Leprosy: The Social Disease

Leprosy is known as the Death before Death; a disease of unparalleled historical stigma and fear that has earned the appellation kushtha, ‘eating away.’ Today, whilst its effects are none the less awful, it is known under the more innocuous title of Hansen’s Disease. In 1948, Dr. Earnest Muir wrote that leprosy was the most dreaded disease—ironically, not because it kills, but rather, because it leaves its victims alive. Leprosy and humans have a long, bitter relationship. Though it has plagued us since at least 2000 BC, we barely understand it four thousand years later and we are still wrestling with its legacy of stigmatization.

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Source: Wikimedia

Meet the Microbes

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Photo source: bioweb.uwlax.edu

The pathogen behind most leprosy cases is Mycobacterium leprae, whose discovery in 1873 by Armauer Hansen was pretty darned epic as it was the first bacterium to be associated with any human disease[3]! Despite the fact that it was the first-ever identified bacterial pathogen, we know very little about it. When Hansen discovered M. leprae, he had little idea that M. leprae would become a source of endless frustration for researchers: a pathogen that, to this very day, resists all attempts to culture it in vitro (isolated from a host). This problem stems from the fact that the bacterium is an obligate intracellular parasite; it can only survive inside of host cells. While this pathogen evolved over the millennia inside its hosts, it lost over 1,500 genes, including ones that program the metabolic pathways necessary for the bacteria to create various compounds and energy required for life[7]. Consequently, it now completely relies on its host to survive. While this so-called genome reduction is common in most intracellular parasites, M. leprae is famous for taking it a step further, with a higher number of non-functioning genes and amount of DNA relative to any other bacteria or archaea [10].

Scientists study this microbe by culturing it on the feet of mice and armadillos, but we have no animal models that accurately mimic the human disease[10]. While this limitation has caused the physiology and mechanism of pathogenesis to remain mostly a mystery to this day, various characteristics of these pathogens have been identified [7]. M. leprae are non-motile, non-spore-forming, rod-shaped bacteria. They are incredibly slow-growing, with one of the longest known generation times for bacteria (12-14 days), and they prefer to grow at 33°C (91°F)[10]. This explains why leprosy tends to be focused in the extremities, as the core temperature of humans is 37°C (98.6°F) and the periphery is marginally cooler.

The first genome of M. leprae was sequenced in 2001. Further sequencing has shown that the strains found worldwide are nearly identical (99.99%) and has also allowed us to identify their genes. Researchers are currently working on identifying each of the 1604 proteins and their functions, which will help us understand more about this mysterious blighter[7,10].

Humans are the main reservoir of M. leprae, although it has also been found in nine-banded armadillos and various primates[10]. More recently, a second species of Mycobacterium has been identified as a causal agent of leprosy: Mycobacterium lepromatosis. This strain is 90% similar to M. leprae, and diverged an estimated 10 million years ago. It causes diffuse lepromatous leprosy, a version of leprosy that causes a heavy bacterial burden in the organs of patients instead of being isolated to the peripheral nervous system (bear with me, this will be discussed later!)[11].

Leprosy

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Source: kardzmed, wikimedia

Leprosy is one of the oldest diseases, and possibly the most dreaded. It has caused social stigma and ostracism unrivaled by any other disease, worming its way into human religions, literature, art, and society[3]. And yet, despite its insidious and constant association with us for over four-thousand years, we understand little about both the pathogen and the disease itself. While the prevalence of leprosy has plummeted since the 1400s, there are still over 200,000 cases each year (in 2011, 105 countries reported 219,075 cases)[3]. The majority of these cases arise in India, followed by Brazil, Indonesia, Bangladesh, the Democratic Republic of the Congo, Ethiopia, Nepal, and Nigeria. It is a worldwide disease that also influences first world countries: in the United States, there are over 300 cases a year[7].

M. leprae has an incredibly long incubation period. After infection, it can take anywhere from 5 to 40 years for the symptoms to present. The transmission of the disease is poorly understood, but is believed to be from exposure to airborne droplets breathed out by an infected patient. However,  M. leprae is actually not very virulent, and, contrary to age long belief, most leprosy patients are not infectious[10]. Furthermore, 95% of modern humans are genetically resistant to leprosy[1,5]!

