title: Activation of microglia by retroviral infection correlates with transient clearance of prions from the brain but does not change incubation time.
abstract: Prion diseases are fatal transmissible diseases, where conversion of the endogenous prion protein (PrPC) into a misfolded isoform (PrPSc) leads to neurodegeneration. Microglia, the immune cells of the brain, are activated in neurodegenerative disorders including prion diseases; however, their impact on prion disease pathophysiology is unclear with both beneficial PrPSc-clearing and detrimental potentially neurotoxic effects. Moreover, monocytes entering the brain from the periphery during disease course might add to disease pathophysiology. Here, the degree of microglia activation in the brain of prion infected mice with and without an additional intraperitoneal retrovirus infection was studied. Peripheral murine retrovirus infection leads to activation of parenchymal microglia without recruitment of monocytes. This activation correlated with transient clearance or delay in accumulation of infectious prions specifically from the brain at early time points in the diseases course. Microglia expression profiling showed upregulation of genes involved in protein degradation coinciding with prion clearance. This enforces a concept where microglia act beneficial in prion disease if adequately activated. Once microglia activation has ceased, prion disease reemerges leading to disease kinetics undistinguishable from the situation in prion-only infected mice. This might be caused by the loss of microglial homeostatic function at clinical prion disease.
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christiane
authors: C
authors: Muth
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Katharina
authors: K
authors: Schröck
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Charlotte
authors: C
authors: Madore
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Kristin
authors: K
authors: Hartmann
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Zain
authors: Z
authors: Fanek
authors: Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Oleg
authors: O
authors: Butovsky
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Markus
authors: M
authors: Glatzel
authors: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors: Susanne
authors: S
authors: Krasemann
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology*; D055256:Infectious Disease Incubation Period; D051379:Mice; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D017096:Prion Diseases / Q000150:complications / Q000276:immunology*; D011328:Prions / Q000276:immunology*; D059748:Proteolysis; D012192:Retroviridae Infections / Q000150:complications / Q000276:immunology*
chemical_list: D011328:Prions
keywords: clearance; microglia; microglia signature; monocytes; neurodegeneration; prion disease; prions; protein misfolding; retrovirus