ReviewGenetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae
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)
The ophthalmic trials of G.H.A. Hansen
Surv Ophthalmol
(2002)- et al.
Genetic dissection of immunity in leprosy
Curr Opin Immunol
(2005) - et al.
Leprosy
Lancet
(2004) - et al.
Linkage disequilibrium in humans: models and data
Am J Hum Genet
(2001) - et al.
Identification of a novel gene linked to parkin via a bi-directional promoter
J Mol Biol
(2003) - et al.
Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain
Neurosci Lett
(1999) - et al.
Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps of transected peripheral nerves
Neuroscience
(1999) - et al.
Inflammatory mediators in demyelinating disorders of the CNS and PNS
J Neuroimmunol
(1992) - et al.
Secretion of nitrite by Schwann cells and its effect on T-cell activation in vitro
Cell Immunol
(1996) - et al.
Mycobacterium leprae infection of human Schwann cells depends on selective host kinases and pathogen-modulated endocytic pathways
FEMS Microbiol Lett
(2004)