resistance against this antibiotic. Currently, a multidrug treatment (MDT) is recommended by the World Health Organization, including dapsone, rifampicin, and clofazimine. The species was discovered in 1873 by the Norwegian physician Gerhard Armauer Hansen, and was the first bacterium to be identified as a cause of disease in humans.[8]
Microbiology
Mycobacterium leprae is an intracellular,
pathogenic bacterium.[3] It is an aerobicbacillus (rod-shaped bacterium) with parallel sides and round ends, surrounded by the characteristic waxy coating of mycolic acid unique to mycobacteria. It is Gram-positive by Gram staining, but Mycobacterium leprae was traditionally stained with carbol fuchsin in the Ziehl–Neelsen stain. Because the bacilli are less acid-fast than Mycobacterium tuberculosis (MTB), the Fite-Faraco staining method, which has a lower acid concentration, is used now.[9][10] In size and shape, it closely resembles MTB. The bacteria are found in the granulomatous lesions and are especially numerous in the nodules. This bacteria often occur in large numbers within the lesions of lepromatous leprosy and are usually grouped together as a palisade.[6]
By optical microscopy of host cells, Mycobacterium leprae can be found singly or in clumps referred to as "globi", the bacilli can be straight or slightly curved, with a length ranging from 1–8 μm and a diameter of 0.3 μm.[11] The bacteria grow best at 27 to 30 °C, making the skin, nasal mucosa and peripheral nerves primary targets for infection by Mycobacterium leprae.[12]
Host range
Mycobacterium leprae has a narrow host range and apart from humans the only other hosts are
obligate intracellular parasite, it lacks many necessary genes for independent survival, causing difficulty in culturing the organism. The complex and unique cell wall that makes members of the genus Mycobacterium difficult to destroy is also the reason for its extremely slow replication rate. Mycobacterium leprae prefers cool temperatures, slightly acidic microaerophilic conditions, and prefers the use of lipids as an energy source over sugars. The growth conditions needed for Mycobacterium leprae are known, but an exact axenic medium to support the growth of Mycobacterium leprae still has yet to be discovered.[18] Since in vitro cultivation is not generally possible, it has instead been grown in mouse foot pads,[14] and in armadillos due to their low core body temperature.[19][18]
Metabolism
The reductive evolution experienced by the Mycobacterium leprae genome has impaired its metabolic abilities in comparison to other Mycobacterium, specifically in its catabolic pathways.[20]
Catabolism
Mycobacterium leprae's inability to be grown in axenic media indicates its reliance on nutrients and intermediates from its host.[21] Many of the catabolic pathways present in other Mycobacterium species are compromised, due to the absence of enzymes that play key roles in degradation of nutrients.[21]Mycobacterium leprae has lost the ability to use common carbon sources, such as acetate and galactose, in its central energy metabolism pathways.[4] Additionally, lipid degradation is impaired, with deficits in key lipase enzymes, and other proteins involved in lipolysis.[22] Functional carbon catabolic pathways continue to exist in the species, such as the glycolytic pathway, the pentose phosphate pathway, and the TCA cycle.[21] These deficiencies extensively restricts the microbe's growth to a limited number of carbon sources, such as host-derived intermediates.[4]
Anabolism
Mycobacterium leprae's anabolic pathways have been largely unaffected by its reductive evolution.[20] The species retains its ability for the synthesis of genetic material, such as purines, pyrimidines, nucleotides, and nucleosides, as well as the synthesis of all amino acids, except for methionine and lysine.[21]
Genome
The first genome sequence of a strain of Mycobacterium leprae was completed in 2001, revealing 1604 protein-coding genes and another 1,116 pseudogenes.[23] The genome sequence of a strain originally isolated in Tamil Nadu, India, and designated TN, was completed in 2013. This genome sequence contains 3,268,203 base pairs (bp) and an average G+C content of 57.8%, which is significantly less than M. tuberculosis, which has 4,441,529 bp and 65.6% G+C.[24]
Comparing the
catabolic systems and their regulatory circuits.[25] This reductive evolution is largely linked to the organism's development into an obligate intracellular bacterium.[26]
Pseudogenes
Many of the genes that were present in the genome of the common ancestor of Mycobacterium leprae and M. tuberculosis have been lost in the Mycobacterium leprae genome.[23][27] Due to Mycobacterium leprae's reliance on a host organism, many of the species' DNA repair functions have been lost, increasing the occurrence of deletion mutations.[26] Because the products supplied by these deleted genes are typically present in the host cells infected by Mycobacterium leprae, the impact that the mutations have on the microbe is minimal, allowing for survival within the host despite its reduced genome.[28] Consequently, Mycobacterium leprae has undergone a dramatic reduction in genome size with the loss of many genes.[4] Over half of the pathogen's genome is now made up by pseudogenes due to the pathogen undergoing what is known as reductive evolution.[4] Among published genomes, Mycobacterium leprae contains the highest number of pseudogens (>1000).[29] Many of these pseudogenes arose from insertions of stop codons which may have been caused by sigma factor dysfunction (a protein needed for initiation of transcription in bacteria) or the insertion of transposon- derived repetitive sequences.[30] Some of the Mycobacterium leprae pseudogens expression levels will alter upon infection of macrophages, which suggests that some Mycobacterium leprae pseudogens are not all "decayed" genes, but could also function in infection, intracellular replication, and replication.[29] This genome reduction is not complete.[27] 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.
