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.

  • Perspective
  • Published:

Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases

Abstract

The field of human genetics of infectious diseases defines the genes and alleles rendering individuals (clinical genetics) and populations (epidemiological genetics) vulnerable to infection, and studies those selected by previous infections (evolutionary genetics). These disciplines—clinical, epidemiological and evolutionary genetics—delineate the redundant and nonredundant functions of host defense genes for past and present survival in natura—in natural ecosystems governed by natural selection. These disciplines, in other words, assess the ecologically relevant and evolutionarily selected roles of human genes and alleles in protective immunity to diverse and evolving microorganisms. The genetic dissection of human immunity to infection in natura provides unique immunological insight, making it an indispensable complement to experimental immunology in vitro and in vivo in plants and animals.

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

Access options

Buy this article

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

Figure 1: Pasteur's pedigree and the genetic theory of infectious diseases.
Figure 2: Human genetics of infectious diseases.
Figure 3: The human model: a genetic dissection of immunity in natura.
Figure 4: Examples of genes characterized by clinical, epidemiological and evolutionary genetic approaches in natura.

Similar content being viewed by others

References

  1. Casanova, J.L. & Abel, L. Inborn errors of immunity to infection: the rule rather than the exception. J. Exp. Med. 202, 197–201 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Casanova, J.L. & Abel, L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat. Rev. Immunol. 4, 55–66 (2004).

    CAS  PubMed  Google Scholar 

  3. Casanova, J.L. & Abel, L. Primary immunodeficiencies: a field in its infancy. Science 317, 617–619 (2007).

    CAS  PubMed  Google Scholar 

  4. Sorensen, T.I., Nielsen, G.G., Andersen, P.K. & Teasdale, T.W. Genetic and environmental influences on premature death in adult adoptees. N. Engl. J. Med. 318, 727–732 (1988).

    CAS  PubMed  Google Scholar 

  5. Alcaïs, A., Abel, L. & Casanova, J.L. Human genetics of infectious diseases. In Human Genetics: Principles and Approaches (eds. Vogel, F., Motulsky, A.G., Antonarakis, S.E. & Speicher, M.) (Springer, Berlin, in the press).

  6. Bamshad, M. & Wooding, S.P. Signatures of natural selection in the human genome. Nat. Rev. Genet. 4, 99–111 (2003).

    CAS  PubMed  Google Scholar 

  7. Ochs, H., Smith, C.I.E. & Puck, J. Primary Immunodeficiencies: A Molecular and Genetic Approach (Oxford Univ. Press, New York, 2007).

    Google Scholar 

  8. Alcaïs, A. & Abel, L. Application of genetic epidemiology to dissecting host susceptibility/resistance to infection illustrated with the study of common mycobacterial infections. in Susceptibility to Infectious Diseases: The Importance of Host Genetics (ed. Bellamy, R.) 7–44 (Cambridge Univ. Press, New York, 2004).

    Google Scholar 

  9. Jobling, M.A., Hurles, M.E. & Tyler-Smith, C. Human Evolutionary Genetics (Garland Science, New York, 2004).

    Google Scholar 

  10. Sabeti, P.C. et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).

    CAS  PubMed  Google Scholar 

  11. Sansonetti, P.J. & Di Santo, J.P. Debugging how bacteria manipulate the immune response. Immunity 26, 149–161 (2007).

    CAS  PubMed  Google Scholar 

  12. Oldstone, M.B. A suspenseful game of 'hide and seek' between virus and host. Nat. Immunol. 8, 325–327 (2007).

    CAS  PubMed  Google Scholar 

  13. Hohl, T.M., Rivera, A. & Pamer, E.G. Immunity to fungi. Curr. Opin. Immunol. 18, 465–472 (2006).

    CAS  PubMed  Google Scholar 

  14. Sacks, D. & Sher, A. Evasion of innate immunity by parasitic protozoa. Nat. Immunol. 3, 1041–1047 (2002).

    CAS  PubMed  Google Scholar 

  15. Jones, J.D. & Dangl, J.L. The plant immune system. Nature 444, 323–329 (2006).

    CAS  PubMed  Google Scholar 

  16. Pradel, E. & Ewbank, J.J. Genetic models in pathogenesis. Annu. Rev. Genet. 38, 347–363 (2004).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Buer, J. & Balling, R. Mice, microbes and models of infection. Nat. Rev. Genet. 4, 195–205 (2003).

    CAS  PubMed  Google Scholar 

  19. Beutler, B. et al. Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).

    CAS  PubMed  Google Scholar 

  20. Beutler, B., Du, X. & Xia, Y. Precis on forward genetics in mice. Nat. Immunol. 8, 659–664 (2007).

    CAS  PubMed  Google Scholar 

  21. Shultz, L.D., Ishikawa, F. & Greiner, D.L. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 7, 118–130 (2007).

    CAS  PubMed  Google Scholar 

  22. Selye, H. In Vivo: The Case for Supramolecular Biology, Presented in Six Informal, Illustrated Lectures (Liveright, New York, 1967).

