Doubt cast on prion infectivity
Test results undermine BSE theory
Lasmezas clarifies experimental conditions
Commentary on no-prion study -- R. Heynkes

Immune effect of prions claimed

Transmission of the BSE Agent to Mice in the Absence of Detectable Abnormal Prion Protein

Science 275: #5298, pp. 402-4049 17 January 1997, submitted August 1996; accepted November 1996, Jean-Philippe Deslys, Olivier Robain, et al.

The agent responsible for transmissible spongiform encephalopathies (TSEs) is thought to be a malfolded, protease-resistantversion (PrPres) of the normal cellular prion protein (PrP). The interspecies transmission of bovine spongiform encephalopathy(BSE) to mice was studied. Although all of the mice injected with homogenate from BSE-infected cattle brain exhibited neurological symptoms and neuronal death, more than 55 percent had no detectable PrPres. During serial passage, PrPres appeared after the agent became adapted to the new host. Thus, PrPres may be involved inspecies adaptation, but a further unidentified agent may actually transmit BSE.

One of the distinct features of the BSE agent is its high ability to infect other species (1, 2, 3), whereas otherTSE agents are easily transmitted only within a species. This species barrier leads to considerable prolongation of the incubation period during interspecies transmission (4). During subsequent experimental passages, TSE agents adapt to the new host: the incubation period shortens and stable pathological properties are acquired(5). According to the prion hypothesis, PrPres (the pathological, protease-resistant isoform of the prion protein) constitutes the infectious agent in TSEs, and replication involves the homotypic interaction between a pathological PrP molecule and the endogenous native protein to produce a conformational conversion to the abnormal isoform. The magnitude of the species barrier would thus be a condition of the extent of congruency between the PrP of the donor species and that of the new host (6). However, this mechanism cannot account for the exceptional ability of the BSE agent to cross the species barrier. This agent has original properties and is suspected to have contaminated humans (2, 7). Thus, we examined BSE transmission and PrPres during primary transmission to mice and in subsequent passages to other mice.

Thirty C57BL/6 mice were inoculated by intracerebral injection of a 25% BSE-infected cattle brain homogenate. After 368 to 719 days, all of the inoculated animals exhibited symptoms of a neurological disease encompassing mainly hindlimb paralysis, tremors, hypersensitivity to stimulation, apathy, and a hunched posture. Biochemical analysis of their brains showed no detectable PrPres accumulation in more than 55% of the mice; these mice we retermed PrPres- (8).

Histological examination revealed neuronal death in all mice, but other classical changes associated withTSEs -- that is, neuronal vacuolation and astrocytosis--were limited to the PrPres+ mice. Neuronal loss was most obvious in the Purkinje cells of the cerebellum, but degenerated neurons were also observed,to a smaller extent, in the CA1 region of the hippocampus. No sign of local inflammation was present. Electron microscopic examinationof degenerated cells showed marginalization and clumping of the chromatin, a characteristic of type I apoptosis (9).

Legends of Figures

PrPres detection by protein immunoblot (26). In (A), brains of mice at the terminal stage of the disease (4 mg brain equivalent) were analyzed. B1, B10, B6, and B4, first passage from cattle brain; 2PB4-1, second passage from B4 mouse; Control, negative control brain (mouse inoculated withthe brain of a healthy cow and killed 800  days after inoculation without clinical signs); Pos, brain pool of mice at terminal stage of experimental scrapie (strain C506M3); Pos/x, dilutions of positive control. In (B), under conditions of maximal sensitivity, the PrPres signal can be detected at a 1 to10,000 dilution of the positive control (2.5 µg brain equivalent). Pos, control, and PrPres- samples correspond to 25 mg brain equivalent. (C) Similar degradation pattern of PrP with a range of doses of PK in a normal mouse brain and a PrPres- brain, showing the absence of PrPres with less resistance to protease than usual in PrPres- brains (27).

