Microbiol. Immunol.

, 45(11),729-736,2001

Minireview

Mycobacterium leprae and Leprosy: A Compendium

Shin Sasaki*'\ Fumihiko Takeshita', Kenji Okuda", and Norihisa lshil'

Departments of'Bioregulation and 'Microbiology, Leprosy Research Center; National Institute of Infectious Diseases,
Higashimurayama, Tokyo 189--0002, Japan, and 'Department of Bacteriology, Yokohama City University School of
Medicine, Yokohama, Kanagawa 236--0004, Japan

Received September 20,2001

Abstract: Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which was discovered by
G.H.A. Hansen in 1873. M. leprae is an exceptional bacterium because of its long generation time and no
growth in artificial media. Entire sequencing of the bacterial genome revealed numerous pseudogenes (inac-
tive reading frames with functional counterparts in M. tuberculosis) which might be responsible for the very
limited metabolic activity of M. leprae. The clinical demonstration of the disease is determined by the qual-
ity of host immune response. Thl-type immune response helps to kill the bacteria, but hosts are encroached
upon when Th2-type response is predominant. The bacteria have affinity to the peripheral nerves and are
likely to cause neuropathy. M. leprae/laminin-a2 complexes bind to alP dystroglycan complexes expressed
on the Schwann cell surface. WHO recommends a chemotherapy protocol [multidrug therapy (MDT)] which
effectively controls the disease and contributes to the global elimination program. Leprosy has been stig-
matized throughout history, and recent topics regarding the disease in Japan are also discussed.

Key words: Mycobacterium leprae, Leprosy, Pseudogene, Thlrrh2 dichotomy, Schwann cells

a karma in Buddhism; the term leprosy originates from

Historical and Global Situation
Leprosy, or Hansen's disease, is a chronic infectious
disease which primarily affects the skin, the peripheral
nerves, the upper respiratory tract, and also the eyes.
The causative microbe is an acid-fast bacterium, M. lep-
rae, which was identified in 1874 by the Norwegian
physician Gerhard Henrik Armauer Hansen. M. leprae
has several unique features, the most exceptional being
that no successful culture has ever been reported in
vitro. Leprosy has been documented since antiquity
and still continues to be endemic in some developing
countries, most of them located in tropical and subtrop-
ical zones. Throughout history, it has been feared as an
incurable disease which causes severe deformities and
disabilities resulting in stigmatization, and therefore the
victims have suffered both from the disease itself and
from public discrimination. Leprosy was considered
as a divine punishment for sin in the Old Testament and
the Latin word lepros, which means defilement (19).
In 1991, the World Health Organization (WHO) and
its Member States committed themselves to eliminate
leprosy as a public health problem by the year 2000
(37), elimination being defined as prevalence <
I case
per 10,000 persons. At the beginning of year 2000, the
deadline of the program, 641,091 leprosy cases were
registered for treatment and 678,758 cases were newly
detected in the world (38). The prevalence rate at the
global level is around 1.25 per 10,000 persons. Among
122 countries where the disease was considered endem-
ic in 1985, 98 countries reached the elimination goal, and
the global prevalence has been reduced by 86%. While
leprosy remains a public health problem in 24 coun-
tries, 677,086 newly detected patients live in the top 11
countries where the disease is endemic, and represent
92% of cases detected worldwide. The prevalence rate in
these top 11 countries remains 4.1 per 10,000, and the

Abbreviations: BB, mid-borderline; BL, borderline lepromatous;

*Address correspondence to Dr. Shin Sasaki, Department of
Bioregulation, Leprosy Research Center, National Institute of
Infectious Diseases, 4-2-1 Aoba-cho, Higashimurayama, Tokyo
189-0002, Japan. Fax: + 81-42-394--9092. E-mail: ssasaki@nih.
go.jp
BT, borderline tuberculoid; ENL, erythema nodosum leprosum;
IFN, interferon; IL, interleukin; LL, lepromatous; MB, multi-
bacillary; MDT, multidrug therapy; PB, paucibacillary; POL-I,
phenolic glycolipid I; RR, reversal reaction; Th cell, helper T
cell; TT, tuberculoid.

