Mycobacterium leprae
Encyclopedia
Mycobacterium leprae, also known as Hansen’s coccus spirilly, mostly found in warm tropical countries, is a bacterium that causes leprosy
(Hansen's disease). It is an intracellular, pleomorphic, acid-fast
bacterium. M. leprae is an aerobic
bacillus (rod-shaped) surrounded by the characteristic waxy coating unique to mycobacteria
. In size and shape, it closely resembles Mycobacterium tuberculosis
. Due to its thick waxy coating, M. leprae stains with a carbol fuscin rather than with the traditional Gram stain. The culture takes several weeks to mature.
Optical microscopy shows M. leprae in clumps, rounded masses, or in groups of bacilli side by side, and ranging from 1-8 μm
in length and 0.2-0.5 μm in diameter.
It was discovered in 1873 by the Norwegian physician Gerhard Armauer Hansen
, who was searching for the bacteria in the skin nodules of patients with leprosy. It was the first bacterium to be identified as causing disease in humans.
The organism has never been successfully grown on an artificial cell culture media. Instead, it has been grown in mouse foot pads and more recently in nine-banded
armadillo
s because they, like humans, are susceptible to leprosy. This can be used as a diagnostic test for the presence of bacilli in body lesions of suspected leprosy patients. The difficulty in culturing the organism appears to be because it is an obligate intracellular parasite
that lacks many necessary genes for independent survival. The complex and unique cell wall that makes members of the Mycobacterium
genus difficult to destroy is apparently also the reason for the extremely slow replication rate.
Virulence factors include a waxy exterior coating, formed by the production of mycolic acid
s unique to Mycobacterium
.
M. leprae was sensitive to dapsone
(diaminodiphenylsulfone, the first effective treatment which was discovered for leprosy in the 1940s), but resistance
against this antibiotic
has developed over time. Therapy with dapsone alone is now strongly contraindicated. Currently, a multidrug treatment (MDT) is recommended by the World Health Organization
, including dapsone
, rifampicin
and clofazimine
. In patients receiving the MDT, a high proportion of the bacilli
die within a short amount of time without immediate relief of symptoms. This suggests many symptoms of leprosy must be due in part to the presence of dead cells.
sequence of M. leprae with that of Mycobacterium tuberculosis
provides clear explanations for these properties, and reveals an extreme case of reductive evolution
. Less than half of the genome contains functional genes
. Gene deletion and decay appear to have eliminated many important metabolic activities, including siderophore
production, part of the oxidative and most of the microaerophilic and anaerobic
respiratory
chains, and numerous catabolic systems and their regulatory circuits.
The genome sequence of a strain of M. leprae, originally isolated in Tamil Nadu
and designated TN, has been completed recently. The sequence was obtained by a combined approach, employing automated DNA
sequence analysis of selected cosmids and whole-genome 'shotgun' clones. After the finishing process, the genome sequence was found to contain 3,268,203 base pair
s (bp), and to have an average G+C content
of 57.8%, values much lower than the corresponding values for M. tuberculosis, which are 4, 441,529 bp and 65.6% G+C,. About 1500 genes are common to both M. leprae and M. tuberculosis. The comparative analysis suggests both mycobacteria derived from a common ancestor and, at one stage, had gene pool
s of similar size. Downsizing from a genome of 4.42 Mbp, such as that of M. tuberculosis, to one of 3.27 Mbp would account for the loss of some 1200 protein
-coding sequences. There is evidence that many of the genes that were present in the genome of the common ancestor of M. leprae and M. tuberculosis have been lost by recombination in the M.leprae genome.
Information from the completed genome can be useful to develop diagnostic skin tests, to understand the mechanisms of nerve damage and drug resistance and to identify novel drug targets for rational design of new therapeutic regimens and drugs to treat leprosy and its complications.
