Kuru, the First Human Prion Disease.

Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923⁻2008). In this review, we summarize the history of this seminal discovery, its anthropological background, epidemiology, clinical picture, neuropathology, and molecular genetics. We provide descriptions of electron microscopy and confocal microscopy of kuru amyloid plaques retrieved from a paraffin-embedded block of an old kuru case, named Kupenota. The discovery of kuru opened new vistas of human medicine and was pivotal in the subsequent transmission of Creutzfeldt⁻Jakob disease, as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.

Kuru: genes, cannibals and neuropathology.

Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.

Replication and spread of CJD, kuru and scrapie agents in vivo and in cell culture.

Transmissible Spongiform Encephalopathy (TSE) agents are defined by their virulence for particular species, their spread in the population, their incubation time to cause disease, and their neuropathological sequelae. Murine adapted human agents, including sporadic CJD (sCJD), New Guinea kuru, and Japanese CJD agents, display particularly distinct incubation times and maximal infectious brain titers. They also induce agent-specific patterns of neurodegeneration. When these TSE agents are transmitted to cultured hypothalamic GT1 cells they maintain their unique identities. Nevertheless, the human kuru (kCJD) and Japanese FU-CJD agents, as well as the sheep 22L and 263K scrapie agents display doubling times that are 8x to 33x faster in cells than in brain, indicating release from complex innate immune responses. These data are most consistent with a foreign viral structure, rather than an infectious form of host prion protein (PrP-res). Profound agent-specific inhibitory effects are also apparent in GT1 cells, and maximal titer plateau in kCJD and FU-CJD differed by 1,000-fold in a cell-based assay. Remarkably, the lower titer kCJD agent rapidly induced de novo PrP-res in GT1 cells, whereas the high titer FU-CJD agent replicated silently for multiple passages. Although PrP-res is often considered to be toxic, PrP-res instead may be part of a primal defense and/or clearance mechanism against TSE environmental agents. Limited spread of particular TSE agents through nanotubes and cell-to-cell contacts probably underlies the long peripheral phase of human CJD.

Agent strain variation in human prion disease: insights from a molecular and pathological review of the National Institutes of Health series of experimentally transmitted disease.

Six clinico-pathological phenotypes of sporadic Creutzfeldt-Jakob disease have been characterized which correlate at the molecular level with the type (1 or 2) of the abnormal prion protein, PrP(TSE), present in the brain and with the genotype of polymorphic (methionine or valine) codon 129 of the prion protein gene. However, to what extent these phenotypes with their corresponding molecular combinations (i.e. MM1, MM2, VV1 etc.) encipher distinct prion strains upon transmission remains uncertain. We studied the PrP(TSE) type and the prion protein gene in archival brain tissues from the National Institutes of Health series of transmitted Creutzfeldt-Jakob disease and kuru cases, and characterized the molecular and pathological phenotype in the affected non-human primates, including squirrel, spider, capuchin and African green monkeys. We found that the transmission properties of prions from the common sporadic Creutzfeldt-Jakob disease MM1 phenotype are homogeneous and significantly differ from those of sporadic Creutzfeldt-Jakob disease VV2 or MV2 prions. Animals injected with iatrogenic Creutzfeldt-Jakob disease MM1 and genetic Creutzfeldt-Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt-Jakob disease MM1 prions, whereas kuru most closely resembled the sporadic Creutzfeldt-Jakob disease VV2 or MV2 prion signature and neuropathology. The findings indicate that two distinct prion strains are linked to the three most common Creutzfeldt-Jakob disease clinico-pathological and molecular subtypes and kuru, and suggest that kuru may have originated from cannibalistic transmission of a sporadic Creutzfeldt-Jakob disease of the VV2 or MV2 subtype.

Kuru and D. Carleton Gajdusek: a close encounter.

Kuru, the first human transmissible spongiform encephalopathy, was transmitted to chimpanzees by D. Carleton Gajdusek (1923-2008). In this review, I briefly summarize the history of this seminal discovery alongside its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease as well as the prediction that bovine spongiform encephalopathy would be transmitted to humans. It was one of the greatest discoveries in biomedical sciences of the 20th century.

Cannibalism, kuru and anthropology.

This essay discusses the image and practice of cannibalism in a wide range of studies. It also presents the anthropological research on kuru which led to the proposal that cannibalism had enabled transmission of the infectious agent, as well as doubts about the hypothesis, and the assertion by some that cannibalism as a socially approved custom did not exist. The figure of the cannibal as an icon of primitivism took form in the encounter between Europe and the Americas. Cannibalism was to become the prime signifier of "barbarism" for a language of essentialized difference that would harden into the negative racism of the nineteenth century. Anthropological and medical research now challenge the derogatory image of the cannibal as we learn more about the many past consumers of human flesh, including ourselves.

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

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 approximately 8-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.

Review. The epidemiology of kuru: monitoring the epidemic from its peak to its end.

