Mamm Genome (2011) 22:19–31 DOI 10.1007/s00335-010-9287-1
Leprosy as a genetic disease Andrea Alter • Audrey Grant • Laurent Abel Alexandre Alcaı¨s • Erwin Schurr
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Received: 11 June 2010 / Accepted: 1 September 2010 / Published online: 9 October 2010 Springer Science+Business Media, LLC 2010
Abstract Leprosy (Hansen’s disease) is a human infectious disease whose etiological agent, Mycobacterium leprae, was identified by G. H. A. Hansen in the 19th century. Despite the high efficacy of multidrug therapy (\0.1% annual relapse rate), transmission is persistent. In 2008, approximately 250,000 new cases were reported to the World Health Organization. Clinically, leprosy presents as either the paucibacillary (1–5 lesions) or the multibacillary ([5 lesions) subtype, Electronic supplementary material The online version of this article (doi:10.1007/s00335-010-9287-1) contains supplementary material, which is available to authorized users. A. Alter E. Schurr Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Medicine, McGill University, Montreal, QC, Canada A. Alter E. Schurr Research Institute of the McGill University Health Centre, McGill Centre for the Study of Host Resistance, Department of Human Genetics, McGill University, Montreal, QC, Canada A. Grant L. Abel A. Alcaı¨s Laboratoire de Ge´ne´tique des Maladies Infectieuses, Institut National de la Sante´ et de la Recherche Me´dicale, U550, 75015 Paris, France A. Grant L. Abel A. Alcaı¨s Faculte´ Me´dicine Necker, Universite´ Paris Rene´ Descartes, 75015 Paris, France L. Abel A. Alcaı¨s St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 11065, USA E. Schurr (&) Montreal General Hospital Research Institute, 1650 Cedar Avenue, Room L11-521, Montreal, QC H3G 1A4, Canada e-mail:
[email protected]
highly reflective of a Th1 (cell-mediated) or Th2 (humoral) host immune response, respectively. Subsequent to Mycobacterium leprae exposure, epidemiological studies (e.g., twin studies and complex segregation analyses) maintain the importance of host genetics in susceptibility to leprosy. The results of genome-wide analyses (linkage and association) and candidate gene studies suggest an independent genetic control over both susceptibility to leprosy per se and development of clinical subtype. Moreover, the emergence of a shared genetic background between leprosy and several inflammatory/autoimmune diseases suggests that leprosy is a suitable model for studying the genetic architecture and subsequent pathogenesis of both infectious and inflammatory/autoimmune diseases. We provide the example of NOD2 (Crohn’s disease gene) and LTA (myocardial infarction gene) and the implication of a common genetic risk factor between these two diseases and leprosy. The value of leprosy as a model disease therefore extends far beyond this ancient disease to common afflictions of the 21st century. The field of human genetics of infectious diseases aims to define the genetic variations accounting for inter-individual variability in the course of human infections. Casanova and Abel (2007) The contribution of the host genetic background to infectious disease susceptibility is not as widely acknowledged as for other common diseases (e.g., Crohn’s disease, type-1 diabetes) despite the abundance of anecdotal and empirical evidence. A frequently cited account demonstrating the inherent spectrum of resistance (or susceptibility) to infection is the accidental exposure of neonates to virulent Mycobacterium tuberculosis-contaminated Bacille Calmette-Gue´rin (BCG) vaccine in Lu¨beck, Germany, in
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1929–1930. Of 251 vaccinated children, 72 children succumbed to tuberculosis (five children died from causes unrelated to tuberculosis), 61 had severe tuberculosis, 95 had mild tuberculosis, and 17 were infected (positive tuberculin test) but asymptomatic, demonstrating the large range in response among humans to a deadly infectious disease (Moegling 1935). Support of a genetic component to infectious disease susceptibility was provided by a Danish study that followed 960 families and calculated the relative risk (RR) of premature death (age range = 15–58 years) in adoptees when a biological or adoptive parent died before age 50. The RR of death due to an infectious disease was 5.81 (95% confidence interval [CI] = 2.47–13.7) if a biological parent died of an infectious disease and 1.19 (95% CI = 0.16–8.99) for cancers. Conversely, the RR of death due to cancers was 5.16 (95% CI = 1.20–22.2) if an adoptive parent died of a cancer and near unity for infectious diseases (Sorensen et al. 1988). As proposed by Jean-Laurent Casanova and Laurent Abel in 2007, genetic determinants of infectious disease susceptibility occur along a spectrum delimited by monogenic (conventional primary immunodeficiencies) and polygenic models of inheritance, predisposing to multiple infections (one gene ? multiple infections) or a single infection (multiple genes ? one infection), respectively. Comprising the balance of the spectrum are monogenic (new primary immunodeficiencies) and major gene(s) models of inheritance, predisposing to a small group of infections (Casanova and Abel 2007). As is the case for other common diseases, the models of inheritance that provide the best explanation for the genetic contribution to common infectious diseases, like leprosy, are often controversial. Koch’s postulates and leprosy In 1873, after two years of examining leprosy families in western Norway, Gerhard Henrik Armauer Hansen (1841–1912) focused on the microscopic investigation of leprous nodules. His seminal discovery of bacilli or ‘‘…staff-like bodies, much resembling bacteria…’’ substantiated his idea of a bacterial etiology for leprosy (Hansen 1875). Because of his outstanding scientific discovery, leprosy is also called Hansen’s disease. In 1890, Hansen’s contemporary, Robert Koch (1843–1910), stated his four famous criteria to establish the microbial etiology of a disease. Ironically, despite being the first bacterium identified to cause a human disease, Mycobacterium leprae (M. leprae) still does not satisfy all of Koch’s postulates: 1.
A specific microorganism can always be found associated with a given disease. Microscopically detectable M. leprae—an acid-fast bacillus—in slit-skin smears is
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2.
