Leprosy Mailing List – February 28, 2013
Ref.: (LML) Reprogramming Adult Schwann Cells. Leprosy infection and disease.
From: Dr. Jaison Barreto, Bauru, Brazil
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Ref : DISCUSSION INITIATED BY DR. BEN NAAFS on the interpretation of the article published in Cell by an outstanding group led by Professor Anura Rambukkana (Rockeffeler Instutute, USA and University Of Edinburgh, UK).
Dear Pieter,
In reference to the communication by Ben to LML, I am pleased to respond to your request to me to write a brief statement in summarizing a version of my own understanding of this revolutionary article, entitled, "Reprogramming Adult Schwann Cells………….promotes dissemination of infection" by Toshihiro Masaki et al Cell vol. 152, 51-67 2013. Regarding this matter I had already exchange of e-mails with Dr. Ben Naafs. I like to thank Ben for taking the initiative to starting up the discussion. Hopefully, in coming weeks and months we will come across variety of interpretations and speculations concerning this ground breaking publication. At present, I shall refrain from, prejudicing any one from free his/her own interpretation and speculation on this manuscript. Before continuing with my task I would like to suggest that the organizing Committee of the forthcoming International Congress of Leprosy should invite Anura to the congress as an invited speaker and conduct a interacting discussion session on the subject with the delegates.
In order to simplify my task, I enclose firstly a) the author's own abstract of the article (see the enclosure 1). Should anyone would like to read the full article but do not have the access to the journal, I shall send with pleasure the e-copy to them per request.
My understanding is essentially similar to that described by Michael Wegner entitled "Mighty Bugs: Leprosy Bacteria Turn Schwann Cell into Stem Cells" published in the same issue of the journal : Cell 152, January 17 ,pages 15-16., a copy of which is also enclosed herewith (see enclosure 2).
My understanding and simple interpretation therefore briefly is as follows:
- M. leprae "the wizard intracellular organism" has an affinity for infecting Schwann Cells of the peripheral neuronal net work among others (like phagocytes, endothelial cells, glands,
epithelial cells etc.). The strategy of the research was based on the objective in finding the
molecular and cellular events of infection in peripheral nervous system in humans which eventually cause systemic spread of infection. Towards such search, the strategy of dissemination of M. leprae infection as put forward by Masaki et al is itself a startling discovery, almost like " big bang" theory in natural physics.
- As a proof of their findings the authors employed very complex sets of high tech based in vitro and in vivo experimental methodologies using mice (not human) Schwann cells . In a nut shell, they demonstrated elegantly that leprosy bacterium cleverly expands its spread by taking advantage of gene plasticity of cells and hijacking and manipulating the transcription factor SOX 10 which is an important factor (among others) for myelination, but the most important characteristic component for Schwann Cell identity. Such hijacking of the host genetic component by the mythical leprosy bacteria, leads to the de-differentiation of the Schwann cells into pluripotent mesenchymal stem cell (MSC) like cells which subsequently has the ability to re-differentiate into cells of mesodermal lineages.
- In order to prove their points further, authors showed that the re-programmed Schwann cells [by heavy infection with M. leprae ] are turned into programmed stem cell like cells (pSLC) or programmed mesenchymal stem cells. These latter can in turn be differentiated into adipocytes (fat cells) and also muscle cells, apparently carrying the viable M. leprae along the line of de-differentiation and re-differentiation process, thus providing the pathway for dissemination of the infection in one hand and on the other maintaining the expansion of bacterial niche within the Schwann cells. In order to draw analogy of their finding in human situations, authors argue that once invaded M. leprae uses its magical spell that promote Schwann cells endurance and regeneration in order to maintain the safe heaven. Peripheral nervous systems (PNS) like brain being an immune privileged site, that may provide a hiding place for M. leprae from the onslaught of hosts immune (both innate and adaptive) attack. It is worth to mention that as a support of the strategy undertaken for this study, the authors seem to be inspired by the work of Miko TL et al 1993, Lancet 342 521-525; Job CK 1989, Int.J.Lepr. Other Mycobact. Dis. 57,532-539, Stoner GL 1979 ,Lancet 2 994-996.
- Furthermore, Masaki et al find that these reprogrammed pSLC still maintaining the active infection secrete plethora of immune-modulatory molecules that attract seemingly only macrophages to which M. leprae is transferred. The latter event in the down stream process results in granuloma formation (in true sense macrophage aggregation) and then infected macrophages serve as the subsequent secondary vehicle for systemic spread of pathogen .
- It should be noted that the maintenance of mycobacterial infection within MSC can be supported by a recent findings by Bikul Das et al in that mycobacterium tuberculosis seems to spread to lung by infecting stem cells and then migrating to Lung (see www. sciencetranslationalmedicine.org. Sci.Trans. Med. 2013 5. 170ra 13.)
My personal simpleton and only preliminary comments:
Concept of regeneration of nerve impairment (not shown in the present study) as well as to maintain the bacterial niche in the Schwann cells, probably imply that non toxic M. leprae can be used as a therapy for tissue regeneration process.
However, such overriding speculation is not possible at this stage. Nevertheless, the study is a revolutionary, if it gets ultimately proven in disease situation, M. leprae together with authors deserve the award of Noble Prize. The study will surely inspire many future research focusing :
i) on the mechanism of exploitation of genomic plasticity of a highly specialized differentiated cell by removing its identity and then reprogramming followed by re-differentiating it. In this respect investigators at large, are engaged in de-differentiating other adult cells like fibroblasts into stem cells (known as induced pluri potent stem cells (iPSC) for therapeutic purpose , but the example of a pathogen having such ability, is the first of its kind.
ii) secondly, the study shows the alternative mechanism for a pathogen to evade hosts immune surveillance and disseminate during the course of leprosy.
iii) thirdly, the study opens up a new field of therapeutic possibility of usefulness of bacteria in tissue regeneration process.
On the other hand, like any other study there are limitations because
i) results obtained are in mouse system and can not be employed as such in real disease context. The limitation is inevitable as no animal model exists to translate the essential features of human leprosy; consequently the present study will be of little help in understanding the patho-physiology of leprosy spectrum and reactions. The present study is geared to understand the process of dissemination of infection which is a prominent feature of multibacillary leprosy only rather than immune-pathology of the disease as a whole;
ii) even in the process of dissemination of infection, it seems M. leprae uses very laborious system. In that context, I would like to pose a question as follows: knowing that we are ignorant about the route of entry of M. leprae infection, if the organism is faced with two types of host cells e.g. phagocytes and Schwann cells, which one of the two M. leprae will infect first?
With this question I leave the field of discussion open to the readers.
Kindest regards,
Pranab Kumar Das
A devoted LML participant.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML Archives: http://www.aifo.it/english/resources/online/lml-archives/index.htm
Contact: Dr Pieter Schreuder << editorlml@gmail.com >>.
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