1. MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis.
- Author
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Rothchild AC, Sissons JR, Shafiani S, Plaisier C, Min D, Mai D, Gilchrist M, Peschon J, Larson RP, Bergthaler A, Baliga NS, Urdahl KB, and Aderem A
- Subjects
- Animals, Cell Survival genetics, Cell Survival immunology, Cytokines biosynthesis, Disease Models, Animal, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Lymphocyte Activation, Macrophages immunology, Macrophages metabolism, Macrophages virology, Mice, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes virology, Transcriptome, Tuberculosis metabolism, Adaptive Immunity genetics, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Immunity, Innate genetics, MicroRNAs genetics, Mycobacterium tuberculosis immunology, Tuberculosis genetics, Tuberculosis immunology
- 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 Mtb-infected 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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2016
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