Kuru is a fatal transmissible spongiform encephalopathy restricted to the Fore people and their neighbours in a remote region of the Eastern Highlands of Papua New Guinea. When first investigated in 1957 it was found to be present in epidemic proportions, with approximately 1000 deaths in the first 5 years, 1957-1961. The changing epidemiological patterns and other significant findings such as the transmissibility of kuru are described in their historical progression. Monitoring the progress of the epidemic has been carried out by epidemiological surveillance in the field for 50 years. From its peak, the number of deaths from kuru declined to 2 in the last 5 years, indicating that the epidemic is approaching its end. The mode of transmission of the prion agent of kuru was the local mortuary practice of transumption. The prohibition of this practice in the 1950s led to the decline in the epidemic, which has been prolonged into the present century by incubation periods that may exceed 50 years. Currently, the epidemiological surveillance is being maintained and further studies on human genetics and the past mortuary practices are being conducted in the kuru-affected region and in communities beyond it.

Review. Understanding kuru: the contribution of anthropology and medicine.

To understand kuru and solve the problems of its cause and transmission required the integration of knowledge from both anthropological and medical research. Anthropological studies elucidated the origin and spread of kuru, the local mortuary practices of endocannibalism, the social effects of kuru, the life of women and child-rearing practices, the kinship system of the Fore and their willingness to incorporate outsiders into it, the myths, folklore and history of the Fore and their neighbours, sorcery as a powerful social phenomenon and way of explaining the causation of disease, and concepts of the treatment of disease. Many scientists from different disciplines, government officers and others have contributed to this chapter of medical history but it is the Fore people who have contributed the most, through their suffering, their cooperative and reliable witness to kuru, and their participation, in various ways, in the research process itself.

Mortuary rites of the South Fore and kuru.

This paper is part of a wider study to explain the historical spread and changing epidemiological patterns of kuru by analysing factors that affect the transmission of kuru. Part of the study has been to look at the mortuary feasts that were the means of transmission of the kuru agent. This paper shows the complexity of Fore eschatology, and the variations and contradictions of human behaviour in relation to mortuary rites and the transmission of kuru. It also confirms that oral ingestion was the primary route of inoculation though some cases of parenteral inoculation may have occurred. The exclusion of alternative routes of transmission is of importance owing to the dietary exposure of the UK and other populations to bovine spongiform encephalopathy prions.

Review. The origin of the prion agent of kuru: molecular and biological strain typing.

Kuru is an acquired human prion disease that primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. The central clinical feature of kuru is progressive cerebellar ataxia and, in sharp contrast to most cases of sporadic Creutzfeldt-Jakob disease (CJD), dementia is a less prominent and usually late clinical feature. In this regard, kuru is more similar to variant CJD, which also has similar prodromal symptoms of sensory disturbance and joint pains in the legs and psychiatric and behavioural changes. Since a significant part of the clinicopathological diversity seen in human prion disease is likely to relate to the propagation of distinct human prion strains, we have compared the transmission properties of kuru prions with those isolated from patients with sporadic, iatrogenic and variant CJD in both transgenic and wild-type mice. These data have established that kuru prions have prion strain properties equivalent to those of classical (sporadic and iatrogenic) CJD prions but distinct from variant CJD prions. Here, we review these findings and discuss how peripheral routes of infection and other factors may be critical modifiers of the kuru phenotype.

Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice.

Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD.

A potential role for transmissible spongiform encephalopathies in Neanderthal extinction.

The Neanderthals were a Eurasian human species of the genus Homo that disappeared approximately 30,000 years ago. The cause or causes of their extinction continues to intrigue specialists and non-specialists alike. Here a contributory role for Transmissible Spongiform Encephalopathies (TSEs) is suggested. TSEs could have infected Neanderthal groups as a result of general cannibalistic activity and brain tissue consumption in particular. Further infection could then have taken place through continued cannibalistic activity or via shared used of infected stone tools. A modern human hunter-gatherer proxy has been developed and applied as a hypothetical model to the Neanderthals. This hypothesis suggests that the impact of TSEs on the Neanderthals could have been dramatic and have played a large part in contributing to the processes of Neanderthal extinction.

[Acquired Creutzfeldt-Jakob disease (CJD)--Kuru, iatrogenic CJD, variant CJD].

Human prion diseases can be classified as sporadic, hereditary or acquired. The acquired forms are known to be caused by the transmission to human from human or animal, via medical appliances, oral intake or parenteral solutions. Usually, peripheral infection such as oral(Kuru) or parenteral (human pituitary hormones) transmission causes cerebellar degenerative form, and central nervous system infection such as neurosurgical treatment, dura mater grafts or corneal grafts transmission causes clinical features similar to sporadic form of Creutzfeldt-Jakob disease (CJD). The variant CJD (vCJD) is considered to be transmitted bovine spongiform encephalopathy(BSE) to human through dietary exposure. The early clinical features of vCJD are dominated by psychiatric symptoms, and minor number of patients have neurological symptoms from the onset. After about 6 months, there are frank neurological signs, including ataxia, cognitive impairment and involuntary movements.