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COMMENTARY: ORAL INFECTION BY THE BOVINE SPONGIFORM ENCEPHALOPATHY PRION

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From: jane.pritchard@...

Sender: BSE-L@... (Bovine Spongiform Encephalopathy)

Reply-to: BSE-L@... (Bovine Spongiform Encephalopathy)

April 27, 1999

PNAS

Vol. 96, Issue 9, 4738-4739,

R.. G. Will and J. W. Ironside

The route by which prion infection spreads from peripheral tissues to the

brain has been the subject of interest and research for decades. The

seminal pathogenesis studies by Hadlow and colleagues (1, 2) demonstrated

that in natural scrapie in Suffolk sheep infectivity initially was

detected at 10-14 months of age in tonsil, lymph nodes, spleen, and

intestine, including ileum and upper colon. The tissue distribution of

infectivity was consistent with uptake from the alimentary tract and, by

implication, oral exposure as the likely portal of entry of infection. By

the time clinical disease developed, peripheral tissues continued to

exhibit a similar distribution and titer of infectivity, but there was

also evidence of infectivity in the central nervous system, with higher

titers of infectivity, initially in the medulla and diencephalon.

Laboratory studies of oral scrapie infection in rodents have confirmed

these findings and suggest that infection spreads from the lymphoreticular

system to the spinal cord, presumptively via the autonomic nervous system,

and thence rostrally to the brain (3). The importance of peripheral

pathogenesis is underlined by the marked increase in incubation time in

mice after splenectomy (4).

There is, however, variation in pathogenesis that is determined by factors

including the interaction between host genome and agent strain. Some

breeds of sheep affected by natural scrapie, for example, Montadales, have

no detectable infectivity in peripheral tissues, and the distribution of

infectivity in the brain may vary according to the breed of sheep (5). In

bovine spongiform encephalopathy (BSE) infectivity has not been detected

in peripheral tissues in natural disease, except for dorsal root ganglia

and possibly bone marrow, although infectivity has been found in terminal

ileum after experimental oral challenge with BSE brain (6). An important

implication of this data is that, accepting the limits of the sensitivity

of bioassay systems, there may be variation in pathogenesis in different

host/agent combinations and extrapolation from date on scrapie, either

natural or experimental, to other agent strains in other species, such as

primates, may be misleading.

In primates only a small and unpredictable proportion of animals develop

disease after oral exposure to tissues containing a high titer of

infectivity such as brain (7). There is little information on pathogenesis

in nonhuman primates after oral exposure, not least because the relative

inefficiency of the oral route makes such experiments difficult to carry

out in practice. In kuru, which is presumed to be caused by peripheral,

and perhaps oral, exposure to infection through ritual cannibalism,

infection has been found by bioassay in lymph nodes, kidney, and spleen

(8). Similar experiments in Creutzfeldt-Jakob disease (CJD) have

demonstrated infectivity in liver, kidney, lung, and lymph nodes.

Examination of peripheral tissues by immumocytochemical techniques, either

histologically or by Western blot, in human prion disease has been fairly

limited and has not documented evidence of peripheral pathogenesis,

although these techniques have a limited sensitivity (9). More widespread

immumocytochemical staining of components of the lymphoreticular system

has been found in new variant CJD (nvCJD) (9), raising the possibility of

a different pathogenesis from sporadic CJD. The study by Bons et al. (10)

in a previous issue of the Proceedings provides new data on the

pathogenesis of prion disease in one primate species after experimental

oral exposure to BSE agent. This paper significantly extends the available

information on the tissue distribution of infectivity in the preclinical

phase of the incubation period in primates and confirms that primates can

be susceptible to oral exposure to the BSE agent. The findings will be of

interest and concern to the scientific community and others in view of the

hypothesis that nvCJD is causally linked to BSE, presumptively through

oral exposure to the BSE agent (11, 12). Consideration of methodological

issues is an important prerequisite to the interpretation of the results.

Immunocytochemical methods for the detection of disease associated prion

protein (PrPsc) depend on the, presumed, denaturation of normal prion

protein (PrPc), because none of the available antibodies can readily

distinguish between the isomers. This differentiation usually involves

partial protein digestion using proteinase K, but this methodology was not

used in this study (10) because only fixed tissues were examined. Bons et

al. have addressed this issue by carefully considering a range of criteria

for the interpretation of PrP antibody immunocytochemical staining.

Although it is highly likely that the positive PrP staining in this report

indicates the presence of PrPsc, the findings would be strengthened if

they were backed up by other techniques such as Western blotting.

The observations in this paper give some indication as to how prion

infection might spread after oral exposure. Of particular interest is the

staining of the epithelium of the gut and tonsil, which raises the

possibility of a number of mechanisms of onward transmission of infection

and subsequent disease. One possibility is that the infectious agent

penetrates the epithelial cells and replicates, another that the gut

epithelial cells express PrPc that acts as a receptor down which the agent

passes, without necessitating entry to cell cytoplasm. It is not known

whether gut epithelial cells express PrPc, but PrPsc can be detected in

gut-associated lymphoid tissue, particularly follicular dendritic cells

(13). An important question is how the infectious agent is transmitted

from the gut lumen to these cells. Immunocytochemical staining was found

in specialized M cells and lymphocytes within the gut epithelium and

lymphoreticular system. These interesting findings may stimulate further

experiments to address this important issue. It is of note that a recent

study has implicated B lymphocytes as necessary for neuroinvasion in one

model of experimental scrapie (14).