Transmission features of BSE into mice at first, second, and third passage (28). Histograms represent the amount of PrPres (expressed as a percentage of the positive control) in the brains of mice at the terminal stage of neurological disease. Diamonds represent the incubation period for each individual mouse tested for PrPres. The positive control corresponds to a brain pool of mice at the terminal stage of experimental scrapie (strain C506M3). At primary passage, individual mice were scored from B1 to B30 according to their incubation periods. The brains of B2, B3, B26, and B27 could not be analyzed and are not represented. The brains of B1 and B4 were inoculated to a second series of mice called, respectively, 2PB1 and 2PB4. At third passage, the recipient mice were called, respectively, 3PB1 and 3PB4. Second passages were also performed with B6, B10, and B15 and are not shown for the sake of clarity; they were consistent with the passages from B1and B4.

Histological examination of the brains of mice at the terminal stage of disease (29). (A and B) Toluidine blue staining in the cerebellum of a PrPres+ mouse (A) and a PrPres- mouse (B). Note the Purkinje cell layer with normal and degenerated cells. Vacuoles in the internal granular layer were seen only in the PrPres+ mouse. These lesions were not seen in aged control mice. Scalebar, 20 µm. (C and D) Immunohistochemistry for GFAPin the thalamus of a PrPres+ mouse (C) and a PrPres- mouse (D). The dark staining of protoplasmic astrocytes and the presence of vacuoles were seen only in the PrPres+ mouse. Scale bar, 20 µm. (E) Electron microscopic examinationof an apoptotic Purkinje cell in the cerebellum of a PrPres- mouse (30). Note the clumping and marginalization of the chromatin, as well as the normal aspect of the nuclear membrane (arrows) and cytoplasmic organelles (arrowheads show the Golgi apparatus and mitochondria). Scale bar, 0.5 µm.

The PrPres- mice were infected with a TSE agent because they could transmit a disease exhibiting the classical features of TSE, that is, PrPres accumulation and spongiform lesions. The brains of PrPres+ mice (for example, B1) and PrPres- mice (for example, B4) were used to inoculate a second seriesof mice. Most of the mice inoculated with PrPres- brains developed a classical TSE, but a few presented the PrPres- pattern again and the incubation periods remained spread. However, as was observed at primary passage, PrPres+ and PrPres- mice had the same range of incubation period (10). Transmission from PrPres+ mice led to an important reduction of incubation time that was very homogeneous (167 ± 2 days, mean ± SEM) with detectable PrPres in all mice.

A third passage was performed with one mouse from the B1 lineage and two mice from the B4 lineage, only one of which had detectablePrPres (Fig. 2). After inoculation with the PrPres- brain, incubation periods were shortened and less variable and all but one of the mice had detectable PrPres at the terminal stage of disease. Transmission from PrPres+ mice gave very similar incubation periods, whether originally inoculated with brain homogenate from the PrPres- or PrPres+ lineages. Finally, as a result of this third passage, the PrPres- pattern had almost disappeared. Thus, the PrPres+ pattern had a selective advantage and was associated with the short and homogeneous incubation periods. Therefore, PrPres could be associated with the adaptation of the agent to its new host.

Because we were able to transmit a TSE agent without detectable PrPres upon three passages, infectivity and PrPres can be dissociated [see also (11)]. The similarity of the clinical signs in PrPres- and PrPres+ mice suggests that neuronal death was the major determinant of central nervous system function impairment. However, the presence of spongiform lesions and overt gliosis was directly linked to that of PrPres (12). The role of PrPres in the pathogenesis of cerebral damage has been shown in vitro (13), as has the requirement for normal PrP in the development of disease and pathological lesions (14, 15). Thus, PrPres is clearly involved in the pathogenic process of TSEs. However, it may not be the transmissible component of the infectious agent.

This concept is supported by the multiplicity of TSE strains. For example, more than eight different strains can replicatein syngeneic C57BL/6 mice but exhibit specific properties (incubation period, distribution of the lesions, and biochemical features) even though the PrP of the host is the same (16, 17). Some strains are even able to retain their specific properties upon transmission to different hosts with different PrP molecules (1,16), whereas others undergo phenotypic changes when passaged in a single host (18). Finally, when mice lacking PrP were inoculated with either the Chandler scrapie strain or the mouse-adapted Fukuoka-1strain of Creutzfeldt-Jakob disease, they did not develop clinical disease, but several brains contained a transmissible agent 20 weeks after inoculation (14, 19).

