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Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles
Christopher A Baker1, Daniel Martin, Laura Manuelidis
1Section of Neuropathology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Abstract:
Neurons are often assumed to be the principal sites for replication of the infectious agents causing Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy because they express high levels of normal and pathological prion protein (PrP). However, isolated brain cell types have not been evaluated for either infection or gene expression. Microglia purified from CJD-infected mice showed infectivity comparable to that of starting brain homogenate but expressed approximately 50-fold less PrP. CJD-infected microglia also displayed morphological changes indicative of cellular activation. To determine the molecular pathways of activation, we evaluated pertinent transcripts, including those linked to inflammation. Semiquantitative reverse transcription-PCR showed a >4-fold increase in cathepsin S, an enzyme important in antigen presentation, the cytokine interleukin-1beta, and the chemokine B-lymphocyte chemoattractant. The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by beta-amyloid, a structure comparable to pathological PrP. These microglial studies emphasize migratory hematopoietic cells in the dispersion, and possibly replication, of the CJD agent. The low PrP levels in these highly infectious and activated cells further support the concept that pathological PrP is the result of infection rather than the infectious agent itself. Because microglia develop a specific pattern of responses to the CJD agent, microglial markers may be exploited in the diagnosis of these spongiform encephalopathies.
Insights
Microglia, not just neurons, are key in Creutzfeldt-Jakob disease (CJD) infection and spread. These immune cells become activated and infectious, suggesting new diagnostic approaches for prion diseases.
Area of Science:
- Neuroscience
- Immunology
- Infectious Diseases
Background:
- Neurons are traditionally considered the primary sites for prion replication in diseases like Creutzfeldt-Jakob disease (CJD).
- However, the role of other brain cells, particularly microglia, in prion infection and disease pathogenesis remains underexplored.
- Prion protein (PrP) expression levels in different cell types are crucial for understanding infection dynamics.
Purpose of the Study:
- To investigate the infectivity and gene expression profile of microglia in CJD-infected mice.
- To determine the molecular pathways involved in microglial activation by the CJD agent.
- To compare microglial responses to the CJD agent with responses to other stimuli like lipopolysaccharide and beta-amyloid.
Main Methods:
- Purification of microglia from CJD-infected mouse brains.
- Measurement of prion infectivity in purified microglia.
- Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) to assess gene expression, focusing on inflammatory markers.
- Morphological analysis of microglia to identify cellular activation.
Main Results:
- Purified microglia from CJD-infected mice exhibited high infectivity, comparable to brain homogenate, despite significantly lower prion protein (PrP) levels (approx. 50-fold less).
- CJD-infected microglia showed signs of cellular activation, with a >4-fold increase in transcripts for cathepsin S, interleukin-1beta, and B-lymphocyte chemoattractant.
- The activation profile in microglia differed substantially from responses induced by bacterial lipopolysaccharide or beta-amyloid.
Conclusions:
- Microglia play a significant role in the dispersion and potential replication of the CJD agent, highlighting the importance of migratory hematopoietic cells in prion diseases.
- The observed low PrP levels in highly infectious, activated microglia support the hypothesis that pathological PrP is a consequence of infection, not the infectious agent itself.
- Specific microglial responses to the CJD agent suggest that microglial markers could be valuable diagnostic tools for spongiform encephalopathies.
