Trends in Genetics
Volume 28, Issue 5, May 2012, Pages 233-243
Journal home page for Trends in Genetics

Review
Host–pathogen interactions revealed by human genome-wide surveys

https://doi.org/10.1016/j.tig.2012.02.001Get rights and content

Genome-wide association studies (GWAS) have now convincingly shown that the diverse outcomes (such as the resolution of infection, clinical deterioration to severe disease, or progression from acute infection to persistent infection) that occur following microbial infection can be at least partly explained by human genetic variation. Unbiased whole-genome approaches have revealed unprecedentedly robust associations between genetic markers and susceptibility to disease, providing clear insights into our understanding of infectious disease biology by revealing the crucial host–pathogen interaction sites. Further work characterizing both the host causative variations and pathogenic microbial strains with distinct host interactions and disease outcomes is now required to provide potential new intervention strategies.

Section snippets

Contribution of human genetic factors in host–pathogen interactions

Every infective episode, that may or may not cause disease, results from a microbe making contact with the host and the immune system making contact with the microbe. In this light, a detailed understanding of host–pathogen interactions will aid our efforts to understand the biology of infection, opening new avenues to vaccination and treatment. There is clear evidence that some individuals respond differently to infectious agents compared to others. Mortality from infection has been shown to

Understanding host–pathogen interactions

This section focuses on all GWAS leading to identification of host–pathogen interactions in infectious diseases where the pathogen has been clearly defined and where the genetic associations identified exceed the formal threshold for genome-wide significance.

Can host genetics help identifying causative pathogen triggers?

An infective trigger is suspected for several diseases thought to be primarily autoimmune or inflammatory, such as type-1 diabetes, systemic lupus erythematosus, IBD, KD and others, many hinted at by the nature of the pathogen-recognition genes associated with these diseases. However, because an infectious trigger has not yet been identified, the concept remains speculative. Here, we use two of these diseases (IBD and KD 63, 64) as case studies and discuss these in more detail.

Future approaches to characterize host–pathogen interactions

Despite the recognized contribution of the GWAS approach to the field of infectious diseases, only a fraction of the heritable component of human infection has been explained by the GWAS approach, indicating that a substantial proportion of other relevant host–pathogen interactions remain to be identified [76]. Because the current GWAS method of using surrogate markers imperfectly captures information for these sequence variants, the challenge to be solved (so that more of the heritable

Concluding remarks

GWAS of human infectious diseases have revealed or retrospectively confirmed the identity of specific host–pathogen interacting molecules at unprecedented levels of accuracy and statistical confidence (Figure 1). Future research should now aim at discerning the precise molecular mechanisms of each interaction, first by identifying the respective causative mutations, and then by ex vivo biological assays, thus providing new targets for the development of potential vaccines or therapies. Once

References (91)

  • P.C. Sabeti

    Detecting recent positive selection in the human genome from haplotype structure

    Nature

    (2002)
  • A. Alcais

    Human genetics of infectious diseases: between proof of principle and paradigm

    J. Clin. Invest.

    (2009)
  • M. Dean

    Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study

    Science

    (1996)
  • C. Tournamille

    Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals

    Nat. Genet.

    (1995)
  • L. Lindesmith

    Human susceptibility and resistance to Norwalk virus infection

    Nat. Med.

    (2003)
  • M. Thorven

    A homozygous nonsense mutation (428G→A) in the human secretor (FUT2) gene provides resistance to symptomatic norovirus (GGII) infections

    J. Virol.

    (2005)
  • B. Carlsson

    The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection

    PLoS ONE

    (2009)
  • D. Van Tyne

    Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum

    PLoS Genet.

    (2011)
  • C.M. Filippi

    Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice

    J. Clin. Invest.

    (2009)
  • D.J. Smyth

    A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region

    Nat. Genet.

    (2006)
  • M. Larsen

    Exhausted cytotoxic control of Epstein–Barr virus in human lupus

    PLoS Pathog.