Because we could transmit a TSE without detectable cerebral PrPres accumulation in the case of interspecies transmission of the BSE agent, the hypothesized existence of an infectious agent in addition to PrPres becomes more likely; in view of the complexity of TSE strain properties, this agent may be a nucleic acid. Moreover, our results suggest a pathogenic mechanism that may account for the peculiar efficacy of the BSE agent in crossing the species barrier. The BSE agent is virulent enough to replicate in the new host without PrPres accumulation. Hence, it is not eliminated,and during replication the agent may acquire the capacity to convert the new host PrP into PrPres. As a result of this adaptation,the transmissible agent would be tightly associated with PrPres,which would confer enhanced virulence and induce the development of classical spongiform lesions.


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  8. It could be argued that we killed our mice too early, when infectivity was not maximal in the brain. However, mice were killed at the premortem stage (that is, just before they would have died of disease). Moreover, it is known from experimental models that PrPres accumulation precedes the appearance of pathology and is detectable several months before clinical signs (17).
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  10. It could be argued that the mice that died of a neurological disease without detectable PrPres had been contaminated with a conventional agent during the inoculation process. This is unlikely because (i) control mice injected with normal cow brain remained healthy, and (ii) histological and electron microscopy examination of brains did not show classical encephalitis (complete lack of inflammatory cells or edema, absence of viral particles) but rather neuronal death, which is a hallmark of TSE and is particularly prominent in cattle BSE (20). It might also be argued that these findings are the result of laboratory contamination with prions during serial passage, but (i) the PrPres- trait was maintained and exhibited specific pathological features, and (ii) the mouse-adapted BSE strain obtained from the series of passages described here has been characterized and is clearly different from the scrapie strain C506M3 handled in our laboratory (17).
  11. A dissociation of PrPres and infectivity has been reported in fractionation and time course experiments as well as with amphotericin B treatment (21). Also, the absence of detectable PrPres has been described in several models of transgenic mice overexpressing a modified PrP and after some Creutzfeldt-Jakob disease transmissions in hamsters (22).
  12. These results are complementary to the observations made in PrP+/0 mice that PrPres accumulation and spongiform lesions reach their maximum extents more than 6 months before the animals die, hence they are dissociated from clinical condition and death (23).
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  19. No scrapie agent was detected from the 2nd to the 12th week after inoculation; this apparently excludes the possibility that sequestered original inoculum was responsible for the infectivity found at 20 weeks.
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  26. Mice were killed at the premortem stage by cervical fracture, and brains were immediately removed. One hemisphere (including the cerebellum) was frozen in liquid nitrogen and stored at -80°C for PrP analysis. (The other hemisphere was fixed for pathological examination.) For PrPres purification, the whole brain hemisphere was homogenized to 10% (w/v) in a 5% glucose solution. Briefly, proteinase K (PK) was used at 10 µg/ml (1 hour at 37°C) and digestion was blocked with phenylmethylsulfonyl fluoride (5 mM). After addition of sarkosyl to 10% and tris (pH 7.4) to 10 mM, samples were incubated for 15 min at room temperature. They were then centrifuged at 245,000g for 4 hours at 20°C on a 10% sucrose cushion (Beckmann TL100 ultracentrifuge). Pellets were resuspended in Laemmli buffer (24) and run on a 12% polyacrylamide gel. Protein immunoblotting procedures using chemiluminescence were as described (17). The standard conditions correspond to the load of samples equivalent to 4 mg of brain and a 1-min exposure time. Sensitivity of the detection can be increased by a higher loading of the gel (up to 25 mg) and a longer exposure time (up to 30 min).
  27. PK doses are expressed in micrograms of 10% brain homogenate per milliliter. Digestion was performed as described above with increasing doses of PK. After denaturation in Laemmli buffer, homogenates equivalent to 1 mg of brain were electrophoresed.
  28. Thirty adult male C57BL/6 mice were injected intracerebrally with 20 µl of 25% BSE-infected brain homogenate. Ten control mice were injected similarly with control cow brain. Subsequent mouse-to-mouse passages used 20 µl of 10% mouse brain homogenates (corresponding to about 1/200 of a mouse brain), except for the 2PB1-1 mouse inoculum (1% homogenate). Twenty mice were injected with a 1% brain homogenate of a mouse infected with experimental mouse scrapie, strain C506M3, constituting the positive control group. Negative control mice were kept in the same room and did not develop any neurological disease. The incubation periods correspond to survival times assessed according to the criteria in (25).
  29. Whole brain hemispheres were fixed in buffered 10% formalin. Pieces of brain were then embedded either in paraffin for immunohistochemistry (7-µm sections) or in Araldite (4-µm sections) for fine morphological examination. Antibodies were a polyclonal antibody to mouse glial fibrillary acidic protein (GFAP) and a horseradish peroxidase-conjugated secondary antibody (Dako). Seven PrPres- and six PrPres+ brains were examined. Spongiform lesions and gliosis could not be seen in any brain region of PrPres- mice. The absence of localized PrPres deposits was confirmed by PrP immunohistochemistry.
  30. Whole brain hemispheres were fixed overnight with a solution of 1% glutaraldehyde and 1% paraformaldehyde in 0.12 M phosphate buffer (pH 7.4). After 1 hour postfixation with 2% osmic acid, they were stained en bloc with uranyl acetate and embedded in Araldite. Ultrathin sections were stained with uranyl acetate and lead citrate before examination with a Philips CM10 electron microscope.
  31. We thank R. Bradley for BSE-infected cattle brain homogenate, C. Weissmann and R. H. Kimberlin for helpful discussions, and R. Rioux and J. C. Mascaro for expert animal care. We also thank P. Fritch and M. Wasowicz, as well as L. Court, who encouraged our research on TSE. Supported by a grant from D.R.E.T. (Paris).

