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Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae

Nature Genetics volume 32, pages 97–105 (2002)Cite this article

An Erratum to this article was published on 01 October 2002

Abstract

Host genetic factors are important in determining the outcome of infections caused by intracellular pathogens, including mycobacteria and salmonellae, but until now have been poorly characterized. Recently, some individuals with severe infections due to otherwise weakly pathogenic mycobacteria (non-tuberculous mycobacteria or Mycobacterium bovis bacille Calmette-Guérin) or Salmonella species have been shown to be unable to produce or respond to interferon-γ. This inability results from mutations in any of five genes encoding essential proteins of the type 1 cytokine cascade: interleukin-12p40, interleukin-12Rβ1, interferon-γR1, interferon-γR2 or STAT1. Ten syndromes have thus far been identified. Recent insights in genetically controlled host defense and susceptibility to mycobacterial disease are discussed.

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Figure 1: The type 1 cytokine pathway and its reported genetic and acquired deficiencies.
Figure 2: Deleterious mutations in type 1 cytokine (receptor) genes.

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References

  1. Hill, A.V.S. The immunogenetics of human infectious disease. Annu. Rev. Immunol. 16, 593–617 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Abbas, A.K., Murphy, K.M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Aderem, A. & Ulevitch, R.J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2001).

    Article  Google Scholar 

  4. Nakanishi, K., Yoshimoto, T., Tsutsui, H. & Okamura, H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 19, 423–474 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EB13 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Zou, W. et al. Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by β-chemokines rather than IL-12. J. Immunol. 165, 4388–4396 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Denis, M. Killing of Mycobacterium tuberculosis within human monocytes: activation by cytokines and calcitriol. Clin. Exp. Immunol. 84, 200–206 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bonecini-Almeida, M.G. et al. Induction of in vitro human macrophage anti-Mycobacterium tuberculosis activity: requirement for IFN-γ and primed lymphocytes J. Immunol. 160, 4490–4499 (1998).

    CAS  PubMed  Google Scholar 

  12. Stenger, S., Rosat, J-P., Bloom, B.R., Krensky, A.M. & Modlin, R.L. Granylysin: a lethal weapon of cytolytic T cells. Immunol. Today 20, 390–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Altare, F. et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection. J. Clin. Invest. 102, 2035–2040 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Picard, C. et al. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of thirteen patients from six kindreds. Am. J. Hum. Genet. 70, 336–348 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Elloumi-Zghal, H. et al. Clinical and genetic heterogeneity of inherited autosomal recessive susceptibility to disseminated Mycobacterium bovis Bacillus Calmette-Guérin infection. J. Inf. Dis. 185, 1468–1475 (2002).

    Article  CAS  Google Scholar 

  16. Frucht, D.M. & Holland, S.M. Defective monocyte costimulation for IFN-γ production in familial disseminated Mycobacterium avium complex infection: abnormal IL-12 regulation. J. Immunol. 157, 411–416 (1996).

    CAS  PubMed  Google Scholar 

  17. Haraguchi, S. et al. Interleukin 12 deficiency associated with recurrent infections. Proc. Natl Acad. Sci. USA 95 13125–13129 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. De Jong, R. et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science 280, 1435–1438 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Altare, F. et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science 280, 1432–1435 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Lichtenauer-Kaligis, E.G.R. et al. Severe outcome of Mycobacterium bovis BCG infections in an unexpectedly large series of novel IL-12 receptor β1 deficient patients, and evidence for the existence of partial IL-12R deficiency. Submitted for publication.

  21. Verhagen, C.E. et al. Residual type 1 immunity in patients genetically deficient for interleukin 12 receptor β1 (IL-12Rβ1): evidence for an IL-12Rβ1-independent pathway of IL-12 responsiveness in human T cells. J. Exp. Med. 192, 517–528 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sakai, T., Matsuoka, M., Aoki, M., Nosaka, K. & Mitsuya, H. Missense mutation of the interleukin-12 receptor β1 chain-encoding genes is associated with impaired immunity against Mycobacterium avium complex infection. Blood 97, 2688–2694 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Altare, F. et al. Interleukin-12 receptor β1 deficiency in a patient with abdominal tuberculosis. Clin. Infect. Dis. 184, 231–236 (2001).

