Leprosy in the Modern World

Megan Brown

BIOL 303: Genetics

4 November 2011

Leprosy in the Modern World

This paper seeks to assess the standing of leprosy in the modern world. First, there will be an overview of the history and etiology of the disease. Then, there will be an examination of research surrounding the origins of leprosy, followed by the impact leprosy has had on human genetics, and the changes that the bacterium behind the disease has undergone in recent years.

The history of leprosy, also known as Hansen’s Disease, is deeply entwined with the entire course of human history. Recent skeletal evidence indicates that leprosy existed at least four thousand years ago (Holden, 2009). Yet it was not until the Crusades that this slow-growing bacteria- Mycobacterium leprae- truly showed its strength (Bakija-Konsuo, 2011). Between the eleventh and thirteenth centuries, there was a leprosy pandemic, spread largely through the emergence, growth, and expansion of trade routes. Leprosy was, and remains, a disease of concern: it is an infection of the skin and nerves whose symptoms include nerve damage, skin lesions, disfigurement, and tissue loss (Li, 2011).

Leprosy is, in fact, not highly contagious. According to the World Health Organization, it is spread through either droplets from the nose and mouth, or through frequent skin-to-skin contact (Leprosy elimination, 2011). Additionally, the advent of a multi-drug therapy (MDT) integrating dapsone, rifampicin and clofazimine has made leprosy curable, and has been largely effective (da Silva Rocha, 2011). The intent of MDT was to avoid the emergence of drug-resistant strains of leprosy (Kai, 2011). While different therapeutic practices around the world have hindered this goal, there are far fewer cases of leprosy seen today than in centuries past. In 2010, the global registered prevalence of leprosy was 228,474 (Leprosy elimination, 2011). That said, a deceleration in the rate of reduction has been observed in recent years, making continued investigation into leprosy worthwhile in order to prevent resurgence(Kai, 2011). Additionally, “hot spots” of high prevalence including places such as India, Brazil, and Madagascar still pose problems.

Simply, as the cause of a disease that has ravaged the planet for millennia, M. leprae is worth examination. Yet the study of this bacterium is challenging. It cannot be grown in anexic cultures, and in cultures with other tissues, it has a lengthy doubling time of nearly thirteen days (Monot, 2005). It is anobligate endosymbiotic species; that is, it cannot survive apart from its host. This characteristic has led to significant reductive evolution: pseudogenes comprise half its genome.

However, what remained unclear was if all strains had experienced such reductive events, and how related said strains were. Using the genome sequence from a strain of M. leprae originating in Tamil Nadu, India- which could be identified after infecting armadillos with the strain and then extracting the DNA again- Monotet al.(2005) were able to hybridize the DNA to microarrays corresponding with the established strain and then perform quantiatative polymerase chain reaction (PCR). What they found was that the strains were strikingly similar: there did not appear to be any further gene loss, nor were there detectable differences in the copy number of repetitive sequences (RLEP, REPLEP, LEPREP, and LEPRPT).In the related M. tuberculosis, the mycobacterial interspersed repetitive unit (MIRU) is a major source of variation (Mazars, 2001), but scientists found that in all strains ofM. leprae, the 20 MIRU loci had identical sequences (Monot, 2005). However, extensive differences were seen within pseudogenes and noncoding regions of the genome.

Questions still remained about what implications these data had for genome topography and global organization. In order to detect single-nucleotide polymorphisms (SNPs), the researcherssequenced parts of a Brazilian strain, Br4923, examining pseudogenes and noncoding regions, as well as a selection of genes. Five SNPs were identified, three of which proved to be informative of multiple strains, and upon further analysis, it was discovered that when compared with other human pathogens, M. leprae had a far lower SNP frequency. Essentially, these findings demonstrate that not only is the genome highly conserved, but it is also highly clonal. These scientists expanded their research and, after analyzing the three informative SNPs in 175 samples from 21 countries and all five infected continents, they found that while there are 64 possible SNP types, only four actually exist. Additionally, they observed a correlation between the SNP profile and the origin of the patient. The map in Figure 1 below depicts their findings, with SNP type 1 represented in yellow, SNP type 2- the rarest- in orange, SNP type 3 in purple, and SNP type 4 in green. While it has been long believed that Alexander the Great’s Greek soldiers brought leprosy back to Europe from their campaign on the Indian subcontinent, which was then transferred westward through the colonial era, as well as further eastward from India, these data suggest alternative explanations. It is possible that SNP type 2 preceded SNP type 1, which was followed by SNP type 3 and SNP type 4, meaning that leprosy originated in East Africa and migrated eastward, giving rise to the variety found in Asia, as well as westward, giving rise to the colonial variety. It is from this strain that the trade variety of West Africa emerged. Likewise, it is also possible that that SNP type 1 emerged first, followed by types 2, 3, and 4.