729
730 S. SASAKI ET AL

Table I. Registered prevalence of leprosy and detection rate in the top II countries where the disease is endemic
Country Registered cases Prevalence Cases detected Detection rate
(I January 2000) per 10,000 in 1999 per 100,000
India 495,073 5.0 537,956 54.3
Brazil 78,068 4.3 42,055 25.9
Myanmar 28,404 5.9 30,479 62.9
Indonesia 23,156 l.l 17,477 8.3
Nepal 13,572 5.7 18,693 78.7
Madagascar 7,865 4.7 8,704 51.6
Ethiopia 7,764 1.3 4,457 7.4
Mozambique 7,403 3.9 5,488 28.7
Congo DR 5,031 1.0 4,221 8.6
Tanzania UR 4,701 1.4 5,081 15.4
Guinea 1,559 2.0 2,475 32.0
Total 672,596 4.1 677,086 41.7
(WHO Weekly Epidemiological Record 75: 225-232, 2000)

Table 2. Comparison of genome features Taxonomically, M. leprae belongs to the genus

Feature M.leprae M. tuberculosis Mycobacterium, which is a single genus of the family
Genome size (bp) 3,268,203 4,411,532 Mycobacteriaceae, in the order Actinomycetales (26). M.
G+C (%) 57.79 65.61 leprae is an obligate intracellular parasite which measures
Protein coding (%) 49.5 90.8 0.3--o.5X4.Q-7.0!-lm and multiplies very slowly, with a
Protein-coding genes (no.) 1,604 3,959 generation time of 12 to 14 days. It grows best around 30
Pseudogenes (no.) 1,116 6 C, and hence it prefers the cooler areas of human bodies.
Gene density (bp per gene) 2,037 1,114
The bacterium can remain viable for several days ex
Average gene length (bp) 1,011 1,012
Average unknown gene length (bp) 338 653 vivo. The gram-positive type of the cell wall is highly
complex and contains proteins, phenolic glycolipid, ara-
(Nature 409: 1007-1011,2001)
binoglycan, peptideglycan, and mycolic acid, the latter
possibly being responsible for its acid-fastness. An
distribution is very uneven (Table 1). Of the 11 countries, antibody against phenolic glycolipid-I (PGL-I) of M.
India accounts for 80% of the detection and is a major leprae can be detected among the patients and healthy
concern for global leprosy control. In Japan, around individuals in area where the disease is endemic, sug-
20 patients a year are newly registered as having leprosy, gesting that the antibody levels reflect the bacterial loads
and more than 50% of the cases detected are among (6). Measurement of anti-PGL-I antibody could be use-
immigrants from countries where the disease is endem- ful in the assessment of patients and groups at highrisk
ic (12). The disease is generally more common in males for leprosy (3, 4), and provides serological parameters in
by a ratio of about 1.5 to 1 (36). monitoring patients following chemotherapy (6).
Although this antibody is useful for diagnostic purposes,
Bacteriology and Genomics of Mycobacterium leprae no neutralization activity against the leprosy bacillus
has been reported.
The pathogen of leprosy, M. leprae, cannot be cultured Considerable progress has been made in the field of
in artificial media, and therefore it is impossible to meet genomics, and the entire genome sequence of M. leprae
Koch's postulates. Instead, it multiplies extensively in has been analysed (8). The most striking feature of the
footpads of nude mice (31), nine-banded armadillos leprosy bacillus genome is the extensive deletion and
(Dasypus novemcinctus) (16), and, to a limited extent, in inactivation of genes referred to as gene degradation
normal mice footpads. Armadillos are also known to be (Table 2); only 49.5% of the genome contains protein-
an extrahuman reservoir of the leprosy bacillus, and coding genes, and 27% contains recognizable pseudo-
may playa role in the epidemiology of the disease in genes (inactive reading frames with functional counter-
humans in the southern and southwestern United States parts in the tuberculosis bacillus) (7, 8). Analysis ofthe
(18). Naturally acquired leprosy has been reported in genomic sequence revealed that the genes encoding var-
three species of non-human primates (chimpanzees, ious enzymes are replaced by pseudogenes (8), which
sooty mangabeys, and cynomolgus macaques), thus suggests limited metabolic activity of the leprosy bacil-
qualifying the disease as a zoonosis (28). lus. This genomic feature might correspond to its unique
 MINIREVIEW 731

bacteriological characteristics such as exceptionally slow
growth and failure to multiply in synthetic media. The
leprosy bacillus seems to be scrapping most of its genet-
ic inheritance in order to thrive, although it maintains
residual elements required to survive inside humans and
some other animals.
Disease Spectrum and Diagnostic Procedures
Infection with the leprosy bacillus, although it is a
unique pathogen, induces very diversifiedclinical features
corresponding to host's immune response. Leprosy
develops apparent polarity in the disease spectrum-
tuberculoid and lepromatous leprosy. Patients with
tuberculoid leprosy generally have a few large macular
hypopigmented or erythematous anaesthetic lesions
which have a well defined, often raised margin or occa-
sionally are scaly plaques (13). By contrast, lepromatous
leprosy is usually widespread and may consist of ery-
thematous macules, and papules and/or nodules. Occa-

Infection with M. leprae

No disease
(healthy carrier?)

