Written by William Boyce ‘25
Edited by Anusha Srinivasan '24
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Part 1: What is Mycobacterium leprae?
Mycobacterium leprae (ML), a rod-shaped bacterium, is the etiologic pathogen causing leprosy, an infectious disease that engenders severe, mutilating skin deformities and peripheral nerve damage throughout the body. Today, leprosy eradication efforts have successfully curbed the disease’s global impact, with over 14 million individuals cured in the last 20 years through multidrug antibiotic therapy, corresponding to a 90% reduction in leprosy’s prevalence rate [2]. However, leprosy’s complete eradication is not currently a reality, as approximately 250,000 new cases are reported annually, primarily in India, Brazil, Indonesia, Bangladesh, the Democratic Republic of the Congo, Ethiopia, Nepal, and Nigeria [2, 3].
For centuries, leprosy’s devastating, chronic symptoms have generated societal stigma against the disease, consequently discouraging research into the bacterium’s infectious mechanisms. In addition to researcher’s inability to culture M. leprae bacteria in vitro, the bacteria expresses an extremely sluggish replication rate of over two weeks, further discouraging research within the field. Resulting from these obstructive factors, scientists “still lack a clear understanding of [M. leprae’s] pathogenesis and physiology… mechanism of transmission, the role of environmental reservoirs (e.g.; soil, water, animals), or differential outcomes of infection in different individuals” [2]. Despite this evident lack of knowledge, new research from the University of Edinburgh has revealed a rather unexpected upside of Mycobacterium laprae infection– the bacteria potentially possesses the ability to regrow and regenerate liver tissue.
Part 2: Mycobacterium leprae and Liver Regeneration
Other than humans, Dasypus novemcinctus, the nine-banded armadillo, is the only other natural host of M. leprae, thereby making it the only reasonable laboratory animal for M. leprae experimentation [4]. Surprisingly, M. leprae infection in armadillos closely matches the “structural, physiological, and functional aspects of leprosy seen in humans” [4]. Controlling for other infections, the researchers treated the subject armadillos with antibiotic, antifungal, and antiparasitic drugs for over one year before M. leprae testing [4]. Upon successful microorganism sterilization, the researchers infected 57 nine-banded armadillos with M. leprae over a period of 10-30 months, then compared their livers with the control livers of uninfected armadillos [4]. In infected armadillos, M. leprae effectively reprograms the entire liver, consequently increasing “total liver/body weight ratio by increasing healthy liver lobules, including hepatocyte proliferation and proportionate expansion of vasculature” [4].
Part 3: Mycobacterium leprae vs. Stem Cells – Regenerative Medicine
Contrasting the University of Edinburgh’s “naturalistic” M. leprae approach to liver regeneration, alternative regenerative approaches seek to implement stem cells, unspecialized cells possessing differentiation capability to generate specific cell types, to stimulate liver tissue regrowth [5]. Modern approaches employ embryonic growth factors Oct3/4, Sox2, c-Myc, and Klf4, which generate induced pluripotent stem cells (iPSCs) from somatic cells [6]. Although recent studies investigating iPSCs demonstrate their effectiveness in tissue regeneration, subcutaneous transplantations of iPS cells into mice also yielded a variety of tumors, posing significant risks [6]. In contrast, M. leprae’s cellular reprogramming mechanisms result in “ML-infected livers [that] are microarchitecturally and functionally normal without damage, fibrosis, or tumorigenesis” [7]. Additionally, no other abnormalities, such as steatosis (fat accumulation in the liver), dysplasia (abnormal cell growth), inflammatory injury, or scarring, were detected in the infected livers. Most notably, the absence of tumorigenesis present in the M. leprae regeneration pathway represents a significant advantage over iPSCs.
Part 4 - Mycobacterium leprae’s Potential Future Applications & Conclusion
Undoubtedly, end-stage liver disease is one of the most significant health issues today, resulting in approximately two million deaths worldwide per year [8]. Although liver transplantation remains the second most prevalent organ transplantation, only 10% of global transplantation requests are fulfilled [8]. Evident from these startling statistics, medicine desperately needs new, regenerative methods to curb liver disease. Despite M. leprae’s unconventionality, perhaps its peculiarity contains medicine’s next major breakthrough in not only liver regeneration, but within other organs as well.
References
1. Bachman J. Dasypus Peba, Nine-banded Armadillo. Male. Natural size. [Internet]. NYPL Digital Collections. 1845 [cited 2022 Dec 11]. Available from: https://digitalcollections.nypl.org/items/510d47da-78ac-a3d9-e040-e00a18064a99
2. Singh P, Cole ST. Mycobacterium leprae: genes, pseudogenes and genetic diversity. Future Microbiol. 2011 Jan;6(1):57–71.
3. Global leprosy situation, 2012. Wkly Epidemiol Rec. 2012 Aug 24;87(34):317–28.
4. admin. The Armadillo Model for Leprosy [Internet]. International Textbook of Leprosy. 2016 [cited 2022 Nov 27]. Available from: https://internationaltextbookofleprosy.org/chapter/armadillos
5. Answers to your questions about stem cell research [Internet]. Mayo Clinic. [cited 2022 Nov 27]. Available from: https://www.mayoclinic.org/tests-procedures/bone-marrow-transplant/in-depth/stem-cells/art-20048117
6. Takahashi K, Yamanaka S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell. 2006 Aug 25;126(4):663–76.
7. Hess S, Kendall TJ, Pena M, Yamane K, Soong D, Adams L, et al. In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis. CR Med [Internet]. 2022 Nov 15 [cited 2022 Nov 27];3(11). Available from: https://www.cell.com/cell-reports-medicine/abstract/S2666-3791(22)00379-2
8. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. Journal of Hepatology. 2019 Jan 1;70(1):151–71.