A further important observation in the study is the immumocytochemical

detection of PrPsc accumulation in the ventral and dorsal root ganglia

throughout the spinal cord and in the cerebral cortex in the preclinical

phase of the incubation period. This finding is consistent with models of

scrapie pathogenesis. However, the exact mechanism of transmission from

lymphoreticular system to central nervous system has not been precisely

defined. Possibilities include transmission via the neuro-immune

connection through the autonomic nerves in organized lymphoid tissue, such

as spleen, or via the autonomic nervous system in the gut. Further studies

are needed to investigate these interesting possibilities.

>From an epidemiological perspective the study by Bons et al. (10) raises

a

number of important issues. First, spongiform change and/or PrP

immunostaining were found in the brains of 20 lemurs from three different

primate centers in France and a simian in Montpellier zoo. The prevalence

of prion infection in the Montpellier primates overall was five of 61

animals, although it is of note that autopsy examination was not carried

out in nine of the 26 animals that had died. Although only two of these

animals had signs of a neurological disease, 18 lemurs from three other

primate

facilities in France were apparently healthy and exhibited positive PrP

immunocytochemical staining. The proportion of primates that had died with

evidence of preclinical or clinical prion disease after presumed oral

exposure to BSE was 19%, which may be an underestimate. On the other

hand, requests for information from other zoos in France on neurological

disease in primates was largely negative, although the response rate was

low. Furthermore, in Montpellier only 8% of primates, including those

still living were PrP-positive. Even this figure is a matter for great

concern if humans had a similar sensitivity to oral BSE exposure. However,

this hypothesis would assume that humans are identical to lemurs in their

susceptibility to BSE, an assumption that may not be justifiable.

Transmission of BSE to marmosets by intracerebral inoculation was reported

in 1993 (15), and this experiment was interpreted by the authors as

follows:

" Our experiments suggested that there was no specific reason to suppose

that the BSE agent was more transmissible to primates than was the scrapie

agent " (16). Scrapie is not thought to be a human pathogen. No primates

are reported to have developed a spongiform encephalopathy in British

zoos, despite the heightened awareness of these diseases after the

identification of a BSE-like illness in a range of potentially exposed zoo

species (17) (although only in a minority of such species). It is of

interest that BSE is experimentally transmissible to mice but not

hamsters, species that are genetically closely related (18).

Second, although two lemurs were PrP-positive after experimental oral

exposure to the BSE agent, it is relevant to question the source of

infection in the primates with apparently " natural " transmission. Three of

the lemurs, which died of spongiform encephalopathy in Montpellier, were

almost certainly exposed to oral infection at the zoo, but the source of

exposure in the other positive animals in Montpellier and the other three

zoos is necessarily uncertain. The animals all were exposed to a food

supplement containing cracklings, the " fourth quarter of beef, " which

might have originated in the United Kingdom. It would be of great interest

to

determine the constituents of this material and in particular whether it

contained central nervous system tissue. Marmosets, which are susceptible

to BSE by intracerebral inoculation, were fed in the United Kingdom

throughout life with a supplement containing meat and bonemeal potentially

contaminated with BSE between 1980 and 1990, but none of more than 100

uninoculated animals developed a spongiform encephalopathy (19). However,

Bons et al. (10) provide data indicating that the neuropathological

profile in the lemurs orally exposed to 0.5-1 g of bovine brain was

similar to that in lemurs with a " natural " spongiform encephalopathy,

suggesting that the disease in this group also may have been caused by

BSE.

The fact that primates are susceptible to a prion disease through oral

exposure to the BSE agent is a finding of great interest. Extrapolating

from this finding to human disease is problematic as the sensitivity of

one species to a particular prion strain does not necessarily indicate the

sensitivity of another species, even if this species is closely related.

Because of this constraint, the study by Bons et al. (10) may discourage

further experiments in other primates if these are aimed at quantifying

the risk posed to public health by oral exposure to the BSE agent, as the

results of such experiments can never provide hard information on what may

happen to the human population after oral exposure to BSE. However, the

paper should stimulate further research into pathogenesis of prion

diseases in view of the intriguing findings in peripheral tissues, and

there is clearly a need for more information on the peripheral

pathogenesis of human prion diseases, not least because of possible public

health implications.

FOOTNOTES

The companion to this Commentary is published on page 4046 in issue 7 of

volume 96.

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The National Academy of Sciences

R. G. Will and J. W. Ironside

National Creutzfeldt-Jakob

Disease Surveillance Unit,

Western General Hospital,

Edinburgh, EH4 2XU, United

Kingdom.

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