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Human Cytomegalovirus Mediates Unique Monocyte-to-Macrophage Differentiation through the PI3K/SHIP1/Akt Signaling Network.
- Source :
-
Viruses [Viruses] 2020 Jun 17; Vol. 12 (6). Date of Electronic Publication: 2020 Jun 17. - Publication Year :
- 2020
-
Abstract
- Blood monocytes mediate the hematogenous dissemination of human cytomegalovirus (HCMV) in the host. However, monocytes have a short 48-hour (h) lifespan and are not permissive for viral replication. We previously established that HCMV infection drives differentiation of monocytes into long-lived macrophages to mediate viral dissemination, though the mechanism was unclear. Here, we found that HCMV infection promoted monocyte polarization into distinct macrophages by inducing select M1 and M2 differentiation markers and that Akt played a central role in driving differentiation. Akt's upstream positive regulators, PI3K and SHIP1, facilitated the expression of the M1/M2 differentiation markers with p110δ being the predominant PI3K isoform inducing differentiation. Downstream of Akt, M1/M2 differentiation was mediated by caspase 3, whose activity was tightly regulated by Akt in a temporal manner. Overall, this study highlights that HCMV employs the PI3K/SHIP1/Akt pathway to regulate caspase 3 activity and drive monocyte differentiation into unique macrophages, which is critical for viral dissemination.
- Subjects :
- Caspase 3 genetics
Caspase 3 metabolism
Class I Phosphatidylinositol 3-Kinases genetics
Cytomegalovirus genetics
Cytomegalovirus Infections genetics
Cytomegalovirus Infections metabolism
Cytomegalovirus Infections virology
Humans
Macrophages metabolism
Monocytes metabolism
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics
Proto-Oncogene Proteins c-akt genetics
Signal Transduction
Cell Differentiation
Class I Phosphatidylinositol 3-Kinases metabolism
Cytomegalovirus physiology
Cytomegalovirus Infections physiopathology
Macrophages cytology
Monocytes cytology
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism
Proto-Oncogene Proteins c-akt metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1999-4915
- Volume :
- 12
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Viruses
- Publication Type :
- Academic Journal
- Accession number :
- 32560319
- Full Text :
- https://doi.org/10.3390/v12060652