Spontaneous cure Indeterminate group

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••

PB MB
negative Skin-smears positive
no Contagious? yes

Type 1 Dominant cytoklne Type 2

(IL-2, IFN-y) profile (ll-4, Il-5)

Fig. 1. Disease spectrum of leprosy (The Lancet 353 : 655-660. 1999; partially modified).
732 S. SASAKI
sionally the disease is diffuse without distinct lesions
(13). Borderline cases positioned in between these two
extremes are also found. It is agreed that crucial defense
at the battlefront against M. leprae is attained by cell-
mediated immunity, and therefore the outcome of infec-
tion depends how the host responds to the pathogen-the
magnitude of cell-mediated immunity determines the
extent of the disease (19).
Early pioneering works revealed an apparent rela-
tionship between the dominant cytokine profiles and
the clinical presentation of leprosy; interleukin 2 (lL-2)
and interferon gamma (IFN-y) were markedly dominant
in tuberculoid lesions, whereas IL-4, IL-5 and IL-I0
were characteristic of lepromatous lesions (30, 39).
Th 1-Th2 dichotomy is a central determinant of type of
host defense (5); the T helper type 1 (Thl) subset char-
acterized by predominant IL-2 and IFN-y preferentially
elicits cell-mediated immunity, whereas Th2 cells which
produce IL-4, 5, and 10 augment humoral immunity.
Both the classic reciprocal relation between antibody
production and cell-mediated immunity and resistance or
susceptibility to the leprosy bacillus can be explained by
T cell subsets differing in patterns of cytokine production.
As a mechanism responsible for T cell activation
against mycobacterium, the CD l-mediated lipid anti-
gen presentation pathway is notable (1, 20). It displays
a unique facet of host defense independent of classical
peptide antigen presentation through MHC molecules.
Recently, Ochoa et al discovered a novel mechanism
by which T cells contribute to host defense against
mycobacteria using a leprosy model (21). Granulysin, an
antimicrobial protein, is preferentially expressed by T
cells in tuberculoid lesions but not lepromatous lesions.
In vitro assay revealed that granulysin-expressing T cells
obtained from leprosy lesions were able to reduce the via-
bility of mycobacteria. This study indicates that gran-
ulysin plays a significant role in host defense against
mycobacteria including M. leprae.
Figure I illustrates the disease spectrum and classifi-
cation of leprosy. Recent epidemiological studies indi-
cate that transmission of the leprosy bacillus is effected
by airborne droplet infection through the respiratory
system, in which the nose plays a central role (9, 11,22).
It is believed that there is widespread subclinical trans-
mission of M. leprae with transient infection of the nose
in areas of endemicity, although most of these cases do
not develop clinical disease (reviewed in (34)). Accord-
ing to the Ridley-Jopling classification system (27), the
disease can be classified into 6 categories: indeterminate
(I), tuberculoid (TT), borderline tuberculoid (BT), mid-
borderline (BB), borderline lepromatous (BL), and lep-
romatous (LL) on the basis of dermatological, neuro-
logical, and histopathological findings. Most of the
ET AL
newly diagnosed patients, however, live in developing
countries where no sufficient medical resources are
available. Since the Ridley-Jopling classification system
is not practical in these countries, WHO established a
more simplified classification system which consists of
just two categories-paucibacillary (PB) and multi-
bacillary (MB) (36). PB leprosy is defined as five or
fewer skin lesions with no bacilli in skin smears, and MB
leprosy cases have six or more lesions and may be skin-
smear positive. As for the correlation between two clas-
sification systems, I, TT, and part of BT are generally
equivalent to PB leprosy, and part of BT, BB, BL, and LL
correspond to MB leprosy. Figure 2 shows the flowchart
for diagnosis and classification cited from an atlas
designed for use in the areas of endemicity (17). The
procedure is very simple and clear, so that patients can be
diagnosed and classified without satisfactory medical
facilities or staff. In advanced countries, for example in
Japan, the Ridley-Jopling classification is generally used
and in-depth examination is preferentially attempted by
using histopathological, serological, and molecular bio-
logical tests.
Leprous Nerve Damage
Peripheral nerves are also a major target of the leprosy
bacillus. The involvement of nerves by the primary
infection and the immunologically mediated episodes
referred to as leprosy reactions result in impairment of
nerve function and severe disabilities. Leprosy causes a
'mononeuritis multiplex' which results in autonomic,
sensory, and motor neuropathy. When detected and
treated appropriately, primary impairments can be
reversible. Actually, skin lesions with sensory distur-
bance are a persuasive clue to suspicion of leprosy.
Most of the nerve destruction in leprosy, however,
takes place during the leprosy reaction which consists of
reversal reaction (RR; type 1 reaction) and erythema
nodosum leprosum (ENL; type 2 reaction). In RR, the
level of cell-mediated immunity against M. leprae is
suddenly elevated and results in an inflammatory
response in the areas of the skin and nerves affected by
the disease. Acute inflammation in RR can destroy
nerves and result in paralysis which can be permanent if
not treated adequately (29). Clinically detectable neu-
ral involvement occurs in approximately 10% of PB
and 40% of MB leprosy patients (33).
How does the leprosy bacillus invade into peripheral
nerves? M. leprae has an extreme predilection for the
Schwann cells which surround peripheral nerve axons
(23). A recent study has demonstrated that the species-
specific PGL of M. leprae triggers uptake into Schwann
cells by creating a complex with laminin-2 (24), an
 MINIREVIEW 733