    Google Scholar 

  23. Casanova, J.L. & Abel, L. Human genetics of infectious diseases: a unified theory. EMBO J. 26, 915–922 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cerundolo, V. & de la Salle, H. Description of HLA class I- and CD8-deficient patients: insights into the function of cytotoxic T lymphocytes and NK cells in host defense. Semin. Immunol. 18, 330–336 (2006).

    CAS  PubMed  Google Scholar 

  25. Mathew, S. & Overturf, G.D. Complement and properdin deficiencies in meningococcal disease. Pediatr. Infect. Dis. J. 25, 255–256 (2006).

    PubMed  Google Scholar 

  26. Nichols, K.E., Ma, C.S., Cannons, J.L., Schwartzberg, P.L. & Tangye, S.G. Molecular and cellular pathogenesis of X-linked lymphoproliferative disease. Immunol. Rev. 203, 180–199 (2005).

    CAS  PubMed  Google Scholar 

  27. Orth, G. Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin. Immunol. 18, 362–374 (2006).

    CAS  PubMed  Google Scholar 

  28. Vanhollebeke, B. et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N. Engl. J. Med. 355, 2752–2756 (2006).

    CAS  PubMed  Google Scholar 

  29. Mosmann, T.R., Cherwinski, H., Bond, M.W., Giedlin, M.A. & Coffman, R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Coffman, R.L. Origins of the TH1-TH2 model: a personal perspective. Nat. Immunol. 7, 539–541 (2006).

    CAS  PubMed  Google Scholar 

  32. 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 

  33. Filipe-Santos, O. et al. Inborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features. Semin. Immunol. 18, 347–361 (2006).

    CAS  PubMed  Google Scholar 

  34. Fieschi, C. et al. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor β1 deficiency: medical and immunological implications. J. Exp. Med. 197, 527–535 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Roesler, J. et al. Recurrent mycobacterial and listeria infections in a child with interferon γ receptor deficiency: mutational analysis and evaluation of therapeutic options. Exp. Hematol. 27, 1368–1374 (1999).

    CAS  PubMed  Google Scholar 

  36. Sanal, O. et al. A case of interleukin-12 receptor β-1 deficiency with recurrent leishmaniasis. Pediatr. Infect. Dis. J. 26, 366–368 (2007).

    PubMed  Google Scholar 

  37. Janeway, C.A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  PubMed  Google Scholar 

  38. Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).

    CAS  PubMed  Google Scholar 

  39. Ku, C.L. et al. Human IRAK-4 deficiency: a selective predisposition to life-threatening pyogenic bacterial infections during childhood reveals an otherwise redundant role for TLRs in protective immunity. J. Exp. Med. (in the press).

  40. Yang, K. et al. Human TLR-7-, -8-, and -9-mediated induction of IFN-α/β and -λ is IRAK-4 dependent and redundant for protective immunity to viruses. Immunity 23, 465–478 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).

    CAS  PubMed  Google Scholar 

  42. Zhang, S.-Y. et al. TLR3 deficiency in otherwise healthy patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007).

    CAS  PubMed  Google Scholar 

  43. Snow, J. On the Mode of Communication of Cholera (John Churchill, London, 1855).

    Google Scholar 

  44. Khoury, M.J., Beaty, T.H. & Cohen, B.H. Fundamentals of Genetic Epidemiology, (Oxford Univ. Press, New York, 1993).

    Google Scholar 

  45. Campino, S., Kwiatkowski, D. & Dessein, A. Mendelian and complex genetics of susceptibility and resistance to parasitic infections. Semin. Immunol. 18, 411–422 (2006).

    CAS  PubMed  Google Scholar 

  46. Brown, K.E. et al. Resistance to parvovirus B19 infection due to lack of virus receptor (erythrocyte P antigen). N. Engl. J. Med. 330, 1192–1196 (1994).

    CAS  PubMed  Google Scholar 

  47. Arenzana-Seisdedos, F. & Parmentier, M. Genetics of resistance to HIV infection: role of co-receptors and co-receptor ligands. Semin. Immunol. 18, 387–403 (2006).

    CAS  PubMed  Google Scholar 

  48. Le Pendu, J., Ruvoen-Clouet, N., Kindberg, E. & Svensson, L. Mendelian resistance to human norovirus infections. Semin. Immunol. 18, 375–386 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Alcaïs, A., Fieschi, C., Abel, L. & Casanova, J.L. Tuberculosis in children and adults: two distinct genetic diseases. J. Exp. Med. 202, 1617–1621 (2005).

