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Pathogenesis of bovine spongiform encephalopathy in sheep


L. J. M. van Keulen1 , M. E. W. Vromans1, C. H. Dolstra1, A. Bossers1 and F.
G. van Zijderveld1

(1) Department of Bacteriology and TSE’s, Central Institute for Animal
Disease Control (CIDC), Wageningen University and Research Centre, P.O. Box
2004, 8203 AA Lelystad, The Netherlands

Received: 16 August 2007 Accepted: 27 November 2007 Published online: 19
December 2007

Abstract The pathogenesis of bovine spongiform encephalopathy (BSE) in
sheep was studied by immunohistochemical detection of scrapie-associated
prion protein (PrPSc) in the gastrointestinal, lymphoid and neural tissues
following oral inoculation with BSE brain homogenate. First accumulation of
PrPSc was detected after 6 months in the tonsil and the ileal Peyer’s
patches. At 9 months postinfection, PrPSc accumulation involved all
gut-associated lymphoid tissues and lymph nodes as well as the spleen. At
this time point, PrPSc accumulation in the peripheral neural tissues was
first seen in the enteric nervous system of the caudal jejunum and ileum and
in the coeliac-mesenteric ganglion. In the central nervous system, PrPSc was
first detected in the dorsal motor nucleus of the nervus Vagus in the
medulla oblongata and in the intermediolateral column in the spinal cord
segments T7–L1. At subsequent time points, PrPSc was seen to spread within
the lymphoid system to also involve all non-gut-associated lymphoid tissues.
In the enteric nervous system, further spread of PrPSc involved the neural
plexi along the entire gastrointestinal tract and in the CNS the complete
neuraxis. These findings indicate a spread of the BSE agent in sheep from
the enteric nervous system through parasympathetic and sympathetic nerves to
the medulla oblongata and the spinal cord.

----------------------------------------------------------------------------
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L. J. M. van Keulen
Email: [email protected]



snip...


Discussion

In this study, we investigated the pathogenesis of a BSE infection in sheep
by following the accumulation of PrPSc in sheep killed at various time
points during the incubation period of BSE. The first tissues to accumulate
PrPSc were the lymphoid tissues of the GALT, followed by the GALT-draining
lymph nodes and the spleen and, at a later stage, the non-GALT lymph nodes.
The temporal spread and pattern of PrPSc deposition in the lymphoid tissues
were similar to those described previously for natural scrapie [21, 22]. In
the spleen of the BSE-infected sheep, however, a more abundant accumulation
of PrPSc was seen in macrophages of the marginal zone. This probably
reflects an active trapping and phagocytosis of PrPSc during a systemic
circulation of the BSE agent. This is in agreement with the studies of
Houston et al., who demonstrated the presence of infectivity in the blood of
orally BSE-infected sheep, both in the preclinical and clinical phase, by
the transmission of BSE to TSE-free recipients through whole-blood
transfusion [12, 14]. The question remains which fraction of the blood
contains BSE infectivity and thus whether the BSE agent is present in blood
plasma or whether it is associated with a cellular component of the blood.
Preliminary results from transfusion with blood fractions have shown
infectivity in the buffy coat but could not exclude infectivity in plasma
and/or red cell fractions [14].

The first peripheral nervous tissues to accumulate PrPSc in the pathogenesis
of BSE in sheep were the post-ganglionic parasympathetic motor neurons in
the submucosal and myenteric plexi of the ENS and the post-ganglionic
sympathetic motor neurons in the coeliac-mesenteric ganglion. The first
accumulations of PrPSc in the CNS were detected in the pre-ganglionic
parasympathetic motor neurons of the DMNV in the brain stem and in the
pre-ganglionic sympathetic motor neurons of the IMLC in the spinal cord.
From these initial sites of PrPSc accumulation in the peripheral and central
nervous system, PrPSc subsequently spread to involve the entire ENS and CNS.
This pathogenetic route of the BSE agent from the ENS through the efferent
motor fibers of the autonomic nervous system to the CNS is similar to the
pathogenesis of natural scrapie in sheep [20]. In scrapie- and BSE-infected
sheep, the preceding infection of the Peyer’s patches could possibly play a
role in facilitating the infection of the post-ganglionic motor neurons of
the ENS. In cattle orally exposed to BSE, infectivity has also been found in
the Peyer’s patches of the ileum [23, 24]. Preliminary observations on the
pathogenesis of BSE in cattle indicate a similar spread of the BSE agent
from the gut through the efferent autonomic nervous system to the CNS [11].
However, the role of the ENS in the pathogenesis of BSE in cattle is still
obscure as PrPSc was not found in the ENS during the early stages of a BSE
infection and only sparsely in the myenteric plexus of cattle in the end
stage of BSE [18].

