MiR 155 regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis
Significance The mechanism by which Mycobacterium tuberculosis (Mtb) modulates the host immune response is not fully understood. We have used a systems biology approach to generate a microRNA regulatory network composed of 77 microRNAs that are associated with Mtb macrophage interactions. We have determined a unique and dual role for one of these regulators, miR 155, as a rheostat regulating the survival of both innate and adaptive immune cells. On the one hand, miR 155 maintains the survival of Mtb infected macrophages, providing a niche favoring bacterial replication. On the other hand, miR 155 maintains the survival of Mtb specific T cells, enabling an effective adaptive response. Our work underscores the value of systems based prediction of pathogen specific microRNA networks as a tool to define host pathogen interactions. 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.
Proceedings of the National Academy of Sciences