The cell fate regulator NUPR1 is induced by Mycobacterium leprae via type I interferon in human leprosy

Mehta, Manali; Lü, Jing; Teles, Rosane M. B.; Montoya, Dennis; Scumpia, Phillip; Sarno, Euzenir Nunes; Ochoa, María Teresa; Ma, Feiyang; Pellegrini, Matteo; Modlin, Robert L.

doi:10.1371/journal.pntd.0007589

Cited by 10 publications

(6 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was documented that interferon beta (IFNB) is increased during cell stress conditions, but the lack of this protein leads to neuroinflammation (51,52). IFNB is essential to start the cell fate pathway driven by NUPR1, a gene signature that contributes to a progressive infection in human cells (53). Oligodendrocyte transcription factor 1 (OLIG1) is an important protein of the remyelination phenotype, usually upregulated after a disturbance in the cell microenvironment (54).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy

et al. 2022

View full text Add to dashboard Cite

Peripheral neuropathy is the main cause of physical disability in leprosy patients. Importantly, the extension and pattern of peripheral damage has been linked to how the host cell will respond against Mycobacterium leprae (M. leprae) infection, in particular, how the pathogen will establish infection in Schwann cells. Interestingly, viable and dead M. leprae have been linked to neuropathology of leprosy by distinct mechanisms. While viable M. leprae promotes transcriptional modifications that allow the bacteria to survive through the use of the host cell's internal machinery and the subvert of host metabolites, components of the dead bacteria are associated with the generation of a harmful nerve microenvironment. Therefore, understanding the pathognomonic characteristics mediated by viable and dead M. leprae are essential for elucidating leprosy disease and its associated reactional episodes. Moreover, the impact of the viable and dead bacteria in Schwann cells is largely unknown and their gene signature profiling has, as yet, been poorly explored. In this study, we analyzed the early differences in the expression profile of genes involved in peripheral neuropathy, dedifferentiation and plasticity, neural regeneration, and inflammation in human Schwann cells challenged with viable and dead M. leprae. We substantiated our findings by analyzing this genetic profiling in human nerve biopsies of leprosy and non-leprosy patients, with accompanied histopathological analysis. We observed that viable and dead bacteria distinctly modulate Schwann cell genes, with emphasis to viable bacilli upregulating transcripts related to glial cell plasticity, dedifferentiation and anti-inflammatory profile, while dead bacteria affected genes involved in neuropathy and pro-inflammatory response. In addition, dead bacteria also upregulated genes associated with nerve support, which expression profile was similar to those obtained from leprosy nerve biopsies. These findings suggest that early exposure to viable and dead bacteria may provoke Schwann cells to behave differentially, with far-reaching implications for the ongoing neuropathy seen in leprosy patients, where a mixture of active and non-active bacteria are found in the nerve microenvironment.

show abstract

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Gene clusters III, V and VI were also induced in the 28h and 32h infected mice both symptomatic and symptom-free. Genes from cluster III are involved in cell division and DNA repair including Nupr1, involved in regulation of cellular catabolic process or programmed cell death, already shown as part of the host response to bacterial infection [86, 87].…”

Section: Resultsmentioning

confidence: 99%

Dual RNA-seq study of the dynamics of coding and non-coding RNAs expression duringClostridioides difficileinfection in a mouse model

Kreis,

Toffano-Nioche,

Denève-Larrazet

et al. 2024

Preprint

View full text Add to dashboard Cite

Clostridioides difficileis the leading cause of healthcare associated diarrhoea in industrialized countries. Many questions remain to be answered about the mechanisms governing its interaction with the host during infection. Non-coding RNAs (ncRNAs) contribute to shaping virulence in many pathogens and modulate host responses, however, their role inC. difficileinfection (CDI) has not been explored. To better understand the dynamics of ncRNAs expression contributing toC. difficileinfectious cycle and host response, we used a dual RNA- seq approach in a conventional murine model. From the pathogen side, this transcriptomic analysis revealed the upregulation of virulence factors, metabolism and sporulation genes, as well as the identification of 61 ncRNAs differentially expressed during infection that correlated with the analysis of available raw RNA-seq datasets from two independent studies. From these data we identified 118 potential new transcripts inC. difficileincluding 106 new ncRNA genes. From the host side, we observed the induction of several pro-inflammatory pathways and, among the 185 differentially expressed ncRNAs, the overexpression of microRNAs (miRNAs) previously associated to inflammatory responses or unknown long ncRNAs and miRNAs. A particular host gene expression profile could be associated to the symptomatic infection. In accordance, the metatranscriptomic analysis revealed specific microbiota changes accompanying CDI and specific species associated with symptomatic infection in mice. This first adaptation ofin vivodual RNA-seq toC. difficilecontributes to unravelling the regulatory networks involved inC. difficileinfectious cycle and host response and provides valuable resources for further studies of RNA-based mechanisms during CDI.ImportanceClostridioides difficileis a major cause of nosocomial infections associated with antibiotic therapy classified as an urgent antibiotic resistance threat. This pathogen interacts with host and gut microbial communities during infection, but the mechanisms of these interactions remain largely to be uncovered. Noncoding RNAs contribute to bacterial virulence and host responses, but their expression has not been explored duringC. difficileinfection. We took advantage of the conventional mouse model ofC. difficileinfection to look simultaneously to the dynamics of gene expression in pathogen, its host and gut microbiota composition providing valuable resources for future studies. We identified a number of ncRNAs that could mediate the adaptation ofC. difficileinside the host and the crosstalk with the host immune response. Promising inflammation markers and potential therapeutic targets emerged from this work open new directions for RNA-based and microbiota-modulatory strategies to improve the efficiency ofC. difficileinfection treatments.

show abstract

“…Supervised analyses were performed to identify Type I and Type II IFN regulated genes as described previously 11,42,43,44 . Differentially expressed genes in TC1 (RR CTL) and TC2 (L-lep CTL) were identified using a Wilcoxon rank sum test with adjusted p value cutoff at 0.05.…”

Section: Interferon Signature Enrichment Analysismentioning

confidence: 99%

The cellular architecture of the antimicrobial response network in human leprosy granulomas

Hughes

Teles

et al. 2021

Nat Immunol

Self Cite

View full text Add to dashboard Cite

Granulomas are complex cellular structures comprised predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated single cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RR), a dynamic process in which some patients with disseminated lepromatous leprosy (L-lep) transition towards self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions, and regulated by IFN-γ and IL-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.Nat Immunol.

show abstract

The cell fate regulator NUPR1 is induced by Mycobacterium leprae via type I interferon in human leprosy

Cited by 10 publications

References 59 publications

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy

Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy

Dual RNA-seq study of the dynamics of coding and non-coding RNAs expression duringClostridioides difficileinfection in a mouse model

The cellular architecture of the antimicrobial response network in human leprosy granulomas

Contact Info

Product

Resources

About