Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection

Abstract

SUMMARY Differentiated cells possess a remarkable genomic plasticity that can be manipulated to reverse or change developmental commitments. Here, we show that the leprosy bacterium hijacks this property to reprogram adult Schwann cells, its preferred host niche, to a stage of progenitor/stem-like cells (pSLC) of mesenchymal traits by downregulating Schwann cell lineage/differentiation-associated genes and upregulating genes mostly of mesoderm development. Reprogramming accompanies epigenetic changes and rendered infected cells highly plastic, migratory and immunomodulatory. We provide evidence that acquisition of these properties by pSLC promotes bacterial spread by two distinct mechanisms: direct differentiation to mesenchymal tissues, including skeletal and smooth muscles, and by forming granuloma-like structures and subsequently release bacteria-laden macrophages. These findings support a model of host cell reprogramming in which a bacterial pathogen uses the plasticity of its cellular niche for promoting dissemination of infection, and provide an unexpected link between cellular reprogramming and host-pathogen interaction.

Emerging roles of gut microbiota and the immune system in the development of the enteric nervous system

“…In addition addition, glial cells show remarkable plasticity and are among the first cells to respond to injury or invasion by pathogens (72,73). Although at present EGCs are the least-studied peripheral glial cells in vertebrates, there is an increasing interest in understanding the complex roles of these cells in gastrointestinal physiology.…”

“…In this respect it is interesting that in rodents, low levels of gliogenesis are detectable in the enteric ganglia of adult animals, raising the possibility that self-renewing glial progenitors of the ENS are used to generate progeny that replenish mEGCs eliminated during the natural turnover of the intestinal mucosa. The potential role of the microbiota and the mucosal immune system in the activation of glial progenitors and the homeostasis of EGCs is currently unclear, but it is interesting that other peripheral glial cells, such as Schwann cells, are capable of reprogramming to stem-like cells when challenged by leprosy bacteria, and that such reprogramming is thought to be mediated by the innate immune system (73,83). mEGCs appear to have additional and perhaps more direct effects on mucosal immunity.…”

Leprosy in the 21st Century

“…This transformation creates a suitable environment for the bacteria to proliferate (7). More recently, it has been shown that further dedifferentiation leads to the reprogramming the Schwann cell to a "stem cell-like" cell with a plethora of new capabilities, such as redifferentiation into mesenchymal cells with the ability to spread infection or attracting macrophages to develop granulomas that could then serve as a Trojan horse for systemic dissemination of M. leprae (3,8). The presence of bacilli in the skin produces the dermatological manifestations of the disease, and nerve infection produces axonal dysfunction and demyelination, leading to sensory loss and its consequences of disability and deformity (2,9).…”

“…The presence of bacilli in the skin produces the dermatological manifestations of the disease, and nerve infection produces axonal dysfunction and demyelination, leading to sensory loss and its consequences of disability and deformity (2,9). In this sense, the degenerative changes associated with infection of the peripheral sensory nerves are considered a crucial event in the natural history of HD (7,8). Once the infection is established, the occurrence of leprosy reactions, because of their inflammatory impact on peripheral nerves, remain an important contributor to sensory loss and dysfunction (9)(10)(11)(12).…”

Disorders of Pigmentation of the Skin - Hypotheses Underlying Interventions by Multiple Systems of Medicine:Is there a Role for Integrated Medicine?

“…In leprosy, the lepromatous end of the spectrum is 11 times more likely to be associated with vitiligo than is tuberculoid leprosy 83 . It has been most recently demonstrated that Mycobacterium leprae alters the genetics of Schwann cells without even penetrating their nuclei and this activates genes that convert the cell into a neural crest stem cell, shielding the bacteria from destructive elements 84 . It has been questioned whether albinism could protect against leprosy, as they are not recorded together despite the fact that in Africa, both oculocutaneous albinism and, until recently, leprosy have high prevalence.…”