Essential enzymes
There are eight essential enzymes for Mycobacterium leprae, and one of them is
The bacterium has a global distribution in humans but the highest prevalence is in sub-Saharan Africa, Asia and South America.[32] The geographic occurrences of Mycobacterium leprae include: Angola, Brazil, Central African Republic, the Democratic Republic of Congo, Federated States of Micronesia, India, Kiribati, Madagascar, Nepal, Republic of Marshall Islands, and the United Republic of Tanzania.[33]
Since the introduction of multidrug therapy (MDT) in the 1980s, the prevalence of leprosy cases has declined by 95%.[34] This decline led the World Health Organization (WHO) to declare leprosy eliminated as a public health problem, defined as a prevalence of less than one leprosy patient per 10,000 population.[35] Aside from Mycobacterium leprae transmission from infected humans, environmental sources could also be an important reservoir. Mycobacterium leprae DNA was detected in soil from houses of leprosy patients in Bangladesh, armadillos' holes in Suriname and habitats of lepromatous red squirrels in the British Isles.[36] One study found numerous reports of leprosy cases with a history of contact with armadillos in the United States.[34] A zoonotic transmission pathway from exposure to armadillos has been proposed, with human patients from a previous study in southeastern United States shown to be infected with the same armadillo-associated Mycobacterium leprae genotype.[37] High rates of Mycobacterium leprae infection were observed in armadillos in the Brazilian state of Pará, and individuals who frequently consumed armadillo meat showed a significantly higher titres of the M. leprae-specific antigen, phenolic glycolipid I (PGL-I) compared with those who did not or ate them less frequently.[38][34]
Evolution
The closest relative to Mycobacterium leprae is Mycobacterium lepromatosis. These species diverged 13.9 million years ago (95% highest posterior density8.2 million years ago – 21.4 million years ago ) The most recent common ancestor of the extant Mycobacterium leprae strains was calculated to have lived 3,607 years ago (95% highest posterior density 2204–5525 years ago). The estimated substitution rate was 7.67 x 10−9 substitutions per site per year, similar to other bacteria.[39]
A study of genomes isolated from medieval cases estimated the mutation rate to be 6.13 × 10−9. The authors also showed that the leprosy bacillus in the Americas was brought there from Europe.[40] Another study suggests that Mycobacterium leprae originated in East Africa and spread from there to Europe and the Middle East initially before spreading to West Africa and the Americas in the last 500 years.[41]
Almost complete sequences of Mycobacterium leprae from medieval skeletons with osteological lesions suggestive of leprosy from different Europe geographic origins were obtained using DNA capture techniques and
high-throughput sequencing. Ancient sequences were compared with those of modern strains from biopsies of leprosy patients representing diverse genotypes and geographic origins, giving new insights in the understanding of its evolution and course through history, phylogeography of the leprosy bacillus, and the disappearance of leprosy from Europe.[40]
Verena J. Schuenemann et al. demonstrated a remarkable genomic conservation during the past 1000 years and a close similarity between modern and ancient strains, suggesting that the sudden decline of leprosy in Europe was not due to a loss of virulence, but due to extraneous factors, such as other infectious diseases, changes in host immunity, or improved social conditions.[40]
The incubation period of Mycobacterium leprae ranges from 9 months to 20 years.
macule at the cutaneous site of entry and the loss of pain sensation are key clinical indications that an individual has a tuberculoid form of leprosy.[44]