................. Skin lesions with

:@~~:,~t~~·~~.~~·: .:':::»> sensory loss
:~;'-\.~~~L1.J:.f::

Leprosy
••
..... •
" ·.:::·v:-.'·.· .

ire• •I}·.;;:·
...• •• ••.•• ..•==:.:::::JI~==;;;;..:.:::::,..
-:.:--.:-:..-:-:.:.:-: :-::;:O;.:::; ::::::::::»:!'"-:"-'.:-:;;.:.-:-,'; ; .:-:,;.:. ""
.. o:.;L;;.:.;;.:. -.:.-.:.4:::.:::::I

Up to 5 skin
lesions
:«:-: ....:-::.. ::/.::::
..........<.;.:.;......
~1IIII!I!I1IIII!I!I~lI,I!IIlIIII!I!IlIIII!I!I
:-:' :.:.•. :.-:.;.:.:.: :.: :.: :.•.::..
.... .... :: ..... . . .:-:.•:-::-:-:.:«::: ...

MB leprosy

Fig. 2. Flowchart for diagnosis and classification of leprosy (A New Atlas of Leprosy, Sasakawa Foundation, Tokyo).

extracellular matrix protein that is present in the basal gested as a responsible for the Schwann cell damage
lamina of Schwann cells. A 21 kDa laminin binding (15). For treatment of leprous neuropathy associated with
receptor on M. leprae has also been identified (32), RR, administration of corticosteroids along with anti-lep-
being a histone-like protein. Then, M. leprae/laminin-a2 rosy chemotherapy is required to prevent irreversible
complexes bind to alP dystroglycan complexes expressed damage.
on the Schwann cell surface (25). Although it is still a
controversial point, Schwann cells are considered to Treatment and Control Strategy
express MHC class II molecules (reviewed in 33). Thus,
a possible mechanism for peripheral nerve damage in RR Leprosy control has three major strategic compo-
is that infected Schwann cells process and present anti- nents: Early detection of patients, adequate treatment, and
gens derived from M. leprae to antigen-specific, inflam- provision of comprehensive care for the prevention of
matory type I T cells and that these T cells subsequent- disabilities and rehabilitation (10). Since the disease is
ly attack and lyse infected Schwann cells (33). caused by infection, needless to say, treatment with
Besides the above mechanism, non-specific inflam- antibiotics against the leprosy bacillus plays a pivotal role
matory effect mediated by TNF-a and TGF-p is also sug- in managing newly diagnosed patients. There are several
734 S. SASAKI
effective chemotherapeutic agents against M. leprae.
Dapsone (diaphenylsulfone: DDS), rifampicin (RFP),
clofazimine (CLF, B663), ofloxacin (OFLX), and
minocycline (MINO) are commonly used in the clinical
field today, since they are components of the multidrug
therapy (MDT) regimen recommended by WHO (36).
Following the classification according to the flowchart
(Fig. 2), PB patients receive 600 mg RFP monthly,
supervised, and 100 mg DDS daily, unsupervised, for 6
months. Single-lesion PB (SLPB) patients can be treat-
ed with a single therapeutic dose consisting of 600 mg
RFP, 400 mg OFLX, and 100 mg MINO. MB cases are
treated with 600 mg RFP and 300 mg CLF monthly,
supervised, and 100 mg DDS and 50 mg CLF daily,
for 12 months.
Leprosy reaction can occur in all borderline and lep-
romatous patients, most commonly during chemothera-
py. Borderline cases develop type 1 reaction (RR), and
type 2 reaction (ENL) takes place in lepromatous patients
(13,33). The common treatment for reaction episodes is
the use of corticosteroids (36), and thalidomide and/or
CLF are also used for ENL cases (13). Prompt and
adequate treatment of leprosy reaction along with anti-
leprosy chemotherapy is the key to preventing irre-
versible nerve damage and disabilities. In the unfortunate
case that permanent impairment occurs, patients should
be given a course of rehabilitation. Since the outcome of
leprosy affects physical, mental, and socio-economical
aspects of patients, a rehabilitation program should ide-
ally cover all of these aspects (reviewed in 35).
From the viewpoint of prevention of the disease, vac-
