Manipulation of infected cells is a widespread mechanism used by pathogens to ensure their survival and spread. Now, Rambukkana and colleagues reveal that Mycobacterium leprae goes one step further, reprogramming the infected cells into a stem cell-like state to ensure bacterial dissemination.
M. leprae establishes infection in adult Schwann cells (the glial cells of the peripheral nervous system), where it is sheltered from immune responses by the blood–brain barrier and is provided with factors that promote its survival. Previous work had also shown that M. leprae infection, as well as other neuronal injury, induces demyelination of Schwann cells, making them more susceptible to infection; these cells are known as dedifferentiated Schwann cells because they are less mature than those associated with adult nerves.
To investigate this further, the authors isolated Schwann cells from adult mice and examined M. leprae infection in vitro. Interestingly, they observed that the cells upregulated numerous genes in response to infection, including some associated with embryonic development and chromatin remodelling. Moreover, the transcription factor SOX10, the master regulator of Schwann cell differentiation and homeostasis, was exported from the nucleus in infected cells, indicating that infection perturbs transcription events specific to the Schwann cell lineage. Further analysis showed that infected cells switched off genes associated with Schwann cell differentiation and switched on early developmental genes. In particular, the authors observed an upregulation of genes associated with epithelial–mesenchymal transition (a cellular dedifferentiation process that is vital for morphogenesis during development), such as those encoding the transcription factors TWIST1, TWIST2, SNAIL2 and MSX2, accompanied by decreased methylation of their promoters. These changes depended on the presence of high numbers of intracellular bacteria.
These observations suggested that the infected Schwann cells had reverted back to a highly immature stage that differs from dedifferentiated Schwann cells generated by injury (which retain expression of SOX10). Consistent with this, infected Schwann cells that had been cultured in mesenchymal stem cell (MSC) medium lacked all Schwann cell-specific markers and instead had acquired new markers, including some expressed by MSCs (a diverse set of multipotent progenitor cells). Importantly, the authors confirmed that these cells were directly derived from infected Schwann cells and could themselves give rise to bone and fat precursors, as is typical of MSCs. Thus, the authors conclude that M. leprae triggers reprogramming of infected Schwann cells into what they term progenitor/stem cell-like cells (pSLCs).
So what is the purpose of this reprogramming event? The authors observed that infected pSLCs could differentiate into skeletal and smooth muscle cells, promoting bacterial dissemination to muscle. Moreover, pSLCs secreted immunomodulatory factors to recruit and infect macrophages, which could themselves infect other tissue macrophages, thus spreading the infection.
Further work is now needed to determine the signals that drive M. leprae-mediated reprogramming of Schwann cells.
ORIGINAL RESEARCH PAPER
Masaki, T. et al. Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection. Cell 152, 51–67 (2013)
This article is modified from the original in Nature Rev. Microbiol. (doi:10.1038/nrmicro2975).