Leprosy, better explained as a combination of two diseases over time that have become conjoined, is curable, but not preventable. The first disease of the combination is a chronic mycobacterial infection, eliciting a surprising amount of immune responses in human beings. The second is a peripheral neuropathy that begins after the first infection sets in, and accompanies the immunological events that transpire. Leprosy, unfortunately, remains at the forefront of global health and has done so for decades. The agent itself, Mycobacterium Leprae, is elusive; uncultivable, the agent presents challenges in the fields of microbiology, pathology, immunology, and genetics. The article I’m writing about focuses in on the current understanding of M. Leprae, and the host cell responses to the pathogen, especially related to “molecular identification of M. leprae, knowledge of its genome, transcriptome, and proteome, its mechanisms of microbial resistance, and recognition of strains by variable-number tandem repeat analysis.”
Leprosy is not going to be eradicated within the clear future, there is no path towards prevention. The exact method of transmission of Leprosy is still a vast unknown. As of now, there has been no highly effective vaccine, nor have there been any practical tools for early diagnosis developed. With that said, however, the full genome (the complete set of genes or genetic material present in a cell or organism) has been sequenced, and in labs across the world, this knowledge is beginning to open up pathways. In the field of molecular microbiology, the reason behind M. Leprae seemingly fastidious nature has begun to be unearthed.
- Leprae itself is a nonmotile (incapable of being moved), non-spore-forming, microaerophilic (requiring oxygen because they cannot ferment or respire anaerobically, but too much oxygen will poison them), acid-fast-staining bacterium that usually forms slightly curved or straight rods (seen below, the slim red fiber-looking rods).
- M. leprae has never been grown on artificial media due to its elusive nature, but can be maintained in axenic cultures in what appears to be a stable metabolic state for a few weeks. As a result, propagation of M. leprae has been restricted to animal models, including the armadillo and normal, athymic, and gene knockout mice (genetically modified mice to better exhibit, in this case, the effects and results of M. Leprae). The growth of the specific agent M. Leprae has been known to vary greatly depending on certain conditions (temperature, medium in which the bacterium was preserved), and so in this study, the metabolism of the bacterium was studied at great length in order to determine whether or not there could be steps taken to provide the world with a prevention method. While the study proved to be relatively inconclusive, the previously thought-to-be-true hypothesis that M. Leprae held remarkable similarities to M. Tuberculosis was disproved. There are many very important differences between the two Mycobacteria, as “M. leprae has many fewer enzymes involved in degradative pathways for carbon and nitrogenous compounds than M. tuberculosis. This is reflected in the [scarcity] of oxidoreductases (the enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor) [among other enzymes]. In addition, other major problems associated with metabolism for M. leprae are that the bacilli have lost anaerobic and microaerophilic electron transfer systems and that the aerobic respiratory chain is severely curtailed, making it impossible for M. leprae to generate ATP from the oxidation of NADH.”
Reductive evolution, the process by which a genome shrinks in length or size as compared to an ancestral genome, is the exact process M. Leprae went through. M. Leprae “…possesses 1,133 inactivated genes (genes lost through mutation, or pseudogenes), compared to six pseudogenes in M. tuberculosis. In addition, a large number of genes apparently have been entirely deleted from the genome. The result of this massive gene loss leaves M. leprae with less than 50% of its genome encoding functional genes, compared to M. tuberculosis, in which 90% of the genome encodes functional genes, and 34% of M. leprae‘s proteins identified in silico appear to be the products of gene duplication events or share common domains. Downsizing of the genome has resulted in the elimination of several metabolic pathways, leaving a pathogen with very specific growth requirements, as discussed above (Metabolism). The largest functional groups of genes in M. leprae are those involved in gene regulation, metabolism and modification of fatty acids and polyketides, cell envelope synthesis, and transport of metabolites.”
In summation, Leprosy as a disease poses major challenges to the world’s understanding in microbiology, immunology, pathology, treatment, and prevention. “The genome of M. leprae has been sequenced, and this organism has been shown to be able to synthesize far fewer proteins than the other major human-pathogenic mycobacteria, M. tuberculosis. Thus, although M. leprae still cannot be cultivated axenically, the new molecular ability to assess its ability to transcribe and synthesize various proteins in response to different environments and stresses will likely provide valuable information about its mechanisms of pathogenicity in the near future.” In addition, “Genetic influences on immunity to M. leprae in humans appear to operate at two levels: some mechanisms act at the level of overall susceptibility, and others function at the level of acquired immunity. One leprosy susceptibility gene has been identified, and several genes possibly influencing adaptive immunity have also been described.”
At this point in time, with failed efforts to reach global immunity by the years 2000 and 2005, the main goal of the Leprosy community is focusing in on early detection. Because early detection would be treating those who are asymptomatic, the challenges presented by this are great; “in many areas with endemic leprosy, even patients with overt disease are finding that resources for diagnosis and treatment are being systematically reduced.” Another possible answer for the cure of leprosy has to do with all patients living with leprosy who contract the infection, but rendering it harmless.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1471987 (all quotations and diagrams are taken from this link)