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)

Amyloid in both CJD and Alzheimer’s diseases is part of an innate immune response. Amyloids can trap environmental metagenomic viruses and other pathogens. We identified two novel circular DNAs (sphinx elements) in CJD and scrapie that may function in infection and pathology. Our findings raise fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environment that can cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging. Download here

History

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).

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. These cells allow better separation of infectious agent particles from pathologic host responses, including pathological PrP. Protein misfolding induced by several different viruses has become 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). The variety of TSEs agent-strains further implicates an agent genome that defines each strain. See CJD Major Discoveries and concepts

References:

1) Kipkorir T, Tittman S, Botsios S, Manuelidis L. Highly infectious CJD particles lack prion protein but contain many viral-linked peptides by LC-MS/MS. J Cell Biochem. 2014 Jun 16. doi: 10.1002/jcb.24873. PMID: 24933657

2) 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

3) 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

4) Miyazawa, K, Emmerling , K Manuelidis, L High CJD infectivity remains after prion protein is destroyed. J Cell Biochem. 112: 3630-3637, 2011 PMID: 21793041

5) 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