cination against the leprosy bacillus is a possible strate-
gy-BCG vaccination is reported to be partially effective
for protection against leprosy (2, 14). But a worldwide
BCG vaccination program against M. leprae is not eco-
nomically feasible (13), and a cost-effective DNA vaccine
could become a promising substitute. At present, no vac-
cination against leprosy is currently available, so adequate
treatment with MDT is only weapon available against M.
leprae in pursuing a global leprosy control program.
Social Sequelae from Leprosy in Japan
Leprosy occupies a very special place in the history of
medicine worldwide; it was extremely feared and con-
sidered one of the most despicable diseases. The victims
were despised and often isolated in "leper" colonies or
leprosariums. Even today, patients are likely to be
shunned by their neighbors and contact is avoided. Par-
ticularly in Japan, the state enforced a "leper" isolation
policy based on the 1953 Leprosy Prevention Law. The
policy was continued even after publication of the advi-
sory by the WHO Expert Committee on Leprosy in
ET AL
1959, in which repeal of special statute for leprosy con-
trol was encouraged. Once diagnosed as having leprosy,
patients were confined in national leprosariums and
strictly isolated from the general public. A considerable
number of women at the leprosarium were forced to
have abortions and men were sterilized. The law con-
tinued up to 1996, long after the development of effective
antibiotics against the leprosy bacillus and after studies
proving that the disease was not as contagious as once
believed.
Former patients launched a lawsuit against the state.
The plaintiffs demanded compensation for inadequate
treatment while they lived in isolated facilities operated
by the state. A verdict was reached and year 2001
became a milestone for the victims of leprosy in Japan.
The May 11 ruling by Kumamoto District Court found
that the Diet contravened the constitution and the Health
Ministry violated human rights by isolating the patients
in national leprosariums for under the 1953 law. It
ordered the government to pay a total of 1.8 billion yen
($15 million) to 127 plaintiffs. Prime Minister Junichi-
ro Koizumi on May 25 announced a government decision
not to appeal the ruling, which ordered the state to pay
compensation to former patients. Following the state-
ment by Koizumi, a bill was passed by the Diet to assure
compensation not only for the plaintiffs but also for all
former leprosarium internees. In addition to the
announcement of a compensation package, the state
officially apologized to the patients for inadequate treat-
ment under the 1953 law. The former patients accepted
the apology from the state, lawsuits still pending were
dropped and a settlement was reached between the plain-
tiffs and the state.
The ruling and official apology by the state provide an
occasion for serious consideration of the miserable his-
tory of leprosy patients. Should the state alone bear
the blame for the isolation policy? Would patients have
been able to join the public community without hin-
drance if the law had been repealed earlier? Why was the
disease stigmatized and the victims were despised
throughout history?
About 4,400 people are still living in 15 leprosariums
nationwide despite the termination of the isolation poli-
cy. Most of them are elderly people who feel that they
will bring humiliation to their relatives if they return
home.
This work was supported by a Health Science Research Grant
of Research on Emerging and Re-emerging Infectious Diseases
from the Ministry of Health, Labor, and Welfare, Japan.
 MINIREVIEW
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