    PubMed  PubMed Central  Google Scholar 

  50. Couzin, J. & Kaiser, J. Genome-wide association. Closing the net on common disease genes. Science 316, 820–822 (2007).

    CAS  PubMed  Google Scholar 

  51. Marquet, S. et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31–q33. Nat. Genet. 14, 181–184 (1996).

    CAS  PubMed  Google Scholar 

  52. Baghdadi, J.E. et al. An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults. J. Exp. Med. 203, 1679–1684 (2006).

    PubMed  PubMed Central  Google Scholar 

  53. Alcaïs, A., Mira, M., Casanova, J.L., Schurr, E. & Abel, L. Genetic dissection of immunity in leprosy. Curr. Opin. Immunol. 17, 44–48 (2005).

    PubMed  Google Scholar 

  54. Abel, L. & Demenais, F. Detection of major genes for susceptibility to leprosy and its subtypes. Am. J. Hum. Genet. 42, 256–266 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Mira, M.T. et al. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat. Genet. 33, 412–415 (2003).

    CAS  PubMed  Google Scholar 

  57. Mira, M.T. et al. Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427, 636–640 (2004).

    CAS  PubMed  Google Scholar 

  58. Schurr, E., Alcaïs, A., de Leseleuc, L. & Abel, L. Genetic predisposition to leprosy: a major gene reveals novel pathways of immunity to Mycobacterium leprae. Semin. Immunol. 18, 404–410 (2006).

    CAS  PubMed  Google Scholar 

  59. Alcaïs, A. et al. Stepwise replication identifies a low-producing lymphotoxin-α allele as a major risk factor for early-onset leprosy. Nat. Genet. 39, 517–522 (2007).

    PubMed  Google Scholar 

  60. Nielsen, R. Molecular signatures of natural selection. Annu. Rev. Genet. 39, 197–218 (2005).

    CAS  PubMed  Google Scholar 

  61. Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–626 (1968).

    CAS  PubMed  Google Scholar 

  62. Hellmann, I., Ebersberger, I., Ptak, S.E., Paabo, S. & Przeworski, M. A neutral explanation for the correlation of diversity with recombination rates in humans. Am. J. Hum. Genet. 72, 1527–1535 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Olson, S. Population genetics. Seeking the signs of selection. Science 298, 1324–1325 (2002).

    CAS  PubMed  Google Scholar 

  64. Bradbury, J. Ancient footsteps in our genes: evolution and human disease. Gene variants selected during evolution may underlie many common diseases. Lancet 363, 952–953 (2004).

    PubMed  Google Scholar 

  65. Vallender, E.J. & Lahn, B.T. Positive selection on the human genome. Hum. Mol. Genet. 13 (review issue 2), R245–R254 (2004).

    CAS  PubMed  Google Scholar 

  66. Dean, M., Carrington, M. & O'Brien, S.J. Balanced polymorphism selected by genetic versus infectious human disease. Annu. Rev. Genomics Hum. Genet. 3, 263–292 (2002).

    CAS  PubMed  Google Scholar 

  67. Hedrick, P.W., Whittam, T.S. & Parham, P. Heterozygosity at individual amino acid sites: extremely high levels for HLA-A and -B genes. Proc. Natl. Acad. Sci. USA 88, 5897–5901 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Hughes, A.L. & Nei, M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335, 167–170 (1988).

    CAS  PubMed  Google Scholar 

  69. Takahata, N., Satta, Y. & Klein, J. Polymorphism and balancing selection at major histocompatibility complex loci. Genetics 130, 925–938 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yawata, M. et al. Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function. J. Exp. Med. 203, 633–645 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nat. Rev. Immunol. 5, 201–214 (2005).

    CAS  PubMed  Google Scholar 

  72. Abi-Rached, L. & Parham, P. Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues. J. Exp. Med. 201, 1319–1332 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Williams, T.N. Human red blood cell polymorphisms and malaria. Curr. Opin. Microbiol. 9, 388–394 (2006).

    CAS  PubMed  Google Scholar 

  74. Allison, A.C. Protection afforded by sickle cell trait against subtertian malarian infection. BMJ 1, 290–294 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Allison, A.C. Two lessons from the interface of genetics and medicine. Genetics 166, 1591–1599 (2004).

    PubMed  PubMed Central  Google Scholar 

  76. Flint, J., Harding, R.M., Boyce, A.J. & Clegg, J.B. The population genetics of the haemoglobinopathies. Baillieres Clin. Haematol. 11, 1–51 (1998).