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a cardinal sign of leprosy (i.e., *100% specific) but is not sensitive as merely 10–50% of leprosy patients (multibacillary cases) are positive (International Leprosy Association 2002). In contrast, molecular detection of M. leprae in nasal swabs (PCR amplification of species-specific pra gene) is not specific. In two leprosy endemic Indonesian villages, 7.8% of the population was PCR ? compared to 0.99% that was diagnosed with leprosy, indicative of asymptomatic carriers (Klatser et al. 1993). Nasal carriage was also transient without ensuing disease as 90 PCR ? individuals were PCR - two years later (Hatta et al. 1995). The microorganism can be isolated and grown in pure culture in the laboratory. A history of failed attempts to culture M. leprae in vitro likely reflects its extreme reductive evolution; this obligate intracellular parasite has retained the minimal gene set required for survival in its natural host(s). The circular genome of M. leprae (TN strain, Tamil Nadu, India) was sequenced in 2001 (Leproma, http://genolist.pasteur.fr/Leproma/) (Cole et al. 2001; Jones et al. 2001). Comparative analysis with the genome and proteome of Mycobacterium tuberculosis (M. tuberculosis) revealed extensive gene loss across all functional categories. Merely 49.5% of the 3.3-Mb M. leprae genome is protein-coding (1604 genes) in contrast to 90.8% of the 4.4-Mb M. tuberculosis genome (3959 genes). Nevertheless, it was discovered that Dasypus novemcinctus (nine-banded armadillo) (Kirchheimer and Storrs 1971) and the footpads of the athymic Nude mouse (Foxn1nu/Foxn1nu) are susceptible to M. leprae infection. The armadillo and T-cell-deficient mouse are invaluable to leprosy research, serving as experimental models of leprosy and biological sources of abundant M. leprae. The pure culture of the microorganism will produce the disease when injected into a susceptible animal. In 1960, Charles C. Shepard was able to reproducibly induce granulomas containing acid-fast bacilli in the footpads of mice after inoculation with bacteria harvested from nasal passages (22/22 ‘‘takes’’) or biopsies (12/16 ‘‘takes’’) of human leprosy cases (Shepard 1960). It is possible to recover the injected microorganism from the experimentally infected animal. Shepard observed the same histopathology after injection of passage material from the footpads demonstrating transmissibility of the granulomatous phenotype (Shepard 1960).
Epidemiology In May 1991, the World Health Assembly passed a resolution to ‘‘eliminate’’ leprosy as a public health
A. Alter et al.: Leprosy as a genetic disease
problem by 2000 as defined by a global reduction in prevalence rate to less than 1 case per 10,000. Simplified diagnosis and the free global distribution of highly effective short-course multidrug therapy facilitated by The Nippon Foundation of Japan (1995–1999, 50 million USD) and Novartis and the Novartis Foundation for Sustainable Development (2000–2010, 54.5–64.5 million USD) largely contributed to this achievement. Compared to 5.35 million cases in 1985, initiatives led by the World Health Organization (WHO) have undeniably reduced the prevalence of leprosy. At the beginning of 2008, the global prevalence of leprosy (i.e., all patients receiving multidrug therapy on December 31, 2007) was 212,802 and the number of new cases detected in 2007 was 254,525. Among countries with a population over 1 million, Brazil (2.045 cases per 10,000), Nepal (1.572 cases per 10,000), and East Timor (1.723 cases per 10,000) had not eliminated leprosy (WHO 2008).
Classification of the leprosy disease spectrum The leprosy bacillus has a tropism for macrophages and peripheral nerve Schwann cells, infection of the latter resulting in sensory and motor function loss. Individual differences in the host immune response directed against M. leprae strongly correlate with the spectrum of clinical and histological phenotypes delimited by the tuberculoid (TT) and lepromatous (LL) subtypes (Ridley-Jopling classification). Tuberculoid cases present a limited number of hypopigmented, anesthetic skin lesions with no microscopically discernable bacteria. The correlated Th1-cell-mediated immune (CMI) response (IL-2, IFN-c) promotes the formation of delineated granulomas—central areas of infected macrophages, often fused into multinucleate giant cells, surrounded by T cells—that successfully limit bacterial replication. Conversely, LL cases present numerous sensitive or anesthetic skin lesions with high bacillary loads. The correlated Th2antibody response (IL-4, IL-10) impedes granuloma formation, allowing for uncontrolled bacterial replication and continuous infiltration of the skin and nerves. Borderline forms, i.e., borderline-tuberculoid (BT), borderline (BB), and borderline-lepromatous (BL), comprise the majority of cases. These individuals present intermediate clinical and histological phenotypes resulting from immunologically unstable responses. With limited accuracy, the Ridley-Jopling designations are approximated in the alternative WHO classification system by reclassifying TT and BT subtypes as paucibacillary (PB), and BB, BL, and LL forms as multibacillary (MB) (Fig. 1).
