Article
Activation of resident brain microglia by viral infection leads to transient clearance of infectious prions from the brain
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Published: | August 25, 2015 |
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Introduction: Prion diseases are transmissible, fatal disorders, where the conversion of the cellular prion protein (PrPC) into a misfolded variant (PrPSc) leads to neurodegeneration. The spreading of the misfolded isoform to and within the brain is an essential step in the establishment and spreading of the disease.
Objectives: In this study, we wanted to assess the interplay of prion and retrovirus infections on the spreading of misfolded prion proteins and disease outcome.
Materials and methods: We used an established prion disease mouse model (RML 5.0) with defined incubation times and brain pathology. For retrovirus infection, we choose the molecular clone Mov3 of the murine retrovirus MoMuLV, since we could show that intraperitoneal injection led to persistent retrovirus infection without overt disease with our inoculation scheme. PrPSc amount was determined by Western blot and immunohistochemistry, whereas the titers of infectious prions in brain and spleen tissue were assessed by bioassay.
Results: In the early phases of the prion disease, an additional virus infection lead to a complete clearance of infectious prion species from the brain. This was accompanied by a transient increase of microglia numbers but no recruitment of monocytes from the periphery. The molecular profile of the retrovirus activated microglia was assessed via nCounter Nanostring analysis and showed upregulation of genes involved in protein degradation. However, transient microglia activation in the early disease phase did not lead to changes in prion disease outcome.
Conclusion: In our study, we could demonstrate transient clearance of infectious prion proteins by microglia activated via retrovirus infection, but this did not lead to differences in disease outcome. However, studies like this might help to characterize and understand microglia function and eventually help to manipulate microglia to reactivate their function in neurodegenerative diseases.