If acquired, leprosy primarily affects the skin, nerves, and eyes. It has a wide range of clinical manifestations as the disease severity relies heavily upon an individual’s unique immune response. Patients often first complain of weakness and numbness in the hands and feet, possibly accompanied by an ulcer. The disease causes light-colored skin lesions to form that resist healing, a loss of sensation in the peripheral limbs, numbness, and muscle weakness. The nerve damage can cause lifelong disfigurement and paralysis. The disease is classified depending on the severity of the symptoms; paucibacillary leprosy describes milder cases with under five lesions, while multibacillary leprosy describes cases where there are over five lesions, along with nodules, thickened sections of skin, and possible nasal mucosa infection[10].  The Ridley-Jopling scale is also widely used, consisting of six different classifications across a spectrum: indeterminate, tuberculoid (rapid and severe nerve damage), borderline tuberculoid, mid-borderline, borderline lepromatous, and lepromatous (chronic, more lesions and long-term complications)[3,4].

Pathogenesis

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Upon infection, M. leprae survives inside of macrophages and Schwann cells. Consequently, leprosy is an infection of the peripheral nervous system (the nervous system sans the brain and spinal cord)[3]. While macrophages are immune cells that recognize and engulf pathogens such as M. leprae, the bacterial pathogen has evolved mechanisms to parasitize the macrophages and alter their lipid balance in order to create the perfect little cellular-abode[10].  Further, mechanisms have been identified that allow M. leprae to decrease the immune response and thus persist within the Schwann cells[9]. Once inside these cells, the bacteria proliferate but they do not produce any toxins and, in fact, have an extremely low virulence level. The problems seem to arise due to the immune response to the bacterial load, with inflammation and fibrosis causing nerve injury[4,7].

There are two main reactions to a leprosy infection that affect 30-50% of patients and cause various complications. Reversal Reactions, or Type 1 reactions, are inflammatory immune responses that damage nerves and cause allergic responses that form bumps and swelling in the skin as well as injure nerves causing tenderness and a loss of function. Eye damage is also a hallmark of reversal reactions. Erythema nodosum leprosum, or Type 2 reactions, occur in patients with higher numbers of the bacteria in their bodies. These reactions cause swelling in the eye, nerve inflammation, damage, and death, swollen lymphnodes, bone pain, arthritis, and swollen fingers or toes[3,10].

The damage done to the nerve by inflammation initially presents as a loss of sensation as the nerve stops functioning. Untreated, nerve death will cause paralysis and deformities. Hands and toes are often described as being frozen into claws. The loss of sensation combined with the deformities increases the risk of the development of ulcers or undetected injuries which, if untreated, lead to secondary infections and tissue death. These secondary infections are what cause the loss of digits or limbs. Leprosy will gradually spread over the entire body, infecting the tissue in the throat and nose, damaging vision and causing extremities to become malformed. Bumps and lesions in the skin form due to the immune response to high numbers of the bacteria[3,4,8]. Thanks to this pathogenesis, leprosy is the leading cause of permanent physical disability due to infectious disease[10].

History

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library.rit.edu

While we cannot be completely certain that the skin diseases described in ancient texts refer to leprosy, it is likely that leprosy has an old relationship with our species. Skeletons that were buried around 2000 BC have been examined, and tests suggest that their owners suffered from leprosy. The oldest written record we have of leprosy dates back to 1550 BC, when it was described in an ancient Egyptian papyrus scroll. Around 1500 BC, the Laws of Manu were written in what is now India. The laws describe skin diseases that have been translated as leprosy and prohibit contact with the people suffering from the disease, describing punishment for people marrying families with infected members. This marks the first historical record of the stigma that dogged leprosy victims due to physical disfigurement. Shortly after, leprosy was mentioned in the Mosaic Law, where illness is described as a punishment for sin and leprosy itself for the most serious crimes. Clinical descriptions dated to around 1400 BC also exist, and in 600 BC we get the name kushtha from India, which translates as ‘eating away[3].’