1) Hypopigmented or reddish skin patches with definite loss of sensation
2) Thickened peripheral nerves
3) Acid-fast bacilli on skin smears or biopsy material
Leprosy
Leprosy or Hansen's disease is a chronic disease caused by the bacteria Mycobacterium leprae and Mycobacterium lepromatosis. Named after physician Gerhard Armauer Hansen, leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions...
(Hansen's disease). It is an intracellular, pleomorphic, acid-fast
Acid-fast
Acid-fastness is a physical property of certain bacteria, specifically their resistance to decolorization by acids during staining procedures.Acid-fast organisms are difficult to characterize using standard microbiological techniques Acid-fastness is a physical property of certain bacteria,...
bacterium. M. leprae is an aerobic
Aerobic organism
An aerobic organism or aerobe is an organism that can survive and grow in an oxygenated environment.Faculitative anaerobes grow and survive in an oxygenated environment and so do aerotolerant anaerobes.-Glucose:...
bacillus (rod-shaped) surrounded by the characteristic waxy coating unique to mycobacteria
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
. In size and shape, it closely resembles Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
. Due to its thick waxy coating, M. leprae stains with a carbol fuscin rather than with the traditional Gram stain. The culture takes several weeks to mature.
Optical microscopy shows M. leprae in clumps, rounded masses, or in groups of bacilli side by side, and ranging from 1-8 μm
Micrometre
A micrometer , is by definition 1×10-6 of a meter .In plain English, it means one-millionth of a meter . Its unit symbol in the International System of Units is μm...
in length and 0.2-0.5 μm in diameter.
It was discovered in 1873 by the Norwegian physician Gerhard Armauer Hansen
Gerhard Armauer Hansen
Gerhard Henrik Armauer Hansen was a Norwegian physician, remembered for his identification of the bacterium Mycobacterium leprae in 1873 as the causative agent of leprosy....
, who was searching for the bacteria in the skin nodules of patients with leprosy. It was the first bacterium to be identified as causing disease in humans.
The organism has never been successfully grown on an artificial cell culture media. Instead, it has been grown in mouse foot pads and more recently in nine-banded
Nine-banded Armadillo
The nine-banded armadillo , or the nine-banded, long-nosed armadillo, is a species of armadillo found in North, Central, and South America, making it the most widespread of the armadillos...
armadillo
Armadillo
Armadillos are New World placental mammals, known for having a leathery armor shell. Dasypodidae is the only surviving family in the order Cingulata, part of the superorder Xenarthra along with the anteaters and sloths. The word armadillo is Spanish for "little armored one"...
s because they, like humans, are susceptible to leprosy. This can be used as a diagnostic test for the presence of bacilli in body lesions of suspected leprosy patients. The difficulty in culturing the organism appears to be because it is an obligate intracellular parasite
Obligate intracellular parasite
Intracellular parasites are parasitic microorganisms - microparasites that are capable of growing and reproducing inside the cells of a host.-Facultative:...
that lacks many necessary genes for independent survival. The complex and unique cell wall that makes members of the Mycobacterium
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
genus difficult to destroy is apparently also the reason for the extremely slow replication rate.
Virulence factors include a waxy exterior coating, formed by the production of mycolic acid
Mycolic acid
Mycolic acids are long fatty acids found in the cell walls of the mycolata taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of mycolata species...
s unique to Mycobacterium
Mycobacterium
Mycobacterium is a genus of Actinobacteria, given its own family, the Mycobacteriaceae. The genus includes pathogens known to cause serious diseases in mammals, including tuberculosis and leprosy...
.
M. leprae was sensitive to dapsone
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
(diaminodiphenylsulfone, the first effective treatment which was discovered for leprosy in the 1940s), but resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
against this antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
has developed over time. Therapy with dapsone alone is now strongly contraindicated. Currently, a multidrug treatment (MDT) is recommended by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
, including dapsone
Dapsone
Dapsone is a medication most commonly used in combination with rifampicin and clofazimine as multidrug therapy for the treatment of Mycobacterium leprae infections . It is also second-line treatment for prophylaxis against Pneumocystis pneumonia caused by Pneumocystis jiroveci Dapsone...
, rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
and clofazimine
Clofazimine
Clofazimine is a fat-soluble riminophenazine dye used in combination with rifampicin and dapsone as multidrug therapy for the treatment of leprosy. It has been used investigationally in combination with other antimycobacterial drugs to treat Mycobacterium avium infections in AIDS patients and...
. In patients receiving the MDT, a high proportion of the bacilli
Bacilli
Bacilli refers to a taxonomic class of bacteria. It includes two orders, Bacillales and Lactobacillales, which contain several well-known pathogens like Bacillus anthracis .-Ambiguity:...
die within a short amount of time without immediate relief of symptoms. This suggests many symptoms of leprosy must be due in part to the presence of dead cells.
Mycobacterium leprae genome
Mycobacterium leprae has the longest doubling time of all known bacteria, and has thwarted every effort at culture in the laboratory. Comparing the genomeGenome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
sequence of M. leprae with that of Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
provides clear explanations for these properties, and reveals an extreme case of reductive evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
. Less than half of the genome contains functional genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
. Gene deletion and decay appear to have eliminated many important metabolic activities, including siderophore
Siderophore
Siderophores are small, high-affinity iron chelating compounds secreted by grasses and microorganisms such as bacteria and fungi...
production, part of the oxidative and most of the microaerophilic and anaerobic
Anaerobic respiration
Anaerobic respiration is a form of respiration using electron acceptors other than oxygen. Although oxygen is not used as the final electron acceptor, the process still uses a respiratory electron transport chain; it is respiration without oxygen...
respiratory
Respiration (physiology)
'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...
chains, and numerous catabolic systems and their regulatory circuits.
The genome sequence of a strain of M. leprae, originally isolated in Tamil Nadu
Tamil Nadu
Tamil Nadu is one of the 28 states of India. Its capital and largest city is Chennai. Tamil Nadu lies in the southernmost part of the Indian Peninsula and is bordered by the union territory of Pondicherry, and the states of Kerala, Karnataka, and Andhra Pradesh...
and designated TN, has been completed recently. The sequence was obtained by a combined approach, employing automated DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
sequence analysis of selected cosmids and whole-genome 'shotgun' clones. After the finishing process, the genome sequence was found to contain 3,268,203 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s (bp), and to have an average G+C content
GC-content
In molecular biology and genetics, GC-content is the percentage of nitrogenous bases on a DNA molecule that are either guanine or cytosine . This may refer to a specific fragment of DNA or RNA, or that of the whole genome...
of 57.8%, values much lower than the corresponding values for M. tuberculosis, which are 4, 441,529 bp and 65.6% G+C,. About 1500 genes are common to both M. leprae and M. tuberculosis. The comparative analysis suggests both mycobacteria derived from a common ancestor and, at one stage, had gene pool
Gene pool
In population genetics, a gene pool is the complete set of unique alleles in a species or population.- Description :A large gene pool indicates extensive genetic diversity, which is associated with robust populations that can survive bouts of intense selection...
s of similar size. Downsizing from a genome of 4.42 Mbp, such as that of M. tuberculosis, to one of 3.27 Mbp would account for the loss of some 1200 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
-coding sequences. There is evidence that many of the genes that were present in the genome of the common ancestor of M. leprae and M. tuberculosis have been lost by recombination in the M.leprae genome.
Information from the completed genome can be useful to develop diagnostic skin tests, to understand the mechanisms of nerve damage and drug resistance and to identify novel drug targets for rational design of new therapeutic regimens and drugs to treat leprosy and its complications.
Diagnostic criteria for leprosy
Diagnostic criteria for leprosy: The diagnosis of leprosy is primarily a clinical one. In one Ethiopian study, the following criteria had a sensitivity of 97% with a positive predictive value of 98% in diagnosing leprosy. Diagnosis was based on one or more of three signs:1) Hypopigmented or reddish skin patches with definite loss of sensation
2) Thickened peripheral nerves
3) Acid-fast bacilli on skin smears or biopsy material