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From: Terry S. Singeltary Sr. (216-119-143-74.ipset23.wt.net)
Subject: Research Project: Emerging Zoonotic Diseases 2004 Annual Report
Date: January 3, 2005 at 10:05 am PST

In Reply to: CWD 2004 Annual Report posted by Terry S. Singeltary Sr. on January 3, 2005 at 10:03 am:

-------- Original Message --------
Subject: Research Project: Emerging Zoonotic Diseases 2004 Annual Report
Date: Sun, 2 Jan 2005 11:53:58 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@LISTSERV.KALIV.UNI-KARLSRUHE.DE


##################### Bovine Spongiform Encephalopathy #####################

Research Project: Emerging Zoonotic Diseases


Location:


Virus
and Prion Diseases of Livestock


2004 Annual Report

1. What major problem or issue is being resolved and how are you
resolving it (summarize project aims and objectives)? How serious is the
problem? What does it matter?
This project was initiated February 20, 2004, as a result of the FY 2004
Appropriations Bill passed by Congress and signed by the President for
research on Emerging Zoonotic Diseases, and focuses on emerging zoonotic
diseases reported in the United States. Many diseases exist that can
infect both man and animals (zoonotic diseases). Diseases with known and
unknown zoonotic disease potential, sporadically arise in animal
populations in the United States. An emerging disease is typically
investigated to rule out the existence of a foreign animal disease. Some
of these are foreign to the United States but can be easily introduced
through movement of man and or animals, as occurred in the 2002 outbreak
of monkey pox virus (MPV). Often known foreign animal diseases are ruled
out but no definitive diagnosis is made. There are currently no rapid or
easily applied tests to detect these diseases at borders or diagnostic
laboratories nor is it known what the ability of the infectious agent is
to infect animals. As a whole, the nation is poorly prepared to detect
and respond to incursions of new or existing diseases that may have
zoonotic potential.

This project is conducted with input from other agencies involved in the
detection and control of zoonotic diseases (USDA-APHIS, CDC, NIH). This
project will establish research on emerging zoonotic diseases as agreed
upon with the NPS as they are reported by these other agencies. With
input from other agencies, the principal research objectives are to
develop rapid diagnostic tests and determine the host range of the
emerging zoonotic disease in domestic animals (those which man comes in
contact with most frequently). Another objective is to work closely with
and assist other government agencies to develop a tactical plan for the
detection, verification, control and response to other incursions of
emerging zoonotic diseases into the United States; including but not
limited to bovine spongiform encephalopathy (BSE) in cattle. In short,
this project will provide the preparedness required to conduct research
triage to an emerging known or potentially zoonotic disease until such
time a permanent formal CRIS research project is established. In many
instances, no additional formal research project may be required beyond
the initial triage research.

2. List the milestones (indicators of progress) from your Project Plan.
2004 1. Convene an interagency meeting to review the Monkey pox outbreak
and future research needs to protect. 2. Review and update the ARS BSE
research plan. 3. Prepare security and biocontainment plan for working
with select agents and high consequence pathogens.

2005 1. Initiate studies to determine whether MPV produces an active
infection (replicates and sheds) in pigs, cattle and sheep. 2. In
collaboration with CDC and APHIS, develop validated diagnostic tests for
MPV in these species a. Validate the orthopox PCR diagnostic test for
use in livestock. b. Validate the MPV-specific PCR diagnostic test for
use in livestock. c. Determine serological cross reactions between
parapox and orthopox in livestock. d. Develop protein based diagnostic
assays. 3. Inoculate cattle with U.S. BSE

2006 1. Conduct any further infection or transmission studies needed
(based on findings from initial studies) to determine MPV pathogenesis
in pigs, cattle and sheep.

2007 1. Provide tissues from BSE inoculated cattle to scientists
conducting BSE research as part of the overall ARS BSE research plan.

3. Milestones:
A. List the milestones that were scheduled to be addressed in FY 2004.
How many milestones did you fully or substantially meet in FY 2004 and
indicate which ones were not fully or substantially met, briefly explain
why not, and your plans to do so.