    CAS  Google Scholar 

  24. Aksu, G. et al. Mycobacterium fortuitum-chelonae complex infection in a child with complete interleukin-12 receptor β 1 deficiency. Pediatr. Infect. Dis. J. 20, 551–553 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Wu, C.-Y. et al. IL-12 receptor β2 (IL-12Rβ2)-deficient mice are defective in IL-12-mediated signaling despite the presence of high affinity IL-12 binding sites. J. Immunol. 165, 6221–6228 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Decken, K. et al. Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans. Infect. Immun. 66, 4994–5000 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. 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, 5699–5708 (2002).

    Article  Google Scholar 

  29. Gollob, J.A. et al. Impairment of STAT activation by IL-12 in a patients with atypical mycobacterial and staphylococcal infections. J. Immunol. 165, 4120–4126 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Ortmann, R., Smeltz, R., Yap, G., Sher, A. & Shevach, E.M. A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J. Immunol. 166, 5712–5719 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Rogge, L. et al. Transcript imaging of the development of human T helper cells using oligonucleotide arrays. Nature Genet. 25, 96–101 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Colantonio, L. et al. Upregulation of integrin α6/β1 and chemokine receptor CCR1 by interleukin-12 promotes the migration of human type 1 helper T cells. Blood 94, 2981–2989 (1999).

    CAS  PubMed  Google Scholar 

  33. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor α-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Jouanguy, E. et al. A novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ. J. Clin. Invest. 105, 1429–1436 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Allende, L.M. et al. A point mutation in a domain of γ interferon receptor 1 provokes severe immunodeficiency. Clin. Diagn. Lab. Immunol. 8, 133–137 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Jouanguy, E. et al. Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J. Clin. Invest. 100, 2658–2664 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jouanguy, E. et al. A human IFNGRl small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nature Genet. 21, 370–378 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Arend, S.M. et al. Multifocal osteomyelitis caused by nontuberculous mycobacteria in patients with genetic defect of the interferon-γ receptor. Neth. J. Med. 59, 140–151 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Sasaki, Y. et al. Genetic basis of patients with Bacille Calmette-Guérin osteomyelitis in Japan: identification of dominant partial interferon γ receptor 1 deficiency as a predominant type. J. Inf. Dis. 185, 706–709 (2002).

    Article  CAS  Google Scholar 

  40. Villella, A. et al. Recurrent Mycobacterium avium osteomyelitis associated with a novel dominant interferon γ receptor mutation. Pediatrics 107, e47 (2001).

  41. Döffinger, R. et al. Partial interferon-γ receptor signalling chain deficiency in a patient with bacille Calmette-Guerin and Mycobacterium abscessus infection. J. Infect. Dis. 181, 379–384 (2000).

    Article  PubMed  Google Scholar 

  42. Dupuis, S. et al. Human interferon-γ-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol. Rev. 178, 129–137 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Dupuis, S. et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293, 300–303 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Dorman, S.E. et al. Viral infections in interferon-γ receptor deficiency. J. Pediatr. 135, 640–643 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Verreck, F.A.W. et al. Human host defence and cytokines in mycobacterial infectious diseases: interleukin-18 cannot compensate for genetic defects in the interleukin–12 system. Clin. Infect. Dis. 35, 210–212 (2002).

    Article  PubMed  Google Scholar 

  46. Ottenhoff, T.H.M., Kumararatne, D. & Casanova, J.L. Novel human immunodeficiencies reveal the essential role of type-1 cytokines in immunity to intracellular bacteria. Immunol. Today 19, 491–494 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Dorman, S.E. & Holland, S.M. Interferon-γ and interleukin-12 pathway defects and human disease. Cytokine Growth Factor Rev. 11, 321–333 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Roesler, J. et al. Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-γ-receptor deficiency: mutational analysis and evaluation of therapeutic options. Exp. Hematol. 27, 1368–1374 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Janssen, R. et al. Divergent role for TNF-α in IFN-γ induced killing of Toxoplasma gondii and Salmonella typhimurium contributes to selective susceptibility of patients with partial IFN-γR1 deficiency. J. Immunol. (in the press).