Test results undermine BSE theory

By Roger Highfield, Science Editor
Telegraph ... Friday 17 January 1997

Evidence published today marks a serious setback for the most promising theory of what causes mad cow disease and Creutzfeldt-Jakob disease.

Spongiform diseases fascinate scientists because the agent that causes them appears quite different to bacteria, viruses and other classes of infectious agent. Increasing numbers of scientists believe that these diseases are caused by an infectious protein - a prion - which, unlike any other infectious agent, lacks genetic material.

Today, however, a team from the neurovirology service of the French Atomic Energy Commission, near Paris, undermines this idea in a paper published in the journal Science, which describes the results of the first detailed study of what happens when BSE adapts to a new host.

Dr Corinne Lasmezas, one of the team, said: "Our work suggests that the transmissible component of the agent is not the abnormal prion protein, though prions do have an important role."

The team found that neuronal damage and degeneration can occur without the build-up of the abnormal prion, thought to be an abnormally shaped form of a protein usually found in brain cells. They repeated an experiment undertaken by two teams in Britain, introducing some BSE-infected tissue into the brains of mice, but with a different approach.

Half of the genetically identical mice showing neurological symptoms consistent with the disease had no build-up of abnormal prion protein, called PrPres, in the brain, said Dr Lasmezas. Nerve death and damage occurred both in the presence and absence of the abnormal prion protein, although the characteristic spongy brain appearance only occurred when abnormal prions were present.

The team also found that the BSE infection could be passed on to other mice from the brains that contained no abnormal prion protein. The findings do not mean the prion is irrelevant to the disease, said Dr Lasmezas.

Lasmezas clarifies experimental conditions and interpretation

Email questions answered on 27 Jan 97 by Dr Lasmezas.

The samples are boiled in the presence of sodium dodecyl sulfate before running on the electrophoresis gel; therefore, the western blot is performed on denatured proteins and the antibodies (polyclonal antibodies directed against PrP and peptides of it) recognize the linear sequence of the molecule. Thus, it is most likely that PrPres would have been detected if it were present, irrespective of its threedimensional structure.

