Innate Immune Response Precedes Mycobacterium leprae–Induced Reprogramming of Adult Schwann Cells

Abstract

Recently, we showed a natural reprogramming process during infection with Mycobacterium leprae (ML), the causative organism of human leprosy. ML hijacks the notable plasticity of adult Schwann cells in the peripheral nervous system (PNS), bacteria's preferred nonimmune niche, to reprogram infected cells to progenitor/stem cell-like cells (pSLCs). Whereas ML appear to use this reprogramming process as a sophisticated bacterial strategy to spread infection to other tissues, understanding the mechanisms may shed new insights into the basic biology of cellular reprogramming and the development of new approaches for generating pSLC for therapeutic purposes as well as targeting bacterial infectious diseases at an early stage. Toward these goals, we extended our studies to identify other players that might be involved in this complex host cell reprogramming. Here we show that ML activates numerous immune-related genes mainly involved in innate immune responses and inflammation during early infection before downregulating Schwann cell lineage genes and reactivating developmental transcription factors. We validated these findings by demonstrating the ability of infected cells to secrete soluble immune factor proteins at early time points and their continued release during the course of reprogramming. By using time-lapse microscopy and a migration assay with reprogrammed Schwann cells (pSLCs) cultured with macrophages, we show that reprogrammed cells possess the ability to attract macrophages, providing evidence for a functional role of immune gene products during reprogramming. These findings suggest a potential role of innate immune response and the related signaling pathways in cellular reprogramming and the initiation of neuropathogenesis during ML infection.

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

“…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.…”

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

“…This is particular challenging for an extremely passive bacterium like ML with a strictly obligate intracellular life style, residing in a specialized and complex host niche such as the adult PNS. ML appear to overcome these challenges by conversion of parent Schwann cells to pSLC with acquired characteristics of differentiation to mesenchymal tissues as well as migratory and immunomodulatory properties [36,51]. Host cell dependence of ML for bacterial survival is well documented but host cell dependence for bacterial dissemination was unknown until recently.…”

“…An important finding is the contribution of innate immune factors during Schwann cell reprogramming and their expression to the highest levels at pSLC stage [36,51]. Although early innate immune factors upregulated in the early stage of infection are likely to promote a reprogramming process, release of these immune factors particularly chemokines/cytokines are more prominent at the pSLC stage [51].…”

“…An important finding is the contribution of innate immune factors during Schwann cell reprogramming and their expression to the highest levels at pSLC stage [36,51]. Although early innate immune factors upregulated in the early stage of infection are likely to promote a reprogramming process, release of these immune factors particularly chemokines/cytokines are more prominent at the pSLC stage [51]. This was demonstrated by the capacity of pSLCs to recruit macrophages and form granuloma-like structures in both in vitro and in vivo models, resembling typical granulomas seen in tissue lesions from leprosy and tuberculosis patients [58,59,60].…”

Inflammation Shapes Stem Cells and Stemness during Infection and Beyond

“…The infected stem-like cells then migrate to the mesenchyme where they re-differentiate to mesenchyme tissue allowing for expansion of the infection (Masaki et al, 2013). The innate immune response has been shown to precede this reprogramming (Masaki et al, 2014). For efficient dissemination, the cells need to evade the host immunity and they do so by inducing an inflammatory response achieved through the release of factors from the stem-like cells.…”