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Fig. 1 Clinical and immunological classification of the leprosy disease spectrum. Clinical manifestations of leprosy are classified according to the Ridley-Jopling (TT, BT, BB, BL, LL) and World Health Organization (PB and MB) schemes. The host immune response (Th1 versus Th2) and bacillary load correlated with each leprosy subtype is indicated below
Uncovering a genetic component in leprosy: twin studies and complex segregation analyses A genetic component to leprosy susceptibility—per se and subtype—was established by two twin studies. Comparing 23 monozygotic and 12 dizygotic twins, 19 (82.6%) vs. 2 (16.7%) were concordant for disease, respectively. Among the 19 monozygotic concordant twin pairs, 17 (89.5%) were concordant for disease subtype (Mohamed Ali and Ramanujam 1966). Similarly, comparing 62 monozygotic and 40 dizygotic twins, 37 (59.7%) vs. 8 (20%) were concordant for disease, respectively. Among the 37 monozygotic and 8 dizygotic concordant twin pairs, 32 (86.5%) and 6 (75%) were concordant for disease subtype (Chakravartti and Vogel 1973). Complex segregation analyses have repeatedly detected evidence of a genetic component and have consistently concluded the existence of a major gene(s) for leprosy per se and subtype. However, a consensus on the mode of inheritance has not emerged, rendering leprosy less suitable to model-based linkage analysis (Abel and Demenais 1988; Abel et al. 1995; Feitosa et al. 1995; Haile et al. 1985; Lazaro et al. 2010; Shaw et al. 2001; Shields et al. 1987; Smith 1979; Wagener et al. 1988). A detailed discussion of different methods for the localization and identification of susceptibility genes in infectious diseases is provided in a recent review (Cobat et al. 2010) and nicely illustrated in a study on tuberculin skin test reactivity (Cobat et al. 2009).
Genome-wide linkage analyses: from linked regions to associated SNPs In the first genome-wide linkage study of leprosy, chromosome region 10p13 was linked to the paucibacillary subtype (multipoint MLS = 4.09) in multicase families
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from Southern India (n = 224) (Siddiqui et al. 2001). Three nonsynonymous single-nucleotide polymorphisms (SNPs) in exon 7 of the underlying mannose receptor, C type 1 (MRC1) gene were suggested to be associated with the paucibacillary subtype (Cooke and Hill 2008; Hill 2006). Recently, the association of a nonsynonymous SNP in exon 7 of MRC1 (G396S) with leprosy in a family-based sample from Vietnam (n = 580) and a population-based sample from Brazil (n = 384 cases) was reported (Alter et al. 2010). In the Brazilian population, the existence of two additional nonsynonymous exon 7 SNPs (A399T and F407L) permitted haplotype analysis that revealed the G396 allele to be a risk factor exclusively in the context of the A399–F407 background. An independent genome-wide scan in multicase families from Brazil (n = 71) detected suggestive evidence of linkage for chromosome regions 6p21 (HLA-DQA LOD scores = 3.23), 17q22 (LOD scores = 2.38), and 20p13 (LOD scores = 1.51), the latter signal attributable almost entirely to the lepromatous and borderline lepromatous families (LOD scores = 1.36) (Miller et al. 2004). Previously in this population, chromosome region 17q— specifically 17q12 and 17q21.33—showed suggestive evidence of linkage to the tuberculoid subtype (Zlr = 2.58) and leprosy per se (Zlr = 2.67), respectively (Jamieson et al. 2004). Expanding the genome-wide linkage analysis to quantitative immune response traits, plasma IgG to M. leprae soluble antigen (MLSA) was linked to chromosomes 8, 17 (17q21), and 21, and IFN-c release to MLSA was linked to chromosomes 6 (6p21.2 and 6q27), 7, 10, 12, and 14 in a subset of 21 families (Wheeler et al. 2006). We undertook a genome-wide scan in multicase families from Vietnam (n = 86) with a balanced distribution of paucibacillary (44%) and multibacillary (56%) cases. Irrespective of clinical leprosy subtype, significant evidence of linkage was detected for chromosome region 6q25–q26 (multipoint MLB LOD = 4.31) and suggestive evidence for regions 6p21 (multipoint LOD = 2.62), 20p12 (LOD = 1.13), and 13q22.1 (LOD = 1.68). In a subsample comprising only the paucibacillary affected sibpairs, we were able to replicate the previously reported peak at 10p13 (LOD = 1.98) (Mira et al. 2003). Interestingly, linkage of chromosome region 13q22.1 to leprosy was supported by the first genome-wide association study (GWAS) of leprosy in a sample from China with the association of SNPs in genes CCDC122 (13q14.11) and C13orf31 (13q14.11) (Zhang et al. 2009). Following the linkage study, we performed a primary association scan of a 6.4-Mb interval on chromosome region 6q25–q26 (43 genes, ZDHHC14 ? PACRG) in single-case families from Vietnam (n = 197). Among six SNPs associated with leprosy (p \ 0.05), four were located in the putative bidirectional promoter for the PARK2 and
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PACRG genes. A secondary association scan of both genes (81 polymorphisms) detected 19 associated SNPs between PARK2 intron 1 and PACRG intron 2 (p \ 0.03). As a result of extensive linkage disequilibrium (LD) among the associated SNPs, only two SNPs (i.e., tag SNPs), namely, rs9356058 and rs1040079, captured all association information. These results strongly implicated PARK2, an E3 ubiquitin-protein ligase involved in targeting proteins for proteasomal degradation (Shimura et al. 2000), in leprosy pathogenesis. We subsequently replicated the association of rs9356058 (Pcorrected = 0.003) and rs1040079 (Pcorrected = 0.001) in a population-based sample from Brazil (n = 587 cases) (Mira et al. 2004). In 2005, the ‘‘TT’’ genotype for rs9356058 was modestly associated with leprosy (p = 0.04) in a population-based sample from northern India (n = 286 cases) prior to correction for multiple testing (Malhotra et al. 2005a). To determine whether PARK2/PACRG variants impact on nonmycobacterial disease, four variants were investigated in the context of enteric fever caused by Salmonella typhi (typhoid fever) and Salmonella paratyphi (paratyphoid fever). Again, the T allele of rs9356058 was modestly associated with enteric fever (p = 0.02) in a population-based sample from Indonesia (n = 115 cases) (Ali et al. 2006). Subsequent to the genetic studies, proteosome function was experimentally implicated in M. leprae pathogenesis. An inhibitor of proteosome activity decreased M. leprae and LPS-stimulated production of TNF-a (p \ 0.05) from peripheral blood mononuclear cells (PBMCs), decreased M. leprae-stimulated production of IL-10 (p \ 0.001) from PBMCs, and, moreover, reduced M. leprae-mediated apoptosis of monocytes (Fulco et al. 2007).