1. Convene an interagency meeting to review the Monkey pox outbreak and
future research needs to protect. Completed. An interagency meeting held
at the NADC on June 30 and July 1, 2004. This meeting involved
scientists from the Centers for Disease Control and Prevention, the
National Wildlife Research Center, Wildlife Services, APHIS, the USGS -
National Wildlife Health Center and the NADC and National Program Staff
of the USDA-Agricultural Research Service (ARS). Research needs were
identified and are part of the 2005 research plan milestones. Laboratory
equipment critical to support pox virus research and diagnostics have
been purchased (including an electron microscope that replaces the
existing aging electron microscope that was no longer supported by its
manufacturer).

2. Review and update the ARS BSE research plan. Completed. The National
Program Staff organized two meetings of ARS scientists to review the
status of BSE research in the U.S. and determine where ARS could make
the greatest contributions and impact. These meetings were held in
Phoenix, Arizona on January 29, 2004 and at the NADC in Ames, IA on
April 14, 2004. An ARS BSE Strategic Research Plan was proposed which
focuses on the following six research goals: .
1)understand infectivity and tissues tropism;.
2)identify determinants of host specificity;.
3)understand the molecular mechanisms of prion replication;.
4)strain characterization and determinants of virulence;.
5)discover a live animal test; and.
6)discover cost effective methods of prion inactivation. An Interagency
Consultation Meeting was held at the USDA, South Building, Washington DC
on May 3, 2004 to present the ARS Research Plan to representatives of
other Federal Agencies (FDA, EPA, APHIS and CDC).

3. Prepare security and biocontainment plan for working with select
agents and high consequence pathogens. Select agent and high consequence
pathogen registration applications are being prepared for MPV and BSE
research. As part of the interagency MPV meeting, an inspection of our
gnotobiotic isolators for use with pigs, calves and lambs was performed.
These facilities were deemed fully adequate for the proposed MPV
research plan. Based on information from the interagency MPV meeting.
Final preparations of identified laboratory and animal research space
for working with MPV will be initiated once space becomes available on
October 1, 2004.

4. Site visits in the United Kingdom to review selected BSE research
protocols and facilities at the Veterinary Laboratory Agency ' Weybridge
and the Institute of Animal Health ' Compton, was completed in April of
2004 by the Research Leader, Center Director and a National Program
Leader. Design plans and standard operating procedures for BSE research
were shared with ARS from these institutes. Based on the information
provided and the best practices learned in the UK since their BSE
outbreak, a research barn to house cattle to be inoculated with BSE has
been designed. Bids have been received and the construction schedule
should allow inoculation of calves in February/March of 2005. This group
of calves will be allowed to mature and develop BSE in order to provide
an initial quantity of BSE infected CNS tissue to support the ARS BSE
strategic research plan.

B. List the milestones that you expect to address over the next 3 years
(FY 2005, 2006, & 2007). What do you expect to accomplish, year by year,
over the next 3 years under each milestone?

2005 1. Initiate studies to determine whether MPV produces an active
infection (replicates and sheds) in pigs, cattle and sheep. 2. In
collaboration with CDC and APHIS, develop validated diagnostic tests for
MPV in these species a. Validate the orthopox PCR diagnostic test for
use in livestock. b. Validate the MPV-specific PCR diagnostic test for
use in livestock. c. Determine serological cross reactions between
parapox and orthopox in livestock. d. Develop protein based diagnostic
assays. 3. Inoculate cattle with U.S. BSE

2006 1. Conduct any further infection or transmission studies needed
(based on findings from initial studies) to determine MPV pathogenesis
in pigs, cattle and sheep. 2. Because the incubation period for BSE is
typically 2 years or longer, it is anticipated that the major activity
during this year will involve monitoring and maintaining cattle
inoculated in 2005. 2007 1. Because the incubation period for BSE is
typically 2 years or longer, it is anticipated that the major activity
during this year will involve termination of the cattle BSE inoculation
experiments that began in 2005. Tissues obtained from this study will be
provided to ARS Scientists participating in the ARS BSE Strategic
Research Plan on separate CRIS projects.

