Genetic dissection of immunity in leprosy

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that affects an estimated 700 000 new individuals each year. A strong contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability observed between individuals exposed to M. leprae. As there is no relevant animal model for human leprosy, forward genetics is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. With respect to genome-wide screens, a major breakthrough has been reported this year; variants in the regulatory region shared by PARK2 and PACRG have been identified as being common risk factors for leprosy.

Introduction

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an obligate intracellular pathogen that principally infects macrophages and Schwann cells [1^•]. Damage to skin and peripheral nerves results in the characteristic deformities and disabilities that contribute to the intense social stigma and discrimination of patients and their families. As leprosy afflicts individuals in their most productive stage of life, it imposes a significant economic burden on the community. Fortunately, the clinical efficacy of multi-drug therapy (MDT) led the World Health Organization to declare in 1991 that leprosy would be eliminated by 2000, with a prevalence of less than 1 case per 10 000 individuals. Of the 122 countries in which leprosy was considered endemic in 1985, 112 had successfully eliminated it by 2003 and more than 13 million patients have been cured by MDT in the past 20 years (WHO leprosy elimination project [status report 2003]; URL: http://www.who.int/lep/Reports/s20042.pdf). Despite this impressive decline in prevalence, the incidence of leprosy has remained unchanged over the past 15 years, with approximately 700 000 new cases per year. Unexpectedly, incidence approximates prevalence, a striking observation in the context of a chronic disease. Although this could partly reflect improved leprosy control and case detection in endemic countries [2], it is also plausible that the global use of MDT has had limited impact on the transmission cycle of M. leprae. It is unclear why the incidence of leprosy is still so high despite effective chemotherapy and the fact that humans are the only relevant reservoir of M. leprae. Thus, important aspects of the intricate relationship between the pathogen and its human host remain to be discovered.

Although leprous nodules were found to contain brown bodies in 1847 [3], these bodies were mistaken for degenerated fat cells until 1873 when Armauer Hansen re-examined the nodules and recognized that they contained bacilli [4]. However, the proof of an infectious agent was difficult to obtain until evidence of direct transmission was shown in 1886 [5]. First named Bacillus leprae [6], the causative agent was assigned to the genus Mycobacterium by Lehmann and Neumann in 1896 [7]. The inability to cultivate M. leprae in vitro and the lack of a suitable animal model have long hampered leprosy research. Progress was made by Charles Shepard in 1960 with the observation of limited M. leprae multiplication after injection into mouse footpads [8], and by Kircheimer and Stoors in 1971 with the demonstration that the nine-banded armadillo is a natural host for systemic infection [9]. More recently, the complete sequencing of the M. leprae genome was an important landmark in the field [10]. When compared to M. tuberculosis, a strong gene decay is observed in M. leprae, resulting in the loss of entire metabolic pathways present in M. tuberculosis. This can render the leprosy bacillus dependent on host metabolic products and might explain its long generation time and inability to grow in culture. From a phylogenetic point of view, M. leprae is a distinct species [11]. In particular, it is not a close relative of M. lepraemurium [12], and conclusions concerning leprosy drawn from mouse models of M. lepraemurium infection should be interpreted with great caution. Due to the absence of in vitro human studies and in vivo animal models, it has been difficult to elucidate the immunological basis of leprosy.