A genome-wide association study Very recently, the first GWAS of leprosy was published. Initially, 491,883 SNPs were analyzed in a ‘‘discovery’’ sample of 706 cases and 1255 controls from eastern China. Subsequently, the 93 SNPs with the strongest evidence of association were genotyped in three replication samples (3254 cases and 5955 controls combined) from eastern and southern China. Among these, 15 SNPs across six genes— HLA-DR-DQ, RIPK2, TNFSF15, CCDC122, C13orf31, and NOD2—were associated with leprosy (2 or more SNPs in each gene had a p \ 1 9 10-10 for all samples combined). Significant heterogeneity was detected across leprosy subtypes (multibacillary versus paucibacillary) for five SNPs across four genes—RIPK2, C13orf31, NOD2, and LRRK2— with stronger evidence of association with the multibacillary subtype. Pathway analysis identified a single network (35 genes total) that included five of the seven genes identified in the GWAS (TNFSF15, HLA-DRB1, RIPK2, NOD2, and
A. Alter et al.: Leprosy as a genetic disease
LRRK2). Remarkably, PARK2 was included in the network as having a known (downstream) direct molecular interaction with LRRK2 (Zhang et al. 2009).
Candidate gene approach HLA complex genes The human leukocyte antigen (HLA) complex (*7.6 Mb) on chromosome 6p22.2–p21.32 comprises five contiguous regions: the extended class I (HIST1H2AA to MOG, 3.9 Mb), the classical class I (C6orf40 to MICB, 1.9 Mb), the classical class III (PPIP9 to NOTCH4, 0.7 Mb), the classical class II (C6orf10 to HCG24, 0.9 Mb), and the extended class II (COL11A2 to RPL12P1, 0.2 Mb) (see MHCmap in http:// www.nature.com/nrg/journal/v5/n12/poster/MHCmap) (Horton et al. 2004). Among the HLA complex, the classical HLA class I (HLA-A, -B, and -C) and classical HLA class II (HLA-DP, -DQ, and -DR) genes have been studied extensively in human genetics of disease susceptibility, including infectious disease, owing to their fundamental role in the host immune response (Klein and Sato 2000b; Yee and Thursz 2004). Each classical HLA class I gene encodes a transmembrane a-chain that noncovalently associates with b-2 microglobulin (B2M, 15q21–q22.2). The heterodimeric class I molecule, expressed on all nucleated cells, presents cytosolic pathogen-associated peptide to CD8? T cells. In addition, the class I molecules (HLA-B and -C) engage killer cell immunoglobulin-like receptors (KIR) expressed on natural killer cells (Kulkarni et al. 2008). Each classical HLA class II gene encodes a transmembrane a (e.g., HLA-DPA1) or b (e.g., HLA-DPB1) chain that noncovalently associates (e.g., HLA-DP). The heterodimeric class II molecule, expressed on B cells and antigen-presenting cells, presents extracellular or intravesicular pathogen-associated peptide to CD4 ? T cells (Th1 and Th2) (Janeway et al. 2001; Klein and Sato 2000a). Of note, the interpretation of linkage and association studies of the HLA complex requires caution because of long-range LD (De La Vega et al. 2005; Lincoln et al. 2005). A substantial number of seminal studies addressing the role of HLA class I and class II genes in leprosy have been conducted. Here we provide only a short summary of select publications. For a comprehensive review of this work, the interested reader is referred to chapters 22 (Orlova and Schurr 2010) and 23 (Mehra et al. 2010) in the recently published book The HLA complex in biology and medicine: a resource book.
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leprosy cases (frequency = 0.040) compared to controls (frequency = 0.129) from southern China (RR = 0.28) (Wang et al. 1999). Among 80 leprosy cases and 120 controls from Turkey, HLA class I serotypes A*9, A*10, A*32, B*5, B*21, Bw*4, Bw*6, Cw*1, and Cw*2 were significantly overrepresented (i.e., risk), and serotypes A*3, B*44, and B*49 were significantly underrepresented in the case group (Kocak et al. 2002). In a more comprehensive study, first the distribution of HLA class I serotypes was determined in 103 leprosy cases and 101 controls from Mumbai, India. In the case group, serotypes A*2, A*11, B*40, and Cw*7 were significantly overrepresented and A*28, B*12, and Cw*3 were significantly underrepresented. Next, the distribution of HLA class I alleles was determined in 32 multibacillary leprosy cases and 67 controls from the same geographic area. In the multibacillary group, alleles A*0206, A*1102, B*1801, B*5110, Cw*0407, and Cw*0703 and haplotypes A*11–B*40 and A*0203–B*4016–Cw*0703 were significantly overrepresented and allele Cw*04011 was significantly underrepresented (Shankarkumar 2004). Classical HLA class II genes The study of the HLA region, particularly HLA class II, in leprosy susceptibility is vast and a complete review of the related literature is beyond the scope of this introduction. Moreover, earlier work has been summarized in several reviews (Fitness et al. 2002; Meyer et al. 1998; Mira 2006; Orlova and Schurr 2010). As such, a limited selection of the most recent publications (i.e., 1993-present) with evidence for association and/or linkage of classical HLA class II genes with leprosy is presented in Supplementary Table 1. Of interest, in the study of 54 tuberculoid leprosy cases and 44 controls from northern India, it was noted that for both susceptibility alleles (DRB1*15 and DRB1*1404), in contrast to the protective allele (DRB1*1301), an arginine residue occupied amino acid positions 13 (DRB*15) and 70/71 (DRB1*1404). Indeed, reanalysis of the data showed that in 87% of cases, arginine occupied positions 13 or 70/ 71 compared to 43% of controls, conferring a RR = 8.8 (p = 5 9 10-6). The side chains of amino acid residues 13, 70, and 71 line pocket four of the HLA-DR molecule, and it was hypothesized by the authors that positively charged residues at these positions may affect peptide binding and/or engagement of the T-cell receptor such that the host immune response favors the development of the tuberculoid subtype (Zerva et al. 1996).