The results of the present study can be compared with previous time course
studies on BSE in sheep in which the same dose and the same BSE brain
homogenate were used for oral inoculation of ARQ/ARQ Romney sheep. In these
studies, infectivity was detected by bio-assay in RIII mice in the Peyer’s
patches at 4 mpi [2]. In contrast, at this time point, PrPSc was detected
immunohistochemically only in the retropharyngeal lymph node and not in the
Peyer’s patches [2, 15]. In our study of ARQ/ARQ Texel sheep, we detected
sparse deposits of PrPSc at 6 mpi in both the tonsil and Peyer’s patches
that were only detected after thorough screening of the entire tissue by
examining sections every 50 µm until the blocks were exhausted. This might
explain the difference with the immunohistochemical studies in the Romney
sheep where PrPSc was only detected in the retropharyngeal lymph node, but
it is in general agreement with the bio-assay, where infectivity was found
in the Peyer’s patches at 4 mpi (but not in the tonsil). In the Texel sheep
killed at 9 mpi, all GALT tissues, the spleen, ENS, IMLC and DMNV were
positive for PrPSc, whereas in the Romney sheep at 10 mpi, PrPSc was only
detected in the retropharyngeal lymph node, and infectivity was only
detected in the spleen. This indicates a more rapid spread of the BSE
infection in the Texel sheep compared to the Romney sheep, since both the
dose and the inoculum were the same in the two studies. Because the age at
inoculation and the PrP genotypes of the animals in both studies were also
the same, the differences in the temporal spread of the BSE agent between
the two breeds must be related to other genetic factors outside the PrP
region, or to other unknown breed factors. In the Romney sheep, the BSE
agent only became widespread at 16 mpi when PrPSc and infectivity were
detected in a wide range of nervous tissues, lymphoreticular tissues and
viscera including the liver. PrPSc in the liver was reported to be present
within Kupffer cells at several stages of the BSE infection (M. Jeffrey,
personal communication). In the Texel sheep however, no PrPSc was detected
in Kupffer cells or hepatocytes at any stage during the BSE infection.

At present, active surveillance of TSE in sheep and goats has been increased
in the EU (EU regulation 214/2005) because of the finding of a BSE-infected
goat in France [7] and possibly in the UK (confirmation by strain typing is
still pending) [16]. Several rapid tests for TSEs in small ruminants are now
available (EU regulation 260/2005), all of which use the medulla oblongata,
and in particular, the obex region as source material for testing. In the
present study, we detected PrPSc in the DMNV at the obex of BSE-infected
sheep from 9 mpi. In a previous study of natural scrapie in sheep, PrPSc was
detected in the DMNV in sheep from 10 months of age [20]. Therefore,
preclinically TSE-infected animals are likely to be identified through rapid
testing as long as the DMNV region in the obex is excised and used for rapid
testing. Further biochemical and/or immunohistochemical tests can then be
used to differentiate BSE from scrapie infection, while final confirmation
of the TSE strain will still require bio-assay in mice.

Acknowledgments We would like to thank Dr Martin Jeffrey for supplying the
BSE brain homogenate. This work was supported by the EU (FAIR CT 98-7006)
and the Dutch Ministry of Agriculture, Nature and Food Quality.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any noncommercial
use, distribution, and reproduction in any medium, provided the original
author(s) and source are credited.