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Source: wikimedia

While we do not know the size or reach of ancient leprosy outbreaks, the disease appears to have originated in India or Africa. Leprosy then spread through Asia to Europe in the 4th and 5th century BC, thanks to the military campaigns of Alexander the Great (skeletal remains identified with leprosy have been found in Egypt and Thailand, dated to 300-400 BC)[3,6]. The Roman conquering of Egypt, along with trade and army movements, spread  leprosy into the Middle East and Greece. During these ancient times, the disease’s social stigma was reinforced. Prevention of the disease was sought through dictating the behavior of those suffering from leprosy, along with cultural practices and religious doctrines intensifying segregation. Ancient legends in China and Africa attributed the disease to deviant behavior such as incest and necrophilia, promoting the belief that the disease was caused by sin[3,6].

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Source: wikimedia

After the fall of the Roman Empire, leprosy persisted worldwide, and remained the most feared disease in Europe until the Black Death struck in the 1300’s. In the two centuries before the Black Death, leprosy was pervasive, possibly infecting a quarter of northern Europeans. Those suffering from leprosy were ejected from society, forced to wear cloaks and announce their presence with a bell or rattle while crying out, “unclean, unclean!” When the plague struck in the form of the Black Death, the leper population, rendered vulnerable by their illness, was decimated. This led to a brief lull in European leprosy cases, until it escalated in the 17th century in Norway, Iceland, and England [5].

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Source: dspace.hil.unb.ca

The last endemic outbreak in leprosy peaked in the mid 1830’s, with 3,000 cases in Norway. During this outbreak, Daniel Danielssen and Carl Boeck published a book characterizing the disease. This book is recognized as the first authoritative publication that distinguishes leprosy from other diseases[3]. In the 1840’s, there was an outbreak in Canada during which patients were kept quarantined in lazarettos, aided by the erection of  12-foot fences; the similarity to prison was not lost on the sufferers, and several protests occurred in the form of arson. Outbreaks shadowed by social exclusions continued worldwide, while the scientific community debated the cause of leprosy. Danielssen and Boeck’s book claimed the disease was hereditary, a belief which persisted until a British physician, Dr. Jardine, attributed it to miasma: “a degeneration which flourishes among a variety of climates, of soils, of stable articles of food, and of race.[3]” It wasn’t until 1873 that the actual agent, M. leprae, was identified by Gerhard Armauer. Despite the cause being identified as bacterial, there was little change in the management and social stigma[3].

During the twentieth century, discrimination and fear continued to shadow leprosy. In the 1930’s, Japan underwent the “no leprosy patients in prefecture” movement. Driven by the belief that leprosy was shameful, the Japanese demanded isolation of all patients in order to preserve the purity of the nation. Meanwhile, in the United States, some states allowed sheriffs to arrest and confine people based on the suspicion that they had leprosy. In China in 1937, eighty people with leprosy—including women and children–were shot and thrown into a pit. In India, the Motor Vehicles Act of 1939 made it illegal for those with leprosy to get drivers licenses, and the Indian Christian, Muslim, and Hindu Marriage Acts listed leprosy as grounds for divorce. In Korea during the late 1950’s a mob beat leprosarium patients to death. Against this backdrop of ignorance, fear, and violence, the scientific field struggled to classify leprosy, starting in 1931 and culminating in Ridley and Jopling’s 1966 paper in which they listed the six types of leprosy based on clinical, histological, and immunological criteria[3].

Despite the fact that leprosy is now curable, the cause well known, and we consider ourselves quite a forward world, we have not been able to shake the stigmatization of leprosy. In most Indian languages leprosy is still called kushta, a term associated with thousands of years of loathing and fear. Leper colonies still exist in India, China, Romania, Egypt, Nepal, Somalia, Liberia, Vietnam, and Japan–despite the fact that with treatment, leprosy patients are not contagious[3,5].  At the same time, scientific knowledge of the pathogen and disease is rapidly growing, with treatments and hopes for complete eradication of the disease being frequent topics of papers.

