MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis

Alissa C. Rothchild, James R. Sissons, Shahin Shafiani, Christopher Plaisier, Deborah Min, Dat Mai, Mark Gilchrist, Jacques Peschon, Ryan P. Larson, Andreas Bergthaler, Nitin S. Baliga, Kevin B. Urdahl, Alan Aderem

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

The regulation of host-pathogen interactions during Mycobacterium tuberculosis (Mtb) infection remains unresolved. MicroRNAs (miRNAs) are important regulators of the immune system, and so we used a systems biology approach to construct an miRNA regulatory network activated in macrophages during Mtb infection. Our network comprises 77 putative miRNAs that are associated with temporal gene expression signatures in macrophages early after Mtb infection. In this study, we demonstrate a dual role for one of these regulators, miR-155. On the one hand, miR-155 maintains the survival of Mtbinfected macrophages, thereby providing a niche favoring bacterial replication; on the other hand, miR-155 promotes the survival and function of Mtb-specific T cells, enabling an effective adaptive immune response. MiR-155-induced cell survival is mediated through the SH2 domain-containing inositol 5-phosphatase 1 (SHIP1)/protein kinase B (Akt) pathway. Thus, dual regulation of the same cell survival pathway in innate and adaptive immune cells leads to vastly different outcomes with respect to bacterial containment.

Original languageEnglish (US)
Pages (from-to)E6172-E6181
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number41
DOIs
StatePublished - Oct 11 2016

Keywords

  • Macrophage
  • MiR-155
  • MicroRNA
  • Mycobacterium tuberculosis
  • T cell

ASJC Scopus subject areas

  • General

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    Rothchild, A. C., Sissons, J. R., Shafiani, S., Plaisier, C., Min, D., Mai, D., Gilchrist, M., Peschon, J., Larson, R. P., Bergthaler, A., Baliga, N. S., Urdahl, K. B., & Aderem, A. (2016). MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 113(41), E6172-E6181. https://doi.org/10.1073/pnas.1608255113