Bacterial-induced cell reprogramming to stem cell-like cells: new premise in host–pathogen interactions

Abstract

Bacterial pathogens employ a myriad of strategies to alter host tissue cell functions for bacterial advantage during infection. Recent advances revealed a fusion of infection biology with stem cell biology by demonstrating developmental reprogramming of lineage committed host glial cells to progenitor/stem cell-like cells by an intracellular bacterial pathogen Mycobacterium leprae. Acquisition of migratory and immunomodulatory properties of such reprogrammed cells provides an added advantage for promoting bacterial spread. This presents a previously unseen sophistication of cell manipulation by hijacking the genomic plasticity of host cells by a human bacterial pathogen. The rationale for such extreme fate conversion of host cells may be directly linked to the exceedingly passive obligate life style of M. leprae with a degraded genome and host cell dependence for both bacterial survival and dissemination, particularly the use of host-derived stem cell-like cells as a vehicle for spreading infection without being detected by immune cells. Thus, this unexpected link between cell reprogramming and infection opens up a new premise in host-pathogen interactions. Furthermore, such bacterial ingenuity could also be harnessed for developing natural ways of reprogramming host cells for repairing damaged tissues from infection, injury and diseases.

Cell Biology of Intracellular Adaptation of Mycobacterium leprae in the Peripheral Nervous System

“…Although such early demyelination in vivo may not initially lead to clinical manifestation, as peripheral nerves possess a remarkable capacity to regenerate following injury, it may lead to activation of additional signaling from Schwann cells similar to nerve injury (101). Functional consequences like demyelination provide a survival advantage for M. leprae, as it induces dedifferentiation and proliferation and generates myelin-free Schwann cells with high plasticity, which naturally promote remyelination and nerve regeneration and are also highly susceptible to M. leprae invasion (103). This suggests that initial interactions with and activation of Schwann cells are crucial, as these events set the stage for subsequent intracellular survival and replication within the peripheral nerves.…”

“…This, alongside acquired migratory and immunomodulatory properties as in mesenchymal stem cells (142), may enable the bacteria to exit peripheral nerves, potentially breaching the BNB by immunomodulatory agents that reprogrammed cells can release and that can thus enter the bloodstream, recruit macrophages, or directly transdifferentiate into desired tissue cell types once reaching other preferred target cells like muscles, bone, and adipose tissues (Fig. 6) (103, 110). An additional bacterial advantage is that reprogrammed Schwann cells, but not normal Schwann cells, show more efficient cell-cell transfer of the bacteria to fibroblasts from both skin and peripheral nerve origins (114).…”

Pathogenic mechanisms of intracellular bacteria

“…Thus, the M. leprae-infected Schwann cells acquired the phenotype of progenitor/stem-like cells. Accordingly, they could differentiate into myofibers and smooth muscles both in vitro and in vivo, a phenomenon that may facilitate the dissemination of bacteria [47,48]. The exact mechanism of M. leprae-induced reprogramming remains to be elucidated.…”

Functional Impairment of Skin Appendages Due to Peripheral Nerve Involvement by Mycobacterium leprae

“…Signal activation leads to a cellular reparative program, which is believed to initiate demyelination and dedifferentiation-proliferation functions associated with nerve cell injury [ 22 ]. In small diameter, nonmyelinated axons reprograming of surrounding Schwann cells to a dedifferentiated phenotype may interfere with nerve conduction through as yet unknown mechanisms [ 23 ]. Such events underlie the basis for autonomic peripheral neuropathy characteristic of HD.…”