It is not our statement that the species barrier would be a condition of the extend of congruency between donor and receptor PrP. This is one of the conclusion of a very interesting study where Telling et al. (1995) observed that a point mutation in transgenic mice expressing chimaeric human-mouse PrP could be sufficient to overcome the species barrier.

Not only the sequence may be important, but also the "functional" effects of a given sequence on the conformation and charges of the molecule. However, in view of our experimental results, it seems more likely to us that the broad host-range of the BSE agent would be the result of the virulence of the transmissible agent rather than the fact of a "universal" abnormal PrP molecule.

Commentary on No-Prion study

Science 1997; 275: 402-405
Commentary by Roland Heynkes

Durch intrazerebrale Inokulation (Injektion ins Gehirn) wurden 30 C57BL/6-Mäuse mit einem 25%-igen Homogenat (feiner Brei) eines BSE-Gehirnes infiziert. Alle Tiere erkrankten nach 368-719 Tagen mit typischen Symptomen spongiformer Enzephalopathien (schwammförmiger Gehirnerkrankungen) und histopathologisch (unter dem Mikroskop) wurden durch Apoptose (zellulärer Selbstmord) vom Typ I zerstörte Neuronen (Nervenzellen) gefunden.

Interessanterweise konnten nur bei 11 der 30 Mäuse erkennbare Löcher, Astrozytose (Astrozytenvermehrung) sowie durch Antikörpermarkierung auf einem Western Blot proteaseresistente Prionproteine nachgewiesen werden. Für den sogenannten Western Blot wurden Gehirnproteine in einem Polyacrylamidgel nach Größen aufgetrennt und danach auf ein Filter übertragen. Auf diesem Filter können dann die Prionproteine mit Antikörpern sichtbar gemacht werden, sofern sie von den Antikörpern erkannt werden. Ein Zusammenhang zwischen der Inkubationszeit und der Existenz von Löchern, Astrozytose und der Existenz proteaseresistenter Prionproteine bestand nicht.

Die Infektion weiterer Mäuse mit Gehirnbrei von Mäusen mit markierbarem proteaseresistenten Prionprotein führte mit gleichmäßig kurzen Inkubationszeiten bereits nach etwa 150 Tagen zum Tod und in allen Fällen waren wiederum proteaseresistente Prionproteine und Löcher nachweisbar. Dagegen waren die Inkubationszeiten der Empfängermäuse mit 250-850 Tagen sehr unterschiedlich, wenn Gehirnmasse einer toten Maus ohne nachgewiesene Löcher und Prionprotein injiziert worden war. Außerdem traten wiederum nur bei 8 von 13 Mäusen proteaseresistente Prionproteine und Löcher auf. Immerhin war der Anteil der Mäuse ohne proteaseresistente Prionproteine bei der zweiten Passage wesentlich geringer.

Unter den Tieren mit kurzen Inkubationszeiten waren fast nur solche mit proteaseresistentem Prionprotein, während Mäuse mit und ohne proteaseresistente Prionproteine bei den längeren Inkubationszeiten gleich häufig waren. Bei einer dritten Passage waren die Ergebnisse ganz ähnlich. Die Empfänger von Gehirnbrei mit proteaseresistentem Prionprotein starben mit proteaseresistentem Prionprotein und einheitlich kurzen Inkubationszeiten von 150 Tagen. Diesmal starben jedoch die Empfänger von Gehirnbrei ohne proteaseresistentes Prionprotein fast alle mit proteaseresistentem Prionprotein und mit etwas längeren aber deutlich einheitlicheren Inkubationszeiten von 250-450 Tagen.

Die Löcher und die Astrozytose scheinen also an die Akkumulation der von den Antikörpern markierten proteaseresistenten Prionproteinen gekoppelt zu sein, während das Absterben der Neuronen unabhängig von den markierbaren Amyloiden beobachtet wurde.

