MiR-155-regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis.
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.
Center for Infectious Disease Research, Seattle, WA 98109.
Alissa C
AC
Rothchild
Center for Infectious Disease Research, Seattle, WA 98109.
James R
JR
Sissons
Center for Infectious Disease Research, Seattle, WA 98109.
Shahin
S
Shafiani
Institute for Systems Biology, Seattle, WA 98109.
Christopher
C
Plaisier
Center for Infectious Disease Research, Seattle, WA 98109.
Deborah
D
Min
Center for Infectious Disease Research, Seattle, WA 98109.
Dat
D
Mai
Center for Infectious Disease Research, Seattle, WA 98109.
Mark
M
Gilchrist
Novo Nordisk Inflammation Research Center, Seattle, WA 98109.
Jacques
J
Peschon
Center for Infectious Disease Research, Seattle, WA 98109.
Ryan P
RP
Larson
CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna 1090, Austria.
Andreas
A
Bergthaler
Institute for Systems Biology, Seattle, WA 98109.
Nitin S
NS
Baliga
Center for Infectious Disease Research, Seattle, WA 98109.
Kevin B
KB
Urdahl
Center for Infectious Disease Research, Seattle, WA 98109; alan.aderem@cidresearch.org.
Alan
A
Aderem
D056704:Adaptive Immunity / Q000235:genetics*; D000818:Animals; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D054884:Host-Pathogen Interactions / Q000235:genetics* / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D059467:Transcriptome; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051057:Proto-Oncogene Proteins c-akt; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Mycobacterium tuberculosis; T cell; macrophage; miR-155; microRNA
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