4. What were the most significant accomplishments this past year?
A. Single Most Significant Accomplishment during FY 2004:

This project was initiated February 20, 2004, as a result of the FY 2004
Appropriations Bill passed by Congress and signed by the President for
research on Emerging Zoonotic Diseases. The mandate provided funding for
an interagency effort led by ARS to examine the presence of animal
related diseases and pathogen transmissions between animals and humans.
The committee directs that the Agency work directly with the Animal and
Plant Health Inspection Service, the Centers for Disease Control and the
Fish and Wildlife Services' Animal Health Laboratory at Madison, WI, to
develop and improve diagnostics and control efforts in regard to these
diseases. We convened interagency meetings to establish research
priorities that meet the needs of our major partners and stakeholders.
The anticipated outcome of the research activities from this project
will be to provide the initial research which can then expanded in scope
on this or separate CRIS projects focusing specifically on the pathogens
identified from an emerging zoonotic disease episode.

B. Other Significant Accomplishments(s):

We have completed development of a Specific Cooperative Agreement with
the Centers for Disease Control and Prevention to begin collaborative
MPV research.

We have designed a BSE research barn that will be to undergo
construction in FY05.

C. Significant Activities that Support Special Target Populations:

None

5. Describe the major accomplishments over the life of the project,
including their predicted or actual impact.
This project was initiated February 20, 2004, as a result of the FY 2004
Appropriations Bill passed by Congress and signed by the President for
research on Emerging Zoonotic Diseases, and focuses on emerging zoonotic
diseases reported in the United States. The major objectives are to are
to develop rapid diagnostic tests and determine the host range of an
emerging, potentially zoonotic disease in domestic animals (those which
man comes in contact with most frequently). Another objective is to work
closely with and assist other government agencies to develop a tactical
plan for the detection, verification, control and response to other
incursions of emerging zoonotic diseases into the United States;
including but not limited to bovine spongiform encephalopathy (BSE) in
cattle.

6. What science and/or technologies have been transferred and to whom?
When is the science and/or technology likely to become available to the
end-user (industry, farmer, other scientists)? What are the constraints,
if known, to the adoption and durability of the technology products?
None.

7. List your most important publications in the popular press and
presentations to organizations and articles written about your work.
None.

http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=408145&showpars=true&fy=2004

Research Project: Bse and Other Tses Ruminant Herbivors: Diagnosis,
Transmission and Genetics


Location:

Animal
Diseases Research


2004 Annual Report

1. What major problem or issue is being resolved and how are you
resolving it (summarize project aims and objectives)? How serious is the
problem? What does it matter?
Bovine spongiform encephalopathy (BSE) is a fatal disease of cattle,
first reported in the United Kingdom and now found in many European
countries and Japan, with isolated cases in Canada and the United
States. The disorder is related to consumption of feed contaminated with
the carcasses of BSE-infected cattle. Bans on recycling ruminant
material in ruminant feed are effective in reducing the number of
affected animals. However, identification of even a single case results
in economically devastating restriction in international trade, limits
the availability of some byproducts derived through rendering carcasses,
and increases the need for costly surveillance. Chronic wasting disease
(CWD) is another member of the TSE family of disorders, with a more
limited host range and no evidence to date of a zoonotic potential. CWD
is reported in free ranging and farm raised deer and elk in the U.S. and
Canada. CWD is a relatively uncharacterized TSE with novel patterns of
transmission and agent distribution, as well as providing the
considerable challenge of a controlling a persistent disease in free
ranging wildlife.

The objectives of the project are to develop inexpensive, high capacity
live animal and postmortem diagnostic tests, prion detection methods for
monitoring environmental contamination, and pathogenesis/transmission
experiments that provide direction to intervention techniques and
reagents. Control of all domestic prion diseases is important in
reducing trade barriers for U.S. sheep and germplasm and for assuring
the present and future global markets for cattle.

The goals of the project are (i) to develop diagnostic strategies that
contribute to disease control in captive and free ranging animals, (ii)
to identify genetic factors involved in resistance to disease and
reduction of transmission from infected animals, and (iii) to determine
routes of transmission and disease persistence in the population and the
environment.

