubMed  Google Scholar 

  83. Erickson, S. L. et al. Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 372, 560–563 (1994).

    CAS  PubMed  Google Scholar 

  84. Flynn, J. L. & Chan, J. Immunology of tuberculosis. Annu. Rev. Immunol. 19, 93–129 (2001).

    CAS  PubMed  Google Scholar 

  85. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993). A publication that provides key evidence that IL–10 is important for maintaining immune homeostasis.

    CAS  PubMed  Google Scholar 

  86. Moore, K. W., de Waal, M. R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  Google Scholar 

  87. Trinchieri, G. Regulatory role of T cells producing both interferon γ and interleukin 10 in persistent infection. J. Exp. Med. 194, F53–F57 (2001). Important study analysing the role of regulatory T cells in persistent infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Lin, M. T., Hinton, D. R., Parra, B., Stohlman, S. A. & van der Veen R. C. The role of IL-10 in mouse hepatitis virus-induced demyelinating encephalomyelitis. Virology 245, 270–280 (1998).

    CAS  PubMed  Google Scholar 

  89. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    CAS  PubMed  Google Scholar 

  90. Buer, J. et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J. Exp. Med. 187, 177–183 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Gorelik, L. & Flavell, R. A. Transforming growth factor-β in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002).

    CAS  Google Scholar 

  92. Singh, B. et al. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182, 190–200 (2001).

    CAS  PubMed  Google Scholar 

  93. Mahan, M. J., Heithoff, D. M., Sinsheimer, R. L. & Low, D. A. Assessment of bacterial pathogenesis by analysis of gene expression in the host. Annu. Rev. Genet. 34, 139–164 (2000).

    CAS  PubMed  Google Scholar 

  94. Kato-Maeda, M., Gao, Q. & Small, P. M. Microarray analysis of pathogens and their interaction with hosts. Cell Microbiol. 3, 713–719 (2001).

    CAS  PubMed  Google Scholar 

  95. Mahan, M. J., Slauch, J. M. & Mekalanos, J. J. Selection of bacterial virulence genes that are specifically induced in host tissues. Science 259, 686–688 (1993). This paper introduces IVET technology.

    CAS  PubMed  Google Scholar 

  96. VanBogelen, R. A., Greis, K. D., Blumenthal, R. M., Tani, T. H. & Matthews, R. G. Mapping regulatory networks in microbial cells. Trends Microbiol. 7, 320–328 (1999).

    CAS  PubMed  Google Scholar 

  97. Chiang, S. L., Mekalanos, J. J. & Holden, D. W. In vivo genetic analysis of bacterial virulence. Annu. Rev. Microbiol. 53, 129–154 (1999).

    CAS  PubMed  Google Scholar 

  98. Handfield, M. & Levesque, R. C. Strategies for isolation of in vivo expressed genes from bacteria. FEMS Microbiol. Rev. 23, 69–91 (1999).

    CAS  PubMed  Google Scholar 

  99. Camilli, A. & Mekalanos, J. J. Use of recombinase gene fusions to identify Vibrio cholerae genes induced during infection. Mol. Microbiol. 18, 671–683 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Camilli, A., Beattie, D. T. & Mekalanos, J. J. Use of genetic recombination as a reporter of gene expression. Proc. Natl Acad. Sci. USA 91, 2634–2638 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Valdivia, R. H. & Falkow, S. Fluorescence-based isolation of bacterial genes expressed within host cells. Science 277, 2007–2011 (1997).

    CAS  PubMed  Google Scholar 

  102. Valdivia, R. H., Hromockyj, A. E., Monack, D., Ramakrishnan, L. & Falkow, S. Applications for green fluorescent protein (GFP) in the study of host-pathogen interactions. Gene 173, 47–52 (1996).

    CAS  PubMed  Google Scholar 

  103. Barker, L. P., Brooks, D. M. & Small, P. L. The identification of Mycobacterium marinum genes differentially expressed in macrophage phagosomes using promoter fusions to green fluorescent protein. Mol. Microbiol. 29, 1167–1177 (1998).

    CAS  PubMed  Google Scholar 

  104. Chiang, S. L. & Mekalanos, J. J. Use of signature-tagged transposon mutagenesis to identify Vibrio cholerae genes critical for colonization. Mol. Microbiol. 27, 797–805 (1998).

    CAS  PubMed  Google Scholar 

  105. Coulter, S. N. et al. Staphylococcus aureus genetic loci impacting growth and survival in multiple infection environments. Mol. Microbiol. 30, 393–404 (1998).