Classical HLA class I genes
Tumor necrosis factor
In a small sample investigating HLA-B serotypes, B*46 was underrepresented (i.e., protective) in multibacillary
Released in response to infection, tumor necrosis factor (TNF) is a pleiotropic proinflammatory cytokine whose
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effects include the upregulation of endothelial adhesion molecules, stimulation of macrophage/neutrophil phagocytic activity, and the release of nitric oxide and free oxygen radicals (Knight and Kwiatkowski 1999). The contribution of TNF [chromosome 6p21.3 (HLA class III), 2.8 kb] variants to infectious disease susceptibility (e.g., tuberculosis, cerebral malaria) has been studied, particularly the putative promoter SNP at position -308 relative to the transcription start site (TNF-308 allele G = TNF*1, TNF-308 allele A = TNF*2; OMIM*191160) (Knight and Kwiatkowski 1999). The G ? A transition is thought to alter a transcription factor binding site, and in one study using a ‘‘promoter-luciferase-30 UTR’’ construct, TNF*2 (allele A) demonstrated a two-to-threefold greater expression in mitogen-stimulated cells (Abraham and Kroeger 1999). Interestingly, the involvement of TNF in the protective host response to M. leprae was demonstrated by the relatively rapid development of borderline lepromatous leprosy (1–2-year incubation) in two arthritic individuals from the United States after initiation of infliximab treatment (humanized monoclonal anti-TNF antibody). Presumably, a pre-existing infection had been sufficiently contained (i.e., subclinical leprosy) despite previous administration of immunosuppressive treatments (Scollard et al. 2006). TNF association and linkage studies for leprosy are presented in Supplementary Table 2. Despite replicated association of TNF-308 with leprosy per se and subtype, assignment of the susceptibility allele has been inconsistent. Non-HLA genes Solute carrier family 11, member 1 (SLC11A1, formerly NRAMP1) Murine susceptibility to Salmonella typhimurium, Leishmania donovani, Mycobacterium bovis (BCG), and Mycobacterium lepraemurium was mapped to a single glycine ? aspartic acid substitution (G169D) in Slc11a1 (formerly Nramp1), abrogating its expression (Malo et al. 1994; Vidal et al. 1996). Nramp1—a divalent cation transporter—is recruited to the macrophage phagosome membrane subsequent to phagocytosis of live bacteria (or inert particles) where it extrudes divalent cations, seemingly necessary for microbe function, from the phagosome (Gruenheid and Gros 2000; Jabado et al. 2000). In addition, the ability of M. bovis to inhibit phagosome–lysosome fusion, which attenuated the acidification of the M. bovis-containing phagosome, was diminished by Nramp1 (Hackam et al. 1998). The presumed conserved function of the human ortholog was substantiated by the observation that SLC11A1 (formerly NRAMP1) promoted phagosome maturation in a human (U-937) monocytic cell line (Gallant et al. 2007). The
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contribution of SLC11A1 (2q35, 14.9 kb) variants to infectious disease susceptibility (e.g., tuberculosis, buruli ulcer) has been studied (OMIM*600266). SLC11A1 association and linkage studies for leprosy are presented in Supplementary Table 3. Linkage of an extended SLC11A1 haplotype with leprosy per se was substantiated by a single study that associated SLC11A1 (30 UTR TGTG deletion) with the multibacillary subtype (Abel et al. 1998; Meisner et al. 2001). Toll-like receptors (TLRs) TLRs—pluripotent effectors of the innate response—are pattern recognition receptors that bind molecules characterized by their so-called pathogen-associated molecular patterns (PAMPs). For example, among the ten human TLRs, TLR2/TLR6 and TLR2/TLR1 heterodimers bind diacylated and triacylated lipoproteins, respectively. Subsequent to TLR engagement, the cytoplasmic Toll/IL-1 receptor (TIR) domain initiates a signaling pathway that culminates in the nuclear translocation of NF-jB and transcriptional activation of proinflammatory immunomodulatory genes (cytokines and chemokines). In addition, TLRs were shown to promote phagocytosis, stimulate antimicrobial peptide synthesis, upregulate expression of CD80 and CD86 costimulatory molecules, and induce apoptosis (McInturff et al. 2005). Although several TLR variants have been associated with increased risk of infectious disease (e.g., tuberculosis, Meningococcus, and malaria) (Misch and Hawn 2008), very few of them have been clearly replicated and can be considered as convincing. TLR2 was detected on primary human Schwann cells and a TLR2 ligand, M. leprae-specific 19-kDa lipopeptide, induced apoptosis. TLR2? apoptotic Schwann cells were similarly observed in leprosy skin biopsies (Oliveira et al. 2003). TLR2-dependent IL-12p40 production was detected from primary human monocytes and monocyte-derived dendritic cells after stimulation with a 19- or 33-kDa M. leprae lipopeptide. In tuberculoid skin biopsies (n = 10), 40–50% of granulomatous cells were TLR2? (predominantly TLR2/TLR1 heterodimers), of which 90–95% were of the monocyte/macrophage lineage and 5% were dendritic cells. In contrast, TLR2 and TLR1 expression was relatively much weaker in lepromatous skin biopsies (Krutzik et al. 2003). Treatment of monocytes with a TLR2/TLR1 ligand (M. tuberculosis 19-kDa lipopeptide) induced differentiation into macrophages (DC-SIGN? CD16?) and dendritic cells (CD1b?DC-SIGN-). Interestingly, TLR2/TLR1-mediated differentiation of peripheral monocytes from lepromatous cases was limited to macrophages (impaired dendritic cell differentiation was not observed in peripheral monocytes from tuberculoid