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

    Article  CAS  PubMed  Google Scholar 

  51. Ting, L.-M., Kim, A.C., Cattamanchi, A. & Ernst, J.D. Mycobacterium tuberculosis inhibits IFN-γ transcriptional responses without inhibiting activation of STAT1. J. Immunol. 163, 3898–3906 (1999).

    CAS  PubMed  Google Scholar 

  52. Nau, G.J. et al. Human macrophage activation programs induced by bacterial pathogens. Proc. Natl Acad. Sci. USA 99, 1503–1508 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cooke, G.S. & Hill, A.V.S. Genetics of susceptibility to human infectious disease. Nature Rev. Genet. 2, 967–977 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Döffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nature Genet. 27, 277–285 (2001).

    Article  PubMed  Google Scholar 

  55. Selvaraj, P., Narayanan, P.R. & Reetha, A.M. Association of functional mutant homozygotes of the mannose binding protein gene with susceptibility to pulmonary tuberculosis in India. Tuberc. Lung Dis. 79, 221–227 (1999).

    Article  CAS  Google Scholar 

  56. Wilkinson, R.J. et al. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1β on tuberculosis. J. Exp. Med. 189, 1863–1874 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Greenwood, C.M.T. et al. Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am. J. Hum. Genet. 67, 405–416 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Siddiqui, M.R. et al. A major susceptibility locus for leprosy in India maps to chromosome 10p13. Nature Genet. 27, 439–441 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Burghes, A.H.M., Vaessin, H.E.F. & de La Chapelle, A. The land between Mendelian and multifactorial inheritance. Science 293, 2213–2214 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Holland, S.M. et al. Abnormal regulation of interferon-γ, interleukin-12, and tumor necrosis factor-α in human interferon-γ receptor I deficiency. J. Infect. Dis. 178, 1095–1104 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Pierre-Audigier, C. et al. Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon γ receptor deficiency. Clin. Infect. Dis. 24, 982–984 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Altare, F. et al. A causative relationship between mutant IFNγ R1 alleles and impaired cellular response to IFNγ in a compound heterozygous child. Am. J. Hum. Genet. 62, 723–726 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Rosenzweig, S. et al. 561del4 defines a novel small deletion hotspot in the interferon-γ receptor 1 chain. Clin. Immunol. 102, 25–27 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Cunningham, J.A. et al. Disseminated bacille Calmette-Guerin infection in an infant with a novel deletion in the interferon-γ receptor genes. Int. J. Tuberc. Lung Dis. 4, 791–794 (2000).

    CAS  PubMed  Google Scholar 

  67. Noordzij, J.G. et al. Complete defects in interferon γ receptor dependent signaling are associated with different clinical phenotypes. Pediatr. Res. (in the press).

  68. Edgar, J.D. et al. Interferon-γ receptor deficiency mimicking Langerhans' cell histiocytosis. J. Pediatr. 139, 600–603 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Dorman, S.E. & Holland, S.M. Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection. J. Clin. Invest. 101, 2364–2369 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Holland, S.M. Immune deficiency presenting as mycobacterial infection. Clin. Rev. Allergy Immunol. 20, 121–137 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Netherlands Leprosy Foundation, the Commission of the European Communities, Netherlands Organization for Scientific Research (NWO/ZON-MW) and the Royal Netherlands Academy of Arts and Sciences. We thank R.R.P. de Vries and C.J.M. Melief for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, P.O. Box 9600, Leiden, 2300 RC, The Netherlands

    Tom H.M. Ottenhoff, Frank A.W. Verreck & Marieke A. Hoeve

  2. Department of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600, Leiden, 2300 RC, The Netherlands

    Elgin G.R. Lichtenauer-Kaligis & Jaap T. van Dissel

  3. Immunology Division, Hacettepe University Children's Hospital, Ankara, Turkey

    Ozden Sanal

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  1. Tom H.M. Ottenhoff
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Correspondence to Tom H.M. Ottenhoff.

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Ottenhoff, T., Verreck, F., Lichtenauer-Kaligis, E. et al. Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 32, 97–105 (2002). https://doi.org/10.1038/ng0902-97

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