The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

Abstract

Human sporadic Creutzfeldt-Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and Ϸ8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases.sporadic CJD ͉ bovine spongiform encephalopathy ͉ viral adaptation ͉ prion protein receptor ͉ tissue culture infection

Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms

“…Both strains induced large PrP-res fibril accumulations within the GT1 cell cytoplasm ultrastructurally, and by Western blot. 3,14 The amount of residual PrP and PrP-res in p18 particles of both strains was also the same. Thus total PrP-res levels did not account for this strain-specific sensitivity.…”

“…The TCID assay has been verified in parallel animal inoculations, and indicator cells infected by different agents also recapitulate agent-specific titer differences by animal assay. 3,7,12,19,20,[42][43][44]50 Figure 6 shows 2 representative assays at early passages after infecting indicator cells. Figure 6A shows the urea and Figure 6B the GdnHCl effects on titer.…”

“…Our view is that a separate foreign viral particle of~22 nm binds to its essential PrP membrane receptor to induce abnormal PrP-res amyloid. 4 While PrP-res is an excellent surrogate marker for agentinduced disease in established animal and culture models, e.g., 3,5-8 strain-specific PrP folding patterns have not been apparent (reviewed in ref 9 ). Moreover, PrP itself is insufficient for infection.…”

“…1,2 There are at least 4 distinct infectious human CJD agents that show major differences in incubation time and neuropathology when compared in normal wt mice. 3 These 4 agents are the worldwide sporadic CJD (sCJD) agent, the more virulent Asiatic CJD strain (FU-CJD) that has not been identified in the Western hemisphere, the kuru agent of New Guinea, and variant CJD (vCJD) caused by the epidemic UK BSE agent. Misfolded prion amyloid resists limited proteinase K (PK) digestion (PrP-res), and presumably encodes all the different TSE agent-strains that infect mammals.…”

“…To further investigate agent particle structure and improve universal decontamination methods, we developed neuronal GT1 mouse cell cultures that stably support a variety of different TSE agent-strains. 3,42 We also devised a rapid and reproducible quantitative end-point tissue culture assay for representative CJD and scrapie agents that is only slightly less sensitive (by 0.5 logs or 3-fold) as compared to very expensive end-point animal assays that take~600 days. 7,19 This small difference in end-point sensitivity is statistically and biologically insignificant, especially for the 4 to >5 log (10,000 to >100,000 fold) titer losses reported here.…”