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cases) and this was reflected in the absence of CD1b? cells in lepromatous skin biopsies (Krutzik et al. 2005). TLR1 (4p14, 8.5 kb), TLR2 (4q32, 21.8 kb), and TLR4 (9q32-q33, 13.3 kb) association studies for leprosy are presented in Supplementary Table 4. As for TNF-308, despite replicated association of TLR variants with leprosy per se and subtype, no consistent susceptibility allele has been identified. Interestingly, individuals homozygous for the protective TLR1 SNP rs5743618 G allele (602-serine) had lower TLR1 cell surface levels due to impaired cell surface trafficking, suggesting that M. leprae benefits from functional TLR1 (Johnson et al. 2007). Although rs5743618 was not associated with leprosy (or subtype) in Nepal, TLR1-transfected HEK293 cells with the G allele (602-serine) had reduced constitutive and stimulated NF-jB activity in response to TLR2/TLR1 ligands (whole, irradiated M. leprae, M. leprae cell wall, and triacylated lipopeptide). Moreover, TLR2/TLR1 ligand-stimulated PBMCs from rs5743618 G/G homozygous individuals had reduced production of IL-6, IL-1b, and TNF-a (Misch et al. 2008). In the most recent study of TLR4 variants, M. leprae—unlike LPS, the classical TLR4 ligand—did not induce IL-1b, IL-6, or IL-12p70 production from human monocytes. In addition, in monocytes and PBMCs, prestimulation with M. leprae for 24 h decreased LPS-induced production of IL-1b and IL-6, respectively, suggesting that M. leprae modulates TLR4 signaling (Bochud et al. 2009). Of note, genetic and functional studies relating to the nonsynonymous TLR2 SNP Arg677Trp are not presented as this variant is in fact attributable to a nucleotide substitution in an approximately 23-kb duplicated region that is 93% homologous to TLR2 exon 3 (Kang and Chae 2001; Malhotra et al. 2005b). Additional genes In addition to the presented studies, there are several reported—albeit unreplicated—genetic determinants for leprosy. Those published before 2001 have been reviewed previously (Fitness et al. 2002). As such, the most recent publications (i.e., 2001-present) of genes with evidence for association with leprosy are presented in Supplementary Table 5.
Genetic susceptibility to leprosy: a two-stage model Based on the results of complex segregation analyses, linkage studies, and association studies, a two-stage model of genetic susceptibility to leprosy was proposed (Fig. 2). In stage one, ‘‘group 1’’ genetic risk factors (e.g., PARK2, LTA, 13q22.1, 20p12.3) contribute to the establishment of disease by M. leprae subsequent to exposure (i.e., leprosy
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Fig. 2 Two-stage model of genetic susceptibility to leprosy. Subsequent to M. leprae exposure, group 1 genes confer susceptibility (or resistance) to the establishment of infection and development of clinical disease (i.e., leprosy per se). Among the approximately 5–10% of individuals who develop leprosy, group 2 genes determine the type of host immune response elicited and subsequent clinical subtype manifested (single-lesion PB, PB, MB)
per se). Importantly, the majority of individuals ([90%) exposed to M. leprae are asymptomatic (Chaudhury et al. 1994; Convit et al. 1992; Gupte et al. 1998). In stage two, ‘‘group 2’’ genetic risk factors (e.g., HLA-DRB1*15, 10p13) contribute to the manifestation of single-lesion paucibacillary (possibly self-limiting), paucibacillary, or multibacillary leprosy (i.e., subtype).
Revisiting an ancient disease in modern times Given the fixed number of genes in the human genome (42,457 as of June 10, 2010), it is reasonable to predict that as the genetic determinants of common diseases are revealed, numerous single-gene alleles that predispose to multiple-disease phenotypes will emerge. HLA-DRB1 (OMIM*142857) is a recognized example of this ‘‘single gene—multiple diseases’’ hypothesis. HLA-DRB1 allelic associations include both infectious diseases like malaria (Hill et al. 1991), hepatitis C (Thursz et al. 1999), human immunodeficiency virus (MacDonald et al. 2000; Vyakarnam et al. 2004), and invasive streptococcal infection (Kotb et al. 2002) and inflammatory diseases like nonfamilial idiopathic cardiomyopathy (Hiroi et al. 1999; Nishi et al. 1995), asthma (Moffatt et al. 2001), multiple sclerosis (International Multiple Sclerosis Genetics Consortium et al. 2007; Lang et al. 2002; Oksenberg et al. 2004), rheumatoid arthritis (Jawaheer et al. 2002), and type 1 diabetes (Nejentsev et al. 2007). Based on an expanded view of the single gene—multiple diseases hypothesis that included single biological pathways, the genotype data (Affymetrix GeneChip 500 K Mapping array set) of the Wellcome Trust Case Control Consortium was reanalyzed
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(Eleftherohorinou et al. 2009; Wellcome Trust Case Control Consortium 2007). In the sample of 14,000 United Kingdom Caucasian patients with Crohn’s disease (CD), rheumatoid arthritis (RA), type 1 diabetes (T1D), hypertension, type 2 diabetes, bipolar disorder, or coronary artery disease and 3000 controls, each phenotype (n = 2000) was tested for association with multiple SNPs in genes that defined established pathogen-response pathways (e.g., antigen processing and presentation = 104 genes = 689 SNPs). Several pathways, i.e., antigen processing and presentation (HLA-C, HLA-DQB1, HLA-G), T-cell activation (VAV3, ITPR1, PAK7, PLA2G4A, PPP3R2), cell adhesion molecules (ALCAM, NLGN1, CDH2), and hematopoietic cell lineage (ITGA1), were associated with the three inflammatory diseases (CD, RA, and T1D) corresponding to 12 shared inflammatory disease genes. Both HLA-DRB1 and the pathway analysis study not only support the single-gene/pathway—multiple-diseases hypothesis, but highlight the value of determining the host genetic contribution to infectious disease susceptibility as these genes (and ensuing pathways) are most likely to impact concurrently on inflammatory disease susceptibility. In this respect, leprosy is revealing itself to be an ideal example of an infectious disease whose genetic architecture can be extrapolated to inflammatory diseases given that leprosy susceptibility genes, including NOD2, LTA, and PARK2, have been individually associated with different inflammatory diseases (Fig. 3). Nucleotide-binding oligomerization domain containing 2 (NOD2) is a cytosolic pattern recognition receptor that is expressed in monocytes, macrophages, dendritic cells, and intestinal Paneth cells and binds a ubiquitous bacterial peptidoglycan motif (muramyl dipeptide) that initiates a molecular cascade culminating in NF-kB activation (Shaw et al. 2008). Following the GWAS that identified four SNPs in NOD2 (rs9302752, rs7194886, rs8057341, and rs3135499) as leprosy risk factors in the Chinese