    (2011)
  • J.B. Harley

    Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

    Nat. Genet.

    (2008)
  • W.H. Van Brakel

    The allocation of leprosy patients into paucibacillary and multibacillary groups for multidrug therapy, taking into account the number of body areas affected by skin, or skin and nerve lesions

    Lepr. Rev.

    (1992)
  • F.R. Zhang

    Genomewide association study of leprosy

    N. Engl. J. Med.

    (2009)
  • F. Zhang

    Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy

    Nat. Genet.

    (2011)
  • M.J. Newport

    A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection

    N. Engl. J. Med.

    (1996)
  • G. Vogt

    Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations

    Nat. Genet.

    (2005)
  • R. de Jong

    Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients

    Science

    (1998)
  • T. Thye

    Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2

    Nat. Genet.

    (2010)
  • F. Pereyra

    The major genetic determinants of HIV-1 control affect HLA class I peptide presentation

    Science

    (2010)
  • S. Davila

    Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease

    Nat. Genet.

    (2010)
  • Y. Kamatani

    A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians

    Nat. Genet.

    (2009)
  • V. Kumar

    Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma

    Nat. Genet.

    (2011)
  • F. Altare

    Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency

    Science

    (1998)
  • D. Menard

    Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • L.H. Miller

    The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy

    N. Engl. J. Med.

    (1976)
  • M. Jallow

    Genome-wide and fine-resolution association analysis of malaria in West Africa

    Nat. Genet.

    (2009)
  • A.E. Fry

    Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria

    Hum. Mol. Genet.

    (2008)
  • M.J. Boyle

    Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development

    Proc. Natl. Acad. Sci. U.S.A.

    (2010)
  • J. Mu

    Genome-wide variation and identification of vaccine targets in the Plasmodium falciparum genome

    Nat. Genet.

    (2007)
  • J. Mu

    Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs

    Nat. Genet.

    (2010)
  • S. Mathew et al.

    Complement and properidin deficiencies in meningococcal disease

    Pediatr. Infect. Dis. J.

    (2006)
  • C.A. Fijen

    Assessment of complement deficiency in patients with meningococcal disease in The Netherlands

    Clin. Infect. Dis.

    (1999)
  • M.C. Schneider

    Functional significance of factor H binding to Neisseria meningitidis

    J. Immunol.

    (2006)
  • L.K. Tan

    Advances in the development of vaccines against Neisseria meningitidis

    N. Engl. J. Med.

    (2010)
  • Cited by (34)

    • Respiratory viral infections

      2019, Genomic and Precision Medicine: Infectious and Inflammatory Disease
    • Association of IL28B and IL10 gene polymorphism with predisposition to tick-borne encephalitis in a Russian population

      2016, Ticks and Tick-borne Diseases
      Citation Excerpt :

      Individual differences in the ability of the host innate immune system to efficiently suppress the development of disease are to a large extent predetermined genetically. Many human genes that are involved in the protection against different viral diseases have previously been detected in different populations worldwide (Chapman and Hill, 2012; Khor and Hibberd, 2012). However, human genetic predisposition to tick-borne encephalitis (TBE) has been poorly studied.

    • Primary Immunodeficiencies and Inflammatory Disease: A Growing Genetic Intersection

      2016, Trends in Immunology
      Citation Excerpt :

      On the other hand, environmental triggers of disease are often complex, heterogeneous, and generally poorly understood. Genetic analysis of susceptibility to infections has proven particularly successful to study how the interface between host and environment causes clinical disease [1–3]. In infectious diseases, exposure to the environmental trigger (e.g., microbial pathogens) is absolutely required to reveal the host genetic diversity and associated risk.

    • Mims' Pathogenesis of Infectious Disease

      2015, Mims' Pathogenesis of Infectious Disease
    View all citing articles on Scopus
    View full text