CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages : Antiviral Effects of mTOR Inhibitors

Autor: Poglitsch, M., Weichhart, T., Hecking, M., Werzowa, J., Katholnig, K., Antlanger, M., Krmpotić, Astrid, Jonjić, Stipan, Hörl, W. H., Zlabinger, G. J., Puchhammer, E., Säemann, M. D.
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: American Journal of Transplantation
Volume 12
Issue 6
ISSN: 1600-6135
DOI: 10.1111/j.1600-6143.2012.04002.x
Popis: Human cytomegalovirus (CMV) remains one of the most important pathogens following solid-organ transplantation. Mounting evidence indicates that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of CMV infection in solid- organ recipients. Here we aimed at elucidating the molecular mechanisms of this effect by employing a human CMV (HCMV) infection model in human macrophages, since myeloid cells are the principal in vivo targets of HCMV. We demonstrate a highly di- vergent host cell permissiveness for HCMV with opti- mal infection susceptibility in M2 but not M1 polarized macrophages. Employing an ultrahigh purified HCMV stock we observed rapamycin-independent viral entry and induction of IFN-b transcripts, but no proinflam- matory cytokines or mitogen-activated protein kinases and mTOR activation early after infection. However, in the late infection phase, sustained mTOR activa- tion was observed in HCMV-infected cells and was required for efficient viral protein synthesis including the viral late phase proteins pUL-44 and pp65. Accord- ingly, rapamycin strongly suppressed CMV replication 3 and 5 days postinfection in macrophages. In conclu- sion, these data indicate that mTOR is essential for virus replication during late phases of the viral cycle in myeloid cells and might explain the potent anti-CMV effects of mTOR inhibitors after organ transplantation
Databáze: OpenAIRE
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