Fig. 3 Shared genetic background between leprosy and inflammatory diseases. Positive and negative evidence for association between a gene and common disease phenotype is depicted by ‘‘?’’ and ‘‘-’’, respectively (see text for references)
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population (Zhang et al. 2009), NOD2 variants were investigated in three population-based leprosy samples from New Delhi, India (n = 492 cases), Kolkata, India (n = 382 cases), and Mali (n = 273 cases). The four original SNPs showed no evidence for association with leprosy in any sample, nor did 27 additional NOD2 SNPs tested in the New Delhi sample (Wong et al. 2010). These divergent results highlight the need for ultrahigh-resolution fine mapping to better understand the LD structure of the associated bins. Comparison of the associated bins among ethnically different populations will facilitate the identification of the suspected causal variant(s) as has been convincingly demonstrated in the case of the LTA ? 80A leprosy susceptibility allele (Alcaı¨s et al. 2007). Interestingly, however, two significant SNPs in the GWAS— rs3764147 in C13orf31 and rs9533634 in CCDC122—were associated in all three samples and both genes underlie a Crohn’s disease risk locus on chromosome region 13q14 (Barrett et al. 2008). In contrast, two NOD2 promoter SNPs (rs8044354, rs8043770) and three intronic SNPs (rs13339578, rs4785225, and rs751271) were associated with leprosy in a population-based sample from Katmandu, Nepal (n = 933 patients) (Berrington et al. 2010). Crohn’s disease is a form of inflammatory bowel disease with recognized genetic risk factors (Cooney and Jewell 2009). In 2001, a 1-bp insertion in exon 10 (980 fs), resulting in a premature stop codon (i.e., truncated protein), and two nonsynonymous SNPs (G881R and R675 W) in NOD2 were all independently associated with Crohn’s disease in a family-based sample (n = 235 families) (Hugot et al. 2001). In the same issue of Nature, a different 1-bp insertion in exon 11 of NOD2 (1007fsCins), also resulting in a premature stop codon, was associated with Crohn’s disease in a family-based sample (n = 416 families) and a population-based sample (n = 416 cases) (Ogura et al. 2001). Independently, the same variant (1007fsCins) was found to be both linked to and associated
A. Alter et al.: Leprosy as a genetic disease
with Crohn’s disease in a sample of multicase (n = 194) and single-case families (n = 304), respectively (Hampe et al. 2001). That leprosy and Crohn’s disease share NOD2 as a genetic risk factor is intriguing for two reasons: (1) it supports a common disease model and, in so doing, the controversial hypothesis that Crohn’s disease, like leprosy, manifests as two clinical forms that reflect the immune status of the patient. Proponents of this hypothesis relate the aggressive fistulae-associated form (perforating) to lepromatous leprosy (Th2 response) and the contained stricture-associated form (nonperforating) to tuberculoid leprosy (Th1 response) (Greenstein and Greenstein 1995). Given that leprosy has been a long-standing human model for the study of the Th1–Th2 paradigm, the relevance of acquired immunological principles may extend well beyond this ancient infectious disease to inflammatory diseases of industrialized societies such as Crohn’s disease. (2) It supports a second highly controversial hypothesis that Crohn’s disease, like leprosy, has an infectious etiology and is similarly caused by a mycobacteria, specifically Mycobacterium avium subspecies paratuberculosis (MAP) (Behr and Schurr 2006). MAP causes a diarrheal disease reminiscent of Crohn’s disease in animals called Johne’s disease. Interestingly, MAP RNA (IS 900) was detected in mucosal samples from patients with Crohn’s disease (n = 8/8) and ulcerative colitis (n = 2/2) (Mishina et al. 1996) and this finding was further substantiated in a carefully planned follow-up study (Jeyanathan et al. 2007). Municipal drinking water and milk are suggested reservoirs of MAP (Greenstein 2003). The recent identification of NOD2 as a leprosy susceptibility gene renews the importance of definitively addressing the possibility that Crohn’s disease is the result of an intrinsic host susceptibility to a mycobacterial infection (Schurr and Gros 2009). Obviously, if this were the case, it would bear enormous impact on the therapeutic approach to Crohn’s disease. An important role in the host’s defense against intracellular infections is emerging for soluble lymphotoxin a (LTA) secreted by CD4 ? T cells, B cells, and natural killer cells. In mouse studies, soluble LTA mediates the recruitment of macrophages and lymphocytes to sites of infection where they can cooperatively exert their antimicrobial functions (Roach et al. 2001, 2005). In human studies, among 12 common polymorphisms (minor allele frequency [10%) at the LTA locus, soluble LTA production was significantly less from cells carrying the common LTA ? 80A–LTA ? 368C haplotype. Basic helix-loophelix transcription factors like ABF-1, a transcriptional repressor expressed in lymphoid tissue, bind E2-box consensus motifs (CAGCTG). LTA ? 80 in the 50 UTR of LTA is the second nucleotide in a E2-box motif with a mismatch at position five (CAGCAG). LTA ? 80A maintains the
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1-bp mismatch in the motif (CAGCAG), while LTA ? 80C introduces a 2-bp mismatch (CCGCAG), abrogating ABF-1 binding and subsequent transcriptional repression (Knight et al. 2004). In 2007, we reported the association of this low-producing LTA ? 80 ‘‘A’’ allele with an increased risk of leprosy per se in young patients in two independent family-based samples from Vietnam (combined n = 298) and a population-based sample from India (n = 364 cases) (Alcaı¨s et al. 2007; Alter et al. 2008). A SNP in intron 1 (LTA ? 252) and a nonsynonymous SNP in exon 3 (T26N) were associated with myocardial infarction (MI) in a population-based sample from Japan (n = 1133). Plasmid constructs with the LTA ? 252 risk allele (G allele) showed greater relative reporter gene activity, and recombinant LTA protein with the risk allele at position 26 (aspargine) increased mRNA expression of vascular cell-adhesion molecule 1 (VCAM1) and selectin E (SELE) in human coronary artery smooth-muscle cells (Ozaki et al. 2002). The association of T26N was replicated in a family-based sample of European ancestry (n = 447) with consistent over-transmission of the ‘‘N’’ allele (PROCARDIS Consortium 2004). The association of leprosy with a low-producing LTA allele and of MI with a high-producing LTA allele illustrates the double-edged sword of a single proinflammatory pathway. Combined with additional genetic and/or environmental risk factors, a shortfall in the LTA pathway can precipitate a deficient response to a mycobacterial infection while an excess can lead to a potentially fatal cardiac episode. The broad impact of this protein (and related pathways) highlights LTA as a critical effector molecule in the pathogenesis of infectious and noninfectious diseases. As mentioned, PARK2 is an E3 ubiquitin-protein ligase involved in targeting proteins for proteasomal degradation (Shimura et al. 2000). Early-onset autosomal recessive familial Parkinson disease (PD) and isolated juvenile-onset PD were associated with mutations in the PARK2 gene (Lucking et al. 2000). Subsequently, several polymorphisms in the PARK2 promoter were also associated with leprosy susceptibility (Mira et al. 2004). A shared genetic background between leprosy and PD is supported by the recent association of a SNP in LRRK2—a PD locus—with leprosy susceptibility (Zhang et al. 2009). Functionally, LRRK2 was shown to be a regulator of PARK2 activity (Smith et al. 2005). Interestingly, the genetic determinants of leprosy risk in PARK2 were similarly associated with typhoid and paratyphoid fever (Ali et al. 2006). Together, these data suggest a critical role for PARK2 in both neurological and infectious diseases. In addition to the select examples, a shared genetic background between infectious and inflammatory diseases is supported by further evidence for the association of leprosy susceptibility genes with inflammatory diseases,
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including NOD2 with asthma/allergy (Kabesch et al. 2003; Weidinger et al. 2005) and psoriatic arthritis (Rahman et al. 2003); LTA with Crohn’s disease (Yang et al. 2006), asthma (Migita et al. 2005; Sharma et al. 2006), psoriatic arthritis (Balding et al. 2003), and type 1 diabetes (Boraska et al. 2009; Shin et al. 2008); and vitamin D receptor (VDR) with asthma/atopy (Poon et al. 2004; Raby et al. 2004; Saadi et al. 2009), type 1 diabetes (Reis et al. 2005), and psoriasis (Halsall et al. 2005; Park et al. 1999; Saeki et al. 2002). Recently, two SNPs in leukotriene A4 hydrolase (LTA4H) were associated with protection against multibacillary leprosy without ENL (type-2 reaction) (Tobin et al. 2010). As for the above-mentioned genes, LTA4H was previously associated with asthma (Holloway et al. 2008; Via et al. 2010) and myocardial infarction (Helgadottir et al. 2006) (Fig. 3). In an earlier review we argued that leprosy has proven to be a valuable model for studying the genetic aspect of common infectious diseases, particularly with respect to genetic replication studies (Alter et al. 2008). Here we have argued that leprosy is now proving to be similarly valuable to the understanding of disease pathogenesis beyond infection. As common genetic risk factors continue to emerge, it is reasonable to extrapolate biological concepts and hypotheses from the leprosy disease model to inflammatory diseases. Given that leprosy is a ‘‘good disease’’ to study in the context of genetics because of a clearly discernable phenotype and limited variability among M. leprae isolates, it may serve as a ‘‘surrogate’’ disease for those with an inflammatory etiology. As such, we will continue to pursue genetic determinants of leprosy susceptibility as identifying additional genetic risk factors will implicate new pathways in the complex network of interactions that define not only this ancient host-pathogen relationship but also the common diseases that plague the 21st century. Acknowledgments A. Alcaı¨s was supported the Agence Nationale de la Recherche (ANR) of the Ministere Francais de l’Education Nationale de la Recherche et de la Technologie. A. Grant was supported in part by the Fondation pour la Recherche Me´dicale (FRM). Work in the laboratories of the authors was supported by grants from the Canadian Institutes of Health Research and MAGRALEPRE from the l’Ordre de Malte. E. Schurr is a Chercheur National du Fonds de la Recherche en Sante´ du Que´bec and an International Research Scholar of the Howard Hughes Medical Institute.
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