    CAS  PubMed  Google Scholar 

  77. Agarwal, A. et al. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96, 2358–2363 (2000).

    CAS  PubMed  Google Scholar 

  78. Modiano, D. et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414, 305–308 (2001).

    CAS  PubMed  Google Scholar 

  79. Chitnis, C.E. & Miller, L.H. Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J. Exp. Med. 180, 497–506 (1994).

    CAS  PubMed  Google Scholar 

  80. Tournamille, C., Colin, Y., Cartron, J.P. & Le Van Kim, C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat. Genet. 10, 224–228 (1995).

    CAS  PubMed  Google Scholar 

  81. Hamblin, M.T., Thompson, E.E. & Di Rienzo, A. Complex signatures of natural selection at the Duffy blood group locus. Am. J. Hum. Genet. 70, 369–383 (2002).

    PubMed  Google Scholar 

  82. Geijtenbeek, T.B., van Vliet, S.J., Engering, A., 't Hart, B.A. & van Kooyk, Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu. Rev. Immunol. 22, 33–54 (2004).

    CAS  PubMed  Google Scholar 

  83. Barreiro, L.B. et al. The heritage of pathogen pressures and ancient demography in the human innate-immunity CD209/CD209L region. Am. J. Hum. Genet. 77, 869–886 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Neyrolles, O., Gicquel, B. & Quintana-Murci, L. Towards a crucial role for DC-SIGN in tuberculosis and beyond. Trends Microbiol. 14, 383–387 (2006).

    CAS  PubMed  Google Scholar 

  85. Eisen, D.P. & Minchinton, R.M. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin. Infect. Dis. 37, 1496–1505 (2003).

    CAS  PubMed  Google Scholar 

  86. Seyfarth, J., Garred, P. & Madsen, H.O. The 'involution' of mannose-binding lectin. Hum. Mol. Genet. 14, 2859–2869 (2005).

    CAS  PubMed  Google Scholar 

  87. Casanova, J.L. & Abel, L. Human mannose-binding lectin in immunity: friend, foe, or both? J. Exp. Med. 199, 1295–1299 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Verdu, P. et al. Evolutionary insights into the high worldwide prevalence of MBL2 deficiency alleles. Hum. Mol. Genet. 15, 2650–2658 (2006).

    CAS  PubMed  Google Scholar 

  89. Xue, Y. et al. Spread of an inactive form of caspase-12 in humans is due to recent positive selection. Am. J. Hum. Genet. 78, 659–670 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Reith, W., Lisowska-Grospierre, B. & Fischer, A. Molecular basis of MHC class II deficiency. in Primary Immunodeficiencies: A Molecular Genetic Approach (eds. Ochs, H.D., Smith, C.I. & Puck, J.M.) 227–241 (Oxford Univ. Press, New York, 2007).

    Google Scholar 

  91. Carrington, M. et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283, 1748–1752 (1999).

    CAS  PubMed  Google Scholar 

  92. Thursz, M.R., Thomas, H.C., Greenwood, B.M. & Hill, A.V. Heterozygote advantage for HLA class-II type in hepatitis B virus infection. Nat. Genet. 17, 11–12 (1997).

    CAS  PubMed  Google Scholar 

  93. Jeffery, K.J. et al. The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection. J. Immunol. 165, 7278–7284 (2000).

    CAS  PubMed  Google Scholar 

  94. Glass, W.G. et al. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J. Exp. Med. 203, 35–40 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Bamshad, M.J. et al. A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc. Natl. Acad. Sci. USA 99, 10539–10544 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Stephens, J.C. et al. Dating the origin of the CCR532 AIDS-resistance allele by the coalescence of haplotypes. Am. J. Hum. Genet. 62, 1507–1515 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Novembre, J., Galvani, A.P. & Slatkin, M. The geographic spread of the CCR5 Δ32 HIV-resistance allele. PLoS Biol. [online] 3, e339 (2005).

    PubMed Central  Google Scholar 

  98. Sabeti, P.C. et al. The case for selection at CCR532. PLoS Biol. [online] 3, e378 (2005).

    Google Scholar 

  99. Lalani, A.S. et al. Use of chemokine receptors by poxviruses. Science 286, 1968–1971 (1999).

    CAS  PubMed  Google Scholar 

  100. Vallery-Radot, R. The Life of Pasteur xxi (Garden City Publishing, Garden City, New York, USA, 1926).

    Google Scholar 

Download references

Acknowledgements

We thank the members of our laboratories for discussions and our patients and collaborators worldwide for their trust and patience. Supported by INSERM, University Paris René Descartes, Institut Pasteur, Agence Nationale de la Recherche, the BNP Paribas Foundation, the Schlumberger Foundation, the European Union, the Dana Foundation, the March of Dimes and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jean-Laurent Casanova.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Quintana-Murci, L., Alcaïs, A., Abel, L. et al. Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat Immunol 8, 1165–1171 (2007). https://doi.org/10.1038/ni1535

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1535

This article is cited by

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