CJD Agents & Disease

Many pre-senile dementias of unknown etiology, such as Alzheimer's Disease (AD), share common host-activated neurodegenerative pathways, and these can result from various types of stress, including viral infections (1). Plaques with the same basic birefringent “colored” polarized structures, as shown, are present in CJD, and in various other human neurodegenerative diseases.

(Science 277:94,1997 PMID:9204907)

We established the first rodent models of human sporadic CJD (sCJD) in the 1970s, and showed that CJD was not maternally transmitted, i.e., not a genetic or inherited disease. As many neurotropic viruses, we were able to show that sCJD was carried to lymphoid tissues by white blood cells. CJD and other TSEs agents are not contagious (airborne). TSE agents persist in the environment and spread geographically, as between deer in the USA. While the source of the sCJD agent is unknown, humans inadvertently injected with sCJD contaminated growth hormone developed neurodegenerative disease up to 30 years later.

TSE agents can infect via the GI tract, as in epidemic “mad cow disease”. This UK cow agent causes human vCJD. After exposure, TSE agents spread to spleen and lymph nodes that continue to function normally, and the infection is clinically hidden or latent. Only much later do TSE agents invade the brain to cause incurable neurodegeneration. Our lab investigates host defenses that respond to the infection. These innate immune responses indicate TSE agents are recognizably foreign, unlike host prion protein (PrP).

Our lab investigates host defenses that respond to the infection and amyloid development (1,2). These innate immune responses indicate TSE agents are recognizably foreign, unlike host prion protein (PrP).

Rather, PrP amyloid is a late, innate immune response to infection (1) that can also reduce infection by 5 logs (2). Some of these amyloid-associated changes may coincide with those in AD. However, in CJD, the infection induces the response and can lead to TSE strain-specific misfolding as modeled at left (1).

Many innate immune responses to the CJD agent further substantiate viral induced response Recent work from our lab shows that normal post-mitotic SEP neurons, when differentiated by physiological arrest of cell division, produce low levels of b-interferon transcripts, an unexpected finding. Moreover, CJD infection induces interferon transcripts to rise 60x the amount found in uninfected SEP cells. To further assess additional antiviral responses to the infectious agent, bioinformatic data analysis of SEP transcript libraries revealed a remarkable elevation of many additional innate immune antiviral responses induced by CJD infection (5) as summarized diagrammatically. This is what would be expected for a virus hidden inside cells.

The essential molecules that define the infectious particle (of 20-25nm) remains undefined. Purified and/or recombinant PrP amyloid forms (prions) are not sufficient to reproduce infectious CJD or scrapie propagation (2,3,5). Unfortunately, host responses to infection are not sufficient to stop progressive infection. Effective treatment will require a rigorous molecular definition of the infectious agent. To this end we have developed new tissue culture models that support the replication of several distinct human agent-strains (4). These cells allow better separation infectious agent particles from pathologic host responses, including pathological PrP. Protein misfolding induced by several different viruses has become a well recognized in recent molecular studies, in accord with fundamental principles of pathology. Although many believe that misfolded host PrP is the infectious agent, claims that recombinant PrP can be made into an infectious form have been irreproducible (1,5). The variety of TSEs agent-strains further implicates agent genomes. See CJD Discoveries.

1. Manuelidis, L. Infectious particles, stress and induced prion amyloids: A unifying perspective. Virulence 2013 Jul 1;4(5):373-83. doi: 10.4161/viru.24838. PMID:23633671
2. Miyazawa K, Kipkorir T, Tittman S, Manuelidis L. Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease. PLoS One. 2012;7(4):e35471, PMID: 22509412
3. Miyazawa, K, Emmerling, K Manuelidis, L High CJD infectivity remains after prion protein is destroyed. J Cell Biochem. 112: 3630-3637, 2011 PMID: 21793014
4. Manuelidis, L, Chakrabarty, T, Miyazawa, K, Nduom, N-A, and Emmerling, K. The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents. Proc. Natl. Acad. Sci. USA 106: 13529-13534, 2009. PMID: 19633190
5. Pagano N, Gerard Aguilar Perez, Rolando Garcia-Milian, L Manuelidis. Proliferative arrest induces neuronal differentiation and innate immune responses in normal and Creutzfeldt-Jakob Disease agent (CJ) infected rat septal neurons, PLoS One. 2025 May 28; 20. PMID: 39131355