    CAS  PubMed  Google Scholar 

  106. Mei, J. M., Nourbakhsh, F., Ford, C. W. & Holden, D. W. Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis. Mol. Microbiol. 26, 399–407 (1997).

    CAS  PubMed  Google Scholar 

  107. Schwan, W. R. et al. Identification and characterization of the PutP proline permease that contributes to in vivo survival of Staphylococcus aureus in animal models. Infect. Immun. 66, 567–572 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

  109. Hall, N. et al. Sequence of Plasmodium falciparum chromosomes 1, 3–9 and 13. Nature 419, 527–531 (2002).

    CAS  PubMed  Google Scholar 

  110. Carlton, J. M. et al. Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature 419, 512–519 (2002).

    CAS  PubMed  Google Scholar 

  111. Wilson, M., McNab, R. & Henderson, B. Bacterial Disease Mechanisms: an Introduction to Cellular Microbiology (Cambridge Univ. Press, UK, 2002).

    Google Scholar 

Download references

Acknowledgements

The authors thank M. Probst-Kepper for stimulating discussions, M. Rohde, K. E. J. Dittmar and S. Weiss for the figure on the infected host, and J. Lauber, D. Bruder and R. Geffers for help in preparing the manuscript. J.B. would like to thank D. Bitter-Suermann, J. Wehland and H. von Boehmer for ongoing support and encouragement. The authors are supported by the Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research.

Author information

Authors and Affiliations

  1. German Research Centre for Biotechnology (GBF), Mascheroder Weg 1, Braunschweig, D-38124, Germany

    Jan Buer & Rudi Balling

  2. Institute of Medical Microbiology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, 30625, Germany

    Jan Buer

Authors
  1. Jan Buer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rudi Balling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rudi Balling.

Related links

Related links

Databases

LocusLink

Birc1e

Cd14

IFN-γ

IFNGR1

IFNGR2

IL-4

Il-10

Lgn1

Lps

Nramp1

TLR4

TNF-α

Tnfrp55

Tnfrp75

Toll

FURTHER INFORMATION

Affymetix

Eurogentec

MWG

Phenome project

Sigma Genosys

World Health Report 2002

Glossary

MACROPHAGES

Phagocytic cells that respond to non-self material by releasing substances that stimulate other cells of the immune system and are involved in antigen presentation.

PHAGOLYSOSOME

An organelle in a phagocytic cell that is formed by fusion of an ingested particle with a lysosome containing hydrolytic enzymes that digest the particle.

LYMPHOCYTES

Antigen-specific cells of the immune system.

OPSONIZATION

The process by which factors of the immune-serum coat bacteria and, therefore, enhance phagocytosis.

COMPLEMENT

A large group of interacting plasma proteins that act together to attack extracellular pathogens.

HELMINTHS

A collective term for parasitic worms, including flukes, tapeworms and roundworms.

FACULTATIVE PARASITE

A parasite that is able to survive away from its host.

PHAGOSOME

A membrane-bound vesicle that contains microbes or particulate material from the extracellular environment.

LIPOPOLYSACCHARIDE

(LPS). A complex glycolipid found on the surface of Gram-negative bacteria that is a powerful inflammatory stimulus.

CYTOKINES

A group of proteins that form a dynamic network of intercellular messenger molecules that regulate various aspects of physiology, including the immune response to infection.

GRANULOMA

A site of chronic inflammation that is usually triggered by persistent infectious agents, such as mycobacteria.

NAIVE T CELL

A cell that has not yet encountered antigen.

ENTEROCOLITIS

Inflammation of the small intestine and the colon.

SIGNATURE-TAGGED MUTAGENESIS

A technique for detecting genes that are required for survival and growth in vivo that uses modified transposons to allow high-throughput screening of randomly generated mutants.

DIFFERENTIAL DISPLAY

A technique for detecting those genes that are expressed only under specific conditions; it involves isolation and comparison of mRNA from two or more populations.

DNA MICROARRAYS

An array of PCR products or oligonucleotides (corresponding to either genomic or cDNA sequences) deposited on solid glass slides that can be used to identify patterns of gene expression.

AUXOTROPHIC MUTATION

A mutation that affects the ability of an organism to make a particular molecule that is essential for growth.

FLUORESCENCE-ACTIVATED CELL SORTING

(FACS). A method in which dissociated and individual living-cells are sorted, in a liquid stream, according to the intensity of fluorescence that they emit as they pass through a laser beam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buer, J., Balling, R. Mice, microbes and models of infection. Nat Rev Genet 4, 195–205 (2003). https://doi.org/10.1038/nrg1019

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1019

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing