Elsevier

Seminars in Immunology

Volume 18, Issue 6, December 2006, Pages 404-410
Seminars in Immunology

Review
Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae

https://doi.org/10.1016/j.smim.2006.07.005Get rights and content

Abstract

The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.

Introduction

Leprosy is an ancient scourge of mankind and few human diseases have received such social stigma. In an effort to combat this stigma that not only condemned patients but their entire families, the belief that leprosy was inherited was rightly discredited when Armauer Hansen demonstrated that leprosy is caused by the human pathogenic bacterium Mycobacterium leprae [1], [2]. Unfortunately, the contagious etiology of leprosy was interpreted to mean that host genetic factors are excluded from the risk of acquiring disease. Today we know that this view is not correct. While exposure to and infection by M. leprae are necessary to acquire the disease, heritable factors are equally important in determining who will eventually develop clinical signs of leprosy. The presence of genetic factors that put a host at increased risk of disease following exposure to the infectious agent is now a widely accepted paradigm for most common infectious diseases [3]. We hypothesized that leprosy offers distinct advantages for the molecular identification of host genetic factors in disease susceptibility. Hence, we decided to use leprosy as a human model for the identification of host susceptibility genes in other common infectious diseases, especially tuberculosis, the most important human infectious disease caused by mycobacteria. The strategies used in the molecular genetic study of leprosy susceptibility, the first results obtained and the lessons learned are described in this short review.

Section snippets

Limited microbe diversity contrasts with large clinical disease spectrum

The genome of M. leprae has now been sequenced in totality [4]. Comparison of the M. leprae genome sequence with the genome sequence of Mycobacterium tuberculosis revealed that the leprosy bacillus underwent extensive reductive evolution resulting in the functional loss of approximately 2000 genes (roughly corresponding to half of all functional genes in its closest mycobacterial relatives) and absence of entire metabolic pathways that are functional in M. tuberculosis. Such extensive genome

Positional cloning of leprosy risk factors

We embarked on a genome-wide linkage analysis to identify leprosy susceptibility loci in Ho Chi Minh City, Vietnam. A total of 86 families each comprising 2–5 leprosy affected children were enrolled [23]. Of the 205 leprosy affected children, 90 suffered from the paucibacillary form while 115 were classified as multibacillary cases. Whole genome screening coupled with high resolution linkage analysis showed significant linkage of chromosomal region 6q25 to leprosy per se (MLB lod score 4.31; P = 5

Ubiquitination and E3 ligases

The Parkinson's disease gene PARK2 and its co-regulated gene PACRG span a total of 2 Mb and share an overlapping regulatory region of about 5 kb as well as a common bidirectional promoter [30]. The genes are conserved across metazoans but are only co-regulated in vertebrates since they are found on different chromosomes in lower organisms such as Drosophila melanogaster and Caenorhabditis elegans. PARK2 and PACRG both encode proteins that are involved in the cellular ubiquitination metabolism.

Function of PARK2

Numerous studies have dealt with the potential role of Parkin in cellular physiology ever since homozygosity for loss-of-function mutations in PARK2 had been identified as a major cause of early onset juvenile Parkinson's disease [36]. Parkin is a 465 amino acid protein that carries the RBR domain in its C-terminal region and a ubiquitin-like domain in its N-terminus. The ubiquitin-like domain has been shown to bind to the 26S proteasome [37] directly linking Parkin function to

Involvement of PARK2 in M. leprae immunity

The only experimental evidence linking PARK2 and its co-regulated gene PACRG with host responses to M. leprae is provided by the positional cloning of leprosy per se susceptibility factors described above [26]. How can one envision a link of PARK2 and PACRG with M. leprae triggered host responses? An answer to this question needs to address events upstream and downstream of both genes, i.e. factors that impact on functional activity of Parkin/PACRG and the cellular consequences that result from

Conclusion

The exciting aspect of the identification of PARK2 and PACRG as leprosy susceptibility genes is that now rational hypotheses about leprosy susceptibility can be formulated that can be tested experimentally. Clearly, without genetic studies pointing the way, functional studies of leprosy pathogenesis would not have focused on this important pathway of host–M. leprae interplay. It will be instructive and interesting to see which of the demonstrated and postulated functions of Parkin and possibly

Acknowledgments

Work in the authors laboratories is supported by program PRFMMIP from the Ministère Français de l’Education Nationale de la Recherche et de la Technologie (AA, LA) and by a grant from the Canadian Institutes of Health Research (CIHR) to ES. ES is a Chercheur National of the Fonds de Recherche en Santé du Québec (FRSQ).

References (64)

  • R.R. Jacobson et al.

    Leprosy

    Lancet

    (1999)
  • P. Pallamary

    Translation of Gerhard Armauer Hansen. Spedalskhedens Aarsager [causes of leprosy]

    Int J Lepr

    (1955)
  • J.L. Casanova et al.

    The human model: a genetic dissection of immunity to infection in natural conditions

    Nat Rev Immunol

    (2004)
  • S.T. Cole et al.

    Massive gene decay in the leprosy bacillus

    Nature

    (2001)
  • S.K. Nordeen

    The epidemiology of leprosy

  • D.S. Ridley et al.

    Classification of leprosy according to immunity. A five-group system

    Int J Lepr Other Mycobact Dis

    (1966)
  • J.L. Casanova et al.

    Genetic dissection of immunity to mycobacteria: the human model

    Annu Rev Immunol

    (2002)
  • S. Marquet et al.

    Genetics of susceptibility to infectious diseases: tuberculosis and leprosy as examples

    Drug Metab Dispos

    (2001)
  • J. Fitness et al.

    Genetics of susceptibility to leprosy

    Genes Immun

    (2002)
  • E.D. Shields et al.

    Genetic epidemiology of the susceptibility to leprosy

    J Clin Invest

    (1987)
  • M.R. Chakravarti et al.

    A twin study on leprosy

  • L. Abel et al.

    Complex segregation analysis of leprosy in Southern Vietnam

    Genet Epidemiol

    (1995)
  • W. van Eden et al.

    HLA segregation of tuberculoid leprosy: confirmation of the DR2 marker

    J Infect Dis

    (1980)
  • W. van Eden et al.

    HLA-linked control of predisposition to lepromatous leprosy

    J Infect Dis

    (1985)
  • N.K. Mehra

    Role of HLA linked factors in governing susceptibility to leprosy and tuberculosis

    Trop Med Parasitol

    (1990)
  • L. Zerva et al.

    Arginine at positions 13 or 70–71 in pocket 4 of HLA-DRB1 alleles is associated with susceptibility to tuberculoid leprosy

    J Exp Med

    (1996)
  • M.A. Shaw et al.

    Association and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes

    Genes Immun

    (2001)
  • M.R. Siddiqui et al.

    A major susceptibility locus for leprosy in India maps to chromosome 10p13

    Nat Genet

    (2001)
  • E.N. Miller et al.

    Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians

    Genes Immun

    (2004)
  • WHO

    Leprosy elimination campaigns

    Wkly Epidemiol Rec

    (2002)
  • M. Pelletier et al.

    Immunopathology of BCG infection in genetically resistant and susceptible mouse strains

    J Immunol

    (1982)
  • M.T. Mira et al.

    Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population

    Nat Genet

    (2003)
  • Cited by (0)

    View full text