Figure 1 (Monot, 2005)

As it turns out, understanding the genetics of M. leprae has enabled a greater understanding of the course of human history. Yet this knowledge does not stop here. Recent research in Croatia has demonstrated that leprosy has impacted humans not only in the broad level of migrations, but also at the basic level of genetics (Bakija-Konsuo, 2011). It was the Kingdom of Dubrovnik which established the first quarantine of leprosy patients, and in 1397, the Benedictine Monastary of St. Mary on the island of Mljet was turned into a leprosarium (Buklijaš, 2002 and Wokaunn, M. et al., 2006). For centuries, the population of Mljet has been isolated due to its location; also noteworthy is that neither major migrations nor infectious disease epidemics have take place there.

Recent research has implicated the PARK2- also known as the Parkin- gene, which maps to 6q25.2-q27, as well as the PACRG gene, which maps to 6q25-26 (Mira et al., 2004). These genes overlap, but more importantly are expressed in Schwann cells and macrophages, both of which are important host cells of M. leprae.Furthermore, Mira et al. (2004) showed that an analysis of two SNPslocated in the PACRGgene, rs9356058 and rs1040079,would capture all information regarding the association between the region and leprosy. Thus, the Croatian researchers sought to determine the impact of leprosy on the human genome by comparing these SNPs in the modern day population of Mljet with random samples from Rab, a nearby island with no history of leprosy chosen to mimic the geographic isolation of Mljet, and Split, a larger mainland city that also had no history of leprosy (Bakija-Konsou, 2011). They found a significant difference between the populations of Mljet and Rab with regard to the rs9356058 C allele. This difference was also seen when the populations of Mljet and Split were compared. Therefore, it appears that exposure to leprosy led to selection for the C allele as a protective factor against leprosy, supporting their hypothesis of PARK2’s protective nature.

Thus, leprosy has altered the human genome in subtle ways. Yet, given the persistent presence of leprosy across the globe today, it is not unreasonable to suspect that human genomes are not the only ones changing. Drug-resistant strains of leprosy have been reported for decades, and recent reports warn of strains emerging which are resistant to multiple drugs (Kai et al, 2011). If the goal of global leprosy elimination is to be met, it is paramount that any existing drug-resistant strains be identified and eliminated both quickly and thoroughly. To this end, Kai et al. (2011) conducted a series of molecular epidemiological studies on drug-resistant strains in regions of Vietnam where leprosy is endemic. Researchers took 423 samples of M. leprae from patients with cases of leprosy, and classified the cases as new (those prior to MDT), recent (those currently undergoing MDT), and relapse (those who had developed new lesions after the completion of therapy). They found that while there were no mutations in the rpoB(associated with the drug rifampicin) and gyrA(associated with the drug ofloxacin) gene samples, there were mutations in the folP1(associated with dapsone) gene. In 57% of relapse cases, M. leprae exhibited mutations in folP1, indicating that mutation rate and relapse are strongly correlated. Kai et al. (2011) suggested that this phenomenon could be due either to reinfection by the drug-resistant strain, or to reactivation of a strain which was able to persist after treatment. Additionally, 78% of patients who had either been previously treated with dapsonemonotherapy or had relapsed twice (once after dapsonemonotherapy, and once after MDT) exhibited mutations in this gene.This finding could have implications for treatment of relapse cases, in which MDT may be less effective due to the presence of dapsone-resistant M. leprae. Furthermore, related research in Brazil suggests that relapse in patients who live in areas endemic to leprosy could be due to infection by M. leprae with a different genotype than the original infecting strain (da Silva Rocha, 2011). Therefore, being “cured” of leprosy is no guarantee of future health, particularly for those living in endemic areas.

Though the threat of leprosy may be waning, for thousands of people, leprosy still is a very real problem. Fears of a resurgence of leprosy are not entirely unjustified, and an improved understanding of M. lepraewould better prepare health services worldwide for such an event. Better and more thorough treatment must be developed in order to ensure the elimination of dangerous drug-resistant strains. Additionally, as a disease which has wreaked havoc for millennia, it is worth understanding, and there is still much to learn. Even more worthwhile, however, is the fact that genes associated with leprosy, particularly the Parkinand the PACRG genes, are also associated with other pressing conditions, including Crohn’s disease, rheumatoid arthritis, psoriasis, Parkinson’s and Alzheimer’s. An improved understanding of this gene’s function could be the key to unlocking not only leprosy, but also a variety of other diseases. Perhaps now is the time for leprosy to do some good for the world.

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