References

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Jeffrey M, Martin S, Gonzalez L, Hill P (2005) Natural transmission of BSE
between sheep within an experimental flock. Vet Rec 157:206


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Lockey R, Jeffrey M, Ryder S, Berthelin Baker C, Simmons MM (2005) Tissue
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3. Bruce ME, Chree A, McConnell I, Foster JD, Pearson GR, Fraser H (1994)
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11. Hoffmann C, Ziegler U, Buschmann A, Weber A, Kupfer L, Oelschlegel A,
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bovine spongiform encephalopathy. J Gen Virol 88:1048–1055


12. Houston F, Foster JD, Chong A, Hunter N, Bostock CJ (2000) Transmission
of BSE by blood transfusion in sheep. Lancet 356:999–1000


13. Houston F, Goldmann W, Chong A, Jeffrey M, Gonzalez L, Foster J, Parnham
D, Hunter N (2003) Prion diseases: BSE in sheep bred for resistance to
infection. Nature 423:498


14. Hunter N, Foster J, Chong A, McCutcheon S, Parnham D, Eaton S, MacKenzie
C, Houston F (2002) Transmission of prion diseases by blood transfusion. J
Gen Virol 83:2897–2905


15. Jeffrey M, Ryder S, Martin S, Hawkins SA, Terry L, Berthelin-Baker C,
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spongiform encephalopathy (bse). 1. onset and distribution of
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Scott AC, Wells GAH (1992) Feline spongiform encephalopathy: fibril and PrP
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Pathogenesis of natural scrapie in sheep. Arch Virol Suppl 16:57–71


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Langeveld JPM (1996) Immunohistochemical detection of prion protein in
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http://www.springerlink.com/content/k359v2012472l417/

http://www.springerlink.com/content/k359v2012472l417/fulltext.html

http://scrapie-usa.blogspot.com/2007/12/pathogenesis-of-bovine-spongiform.html


However, in the absence of comprehensive infectivity data to
facilitate a QRA, it was concluded that Specified Risk Materials (SRM)
removal alone was unlikely to be sufficient to eliminate the residual BSE
risk to the consumer from a BSE-infected sheep carcass.


SEE FULL TEXT ;


http://www.efsa.europa.eu/en/science/biohaz/biohaz_opinions/ej442_qra_bse_sheep.html


SEE FULL OPINION 44 PAGES ;


SNIP...


Subject: OPINION, BSE RISK IN SHEEP, HOPING FOR THE BEST, PREPARING FOR THE
WORST
From: "Terry S. Singeltary Sr." <[log in to unmask]>
Reply-To: Sustainable Agriculture Network Discussion Group <[log in to
unmask]>
Date: Fri, 16 Mar 2007 11:29:34 -0600


http://lists.ifas.ufl.edu/cgi-bin/wa.exe?A2=ind0703&L=sanet-mg&P=10348



SCRAPIE USA

http://scrapie-usa.blogspot.com/

http://scrapie-usa.blogspot.com/2007/12/pathogenesis-of-bovine-spongiform.html


NOR-98 ATYPICAL SCRAPIE CASES USA

http://nor-98.blogspot.com/


BSE BASE MAD COW TESTING TEXAS, USA, AND CANADA, A REVIEW OF SORTS


http://madcowtesting.blogspot.com/


MADCOW USDA the untold story

http://madcowusda.blogspot.com/


CHRONIC WASTING DISEASE

http://chronic-wasting-disease.blogspot.com/


Transmissible Mink Encephalopathy TME

http://transmissible-mink-encephalopathy.blogspot.com/


Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States

http://cjdusa.blogspot.com/


CJD QUESTIONNAIRE

http://cjdquestionnaire.blogspot.com/


SEAC 99th meeting on Friday 14th December 2007


Greetings,


AS one of them _lay_ folks, one must only ponder ;


"WITH the Nor-98 now documented in five different states so far in the USA
in 2007, and with the TWO atypical BSE H-BASE cases in Texas and Alabama,
with both scrapie and CWD running rampant in the USA, IS there any concern
from SEAC with the rise of sporadic CJD in the USA from ''UNKNOWN
PHENOTYPE'', and what concerns if any, in relations to blood donations,
surgery, optical, and dental, do you have with these unknown atypical
phenotypes in both humans and animals in the USA ???"


"Does it concern SEAC, or is it of no concern to SEAC?"

"Should it concern USA animal and human health officials?"


snip...


----- Original Message -----
From: xxxxxxxxxx
To: [email protected]
Sent: Thursday, November 22, 2007 5:39 AM
Subject: QUESTION FOR SEAC


Mr Terry S Singeltary Sr.,
Bacliff,
Texas 77518
USA.

Dear Mr Singeltary,


"Thank you for your e-mail of yesterday with the question for SEAC. I can
confirm that this will be asked at the meeting on your behalf and the
question and answer will appear in the minutes of the meeting which will be
published on the SEAC Internet site."


snip...see full text ;


http://seac992007.blogspot.com/



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