12 research outputs found
CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages : Antiviral Effects of mTOR Inhibitors
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 transplantatio
The influence of protein malnutrition on the production of GM-CSF and M-CSF by macrophages
ABSTRACT It is well established that protein malnutrition (PM) impairs immune defenses and increases susceptibility to infection. Macrophages are cells that play a central role in innate immunity, constituting one of the first barriers against infections. Macrophages produce several soluble factors, including cytokines and growth factors, important to the immune response. Among those growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). GM-CSF and M-CSF are important to monocyte and macrophage development and stimulation of the immune response process. Knowing the importance of GM-CSF and M-CSF, we sought to investigate the influence of PM on macrophage production of these growth factors. Two-month-old male BALB/c mice were subjected to PM with a low-protein diet (2%) and compared to a control diet (12%) mouse group. Nutritional status, hemogram and the number of peritoneal cells were evaluated. Additionally, peritoneal macrophages were cultured and the production of GM-CSF and M-CSF and mRNA expression were evaluated. To determine if PM altered macrophage production of GM-CSF and M-CSF, they were stimulated with TNF-α. The PM animals had anemia, leukopenia and a reduced number of peritoneal cells. The production of M-CSF was not different between groups; however, cells from PM animals, stimulated with or without TNF-α, presented reduced capability to produce GM-CSF. These data imply that PM interferes with the production of GM-CSF, and consequently would affect the production and maturation of hematopoietic cells and the immune response