Biological Weapon

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As many of the diseases and pathogens I have previously discussed have included a section on biological warfare, I thought I should be consistent: I am pleased to announce that M. leprae is not considered a potential biological weapon! The fact that we have effective treatment, not to mention 95% of us are resistant, and the inability to grow the pathogen outside of living creatures renders Mycobacterium leprae astonishingly ineffective as far as weapons go.  But, you know, if it starts raining armadillos from enemy planes I’d recommend staying indoors.

Treatment

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Until 1941, the only treatment for leprosy was the use of chaulmoogra oil, extracted from the seeds of Hydnocarpus wightiana. This oil was utilized for 2,500 years, dating back to records found in 600 BC. In the 1900’s, the oil was even injected into infected patients. At around the same time, a compound called Promin was being tested for use against Tuberculosis. As leprosy and tuberculosis are both caused by species of Mycobacterium, it was tested for leprosy as well. This led to the creation of Dapsone (the parent compound of Promin) being created in 1941 as the first effective drug against M. leprae. This cured patients of leprosy, although no treatment can reverse the nerve damage and paralysis. Unfortunately, M. leprae rapidly gained resistance to this drug, giving rise to the modern approach of Multi-Drug Treatment in 1981[3]. Between 1981 and 2011, over 18 million cases of leprosy have been treated through this method, which utilizes dapsone, rifampicin, and (in multibacillary cases) clofazimine. There are a couple drawbacks to this treatment. First, when treating paucibacillary patients, only dapsone and rifampicin are being administered. As M. leprae has a resistance to dapsone in some patients, this means they are only receiving rifampicin treatment which is increasing the risk and rate of M. leprae resistance to this drug. Second, the multi-drug treatment lasts for 6 to 12 months, however in over 15% of cases assessed six months after finishing the treatment, viable M. leprae were detected. This suggests that some of the bacteria manage to survive the treatment, through either dormancy or resistance[3,4,10].

Due to the increasing problem of antibiotic resistance, and with the desire to completely eradicate leprosy, modern research is beginning to examine options in chemotherapeutic regimes, immunotherapy, and vaccination. These studies are hampered by our inability to culture M. leprae in vitro, resulting in more speculation than actual success. The most successful exploration into a vaccine involves the vaccine BCG, which is used to vaccinate against tuberculosis. As the species are related, this vaccine shows some success against leprosy, with protection levels ranging between 20-80%[3,4].

References

[1] Alter, A. et al. “Leprosy as a genetic disease.” Mamm Genome. 2011. 22:19-31.

[2] Casanova, J-L. and Laurent, A. “Human genetics of infectious diseases: a unified theory.” The EMBO Journal. 2007. 26: 915-922.

[3] Dogra, S. et al. “Leprosy – evolution of the path to eradication.” Indian Journal Medical Research. 2013. 137:15-35.

[4] Duthie, M. et al. “Advances and hurdles on the way to a leprosy vaccine.” Human Vaccines. 2011. 7(11):1172-1183.

[5] Gould, Tony. A Disease Apart: Leprosy in the Modern World. New York: St. Martin’s, 2005.

[6] “History of Leprosy.” Stanford University. Web. 24 Feb. 2012. http://www.stanford.edu/class/humbio103/ParaSites2005/Leprosy/history.htm

[7] Parkash, O. and Singh, B. “Advances in proteomics of Mycobacterium leprae.” Scandinavian Journal of Immunology. 2012. 369-378.

[8] Petito, R. et al. “Transforming growth factor-Beta1 may be a key mediator of the fibrogenic properties of neural cells in leprosy.” J Neuropathology Exp Neurology. 2013. 72(4):351-366.

[9] Spencer, J. and Brennan, P. “The role of Mycobacterium leprae phenolic glycolipid I (PGL-I) in serodiagnosis and in the pathogenesis of leprosy.” Leprosy Review. 2011. 82(4):344-357.

[10] Suzuki, K. et al. “Current status of leprosy: epidemiology, basic science, and clinical perspective.” Journal of Dermatology. 2012. 39:121-129.

[11] Vera-Cabrera, Lucio et al, “Case of Diffuse Lepromatous Leprosy Associated with “Mycobacterium lepromatosis.” 2011. J Clin Microbiology. 49(12):4366-4368.

 

 

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