Da sie mit ihren Antikörpern kein proteaseresistentes Prionprotein fanden und wegen der Existenz etlicher Erregerstämme, vermuten die Autoren, daß es Erreger außerhalb der Prione, wahrscheinlich mit Nukleinsäuren als genetischem Material geben müsse. Möglicherweise wurde jedoch bei einem Teil der Mäuse das proteaseresistente Prionprotein wegen einer etwas anderen räumlichen Struktur von den vrwendeten Antikörpern nicht erkannt.

Die Autoren meinen, BSE zeichne sich gegenüber anderen übertragbaren spongiformen Enzephalopathien durch eine wesentlich größere Übertragbarkeit auf andere Spezies aus und dies könne die Prion-Theorie nicht erklären, weil die Höhe der Speziesbarriere von der Ähnlichkeit zwischen infizierenden und körpereigenen Prionproteinen abhänge. Ich kann diese Einschätzung angesichts der erfolgreichen Übertragungen von Scrapie auf sehr viele andere Tierarten nicht teilen.

Wenn überhaupt, dann ist diese Eigenschaft bei BSE lediglich etwas ausgeprägter. Außerdem muß durchaus nicht nur die Ähnlichkeit über die Höhe der Speziesbarriere entscheiden. Beispielsweise könnten die Stabilität gebildeter Polymere, die Selektivtät der Oberflächen im Sinne von Generalschlüssel versus Zimmerschlüssel oder die Verteilung von Ladungen und hydrophoben Bereichen viel wichtiger als die Ähnlichkeit für die Fähigkeit eines Prionproteins zur Überwindung von Speziesbarrieren sein.

Weiterhin interpretieren die Autoren die Verkürzung der Inkubationszeit und die Durchsetzung des Amyloidtyps während der ersten Passagen in einer neuen Wirtsspezies, als eine Adaptation des Erregers. Hinter dieser Ansicht steht die Vorstellung eines genetischen Bauplanes.

Sämtliche Beobachtungen dieses Experimentes lassen sich aber ebenso gut damit erklären, daß zunächst die Inkubationszeit bei der ersten Passage durch die Unterschiede zwischen den fremden und den körpereigenen Prionproteinen und danach durch die Koexistenz verschiedener Varianten wirtseigener proteaseresistenter Prionproteine verlängert wird.

Während zunächst das fremde Prionprotein dem körpereigenen seine Form aufprägt, setzt sich möglicherweise nach und nach die für das Wirtsprionprotein energetisch günstigste Form durch. Dabei können unterschiedliche Formen auch zu verschiedenen klinischen Symptomen, pathologischen Schädigungsmustern und Bandenmustern in der Polyacrylamidgelelektrophorese führen. Die Koexistenz verschiedener Varianten sowie die Oberflächenstrukturen bestimmter Varianten und ihrer Spaltungsprodukte können auch ihre Fähigkeit zur Aggregation beeinflussen.

Could prions help boost body;'s defenses?

By John von Radowitz, Science Correspondent, PA News Jan 8, 1997

Prions, the proteins believed to cause mad cow disease and CJD, could in their harmless form play a crucial role reinforcing the body's defences, scientists believe. A "rogue" type of altered prion which sets up a chain reaction turning other prions "bad" is thought to be responsible for spongiform encephalopathy diseases like CJD. But scientists are still not sure what normal, harmless, prions (PrP) are used for. Researchers in Scotland now claim they could play a key role in the immune system. A team at the Institute for Animal Health in Edinburgh compared ordinary mice with others that lacked the gene for making prions. Then they stimulated the immune systems of the mice and observed how many T-cells they produced. T-cells are white blood cells that either destroy foreign invaders directly or help in the production of antibodies. It was found that the normal mice produced up to twice as many T-cells as the ones lacking prions. Moira Bruce, who led the research team, told New Scientist magazine: "This really does suggest that PrP has some some role in immune activation. It's the first time such a role has been suggested." The researchers also found that in normal mice some T-cells carried PrP on their surfaces. When exposed to a chemical that caused the cells to divide, the amount of PrP increased. This provided support for the theory that certain cells in the immune system may help to spread the rogue prions to the brain.