These goals will be met through the following specific objectives: (1)
development of higher throughput, very inexpensive PrPd detection
methods, to be used diagnostically for postmortem and live animal
testing and in transmission and environmental contamination studies (2)
an efficient biological assay model using a panel of species-specific
transgenic mice, in which the murine gene is replaced by the appropriate
cervid PrP gene for genetic resistance and transmission studies; and (3)
characterization of the cervid PrP genes for identification of alleles
associated with genetic resistance

Our research concerning the transmissible encephalopathies addresses the
elements of our National Program in Animal Production, Product Value and
Safety. 103 Animal Health 100%, Pathogen Detection and Diagnostics,
Genetic Resistance to Disease, Epidemiology of Disease, and Strategies
to Control Infectious and Non-infectious diseases.. It also relates to
National Program 108, Food composition and Intake Food Safety.

The TSEs present a serious problem to US agriculture. Identification of
a single imported cow with BSE in December 2003 resulted in devastating
direct and indirect losses to the cattle, rendering, and pharmaceutical
industries with long term changes in handling of meat and byproducts
implemented by USDA, the Food and Drug Administration, and the Food
Safety Inspection Service. Although CWD affects a far smaller segment of
the agricultural community, the losses of domestic and foreign markets,
restrictions on trade and movement of live animals, and the substantial
costs associated with surveillance of hunter-killed animals represent
major economic losses for the cervid farming and hunting industries.
Agriculture and public health will benefit from reduced disease
prevalence, cost-effective diagnostic and surveillance methods,
prevention measures, and appropriate handling of facilities to reduce
the possibility of re-infection.

2. List the milestones (indicators of progress) from your Project Plan.
Year 1 (FY2003)

Develop monoclonal antibody and target binding molecules for PrP-d
detection.

Transgenic mouse (elk gene) development: construct preparation and
embryonic cell development.

Define the PRNP alleles in white tailed deer.

Identify a potentially contaminated cervid holding area, provide
appropriate biosecurity to insure that no wild ruminant animals enter or
leave the facility from the surrounding area, and restock with
susceptible species

Year 2 (FY2004)

Develop suitable assays for PrP-d detection.

Transgenic mouse (elk gene) development: characterization of homozygous
founder stock.

Describe the organization of the mule deer PRNP gene.

Prepare construct for white tailed deer transgenic mouse.

Monitor livestock in potentially contaminated facility.

Initiate oral exposure of mink to the CWD agent from elk.

Year 3 (FY2005)

Develop applications for PrP-d detection assays in animal tissues and
environmental samples.

Transgenic mouse development (elk gene): assay selected mouse lines.

Prepare construct for mule deer transgenic mouse.

Continue to monitor animals in potentially contaminated facility.

3. Milestones:
A. List the milestones that were scheduled to be addressed in FY 2004.
Which were fully or substantially met?

The milestones below were scheduled for FY2004 and have been partially met.

Develop suitable assays for PrP-d detection. This work is in progress.
We have developed assays using immunohistochemistry and enzyme-linked
immunosorbent assay. These techniques have not been shown to be
sensitive or specific enough to detect a marker in the blood of
naturally infected sheep. Additional work with more sensitive techniques
including mass spectroscopy and infrared spectroscopy will be performed
in year 2.

Transgenic mouse (elk gene) development: characterization of homozygous
founder stock. Prepare construct for white tailed deer transgenic mouse

Transgenic mouse development is progressing but is still in stage 1
(development of defined constructs and embryic stem cells.

The following milestones were described for FY 2004 and have been fully met.

Describe the organization of the mule deer PRNP gene.

Monitor livestock in potentially contaminated facility.

Initiate oral exposure of mink to the CWD agent from elk.

B. List the milestones that you expect to address over the next three
years. What do you expect to accomplish year by year?

Development and application of assays for diagnostic testing (FY2005)
and field testing of candidate assays (FY2006 and FY2007).

Development of assays for environmental contamination (FY2005 and 2006)
with remedial measures evaluated (FY2007).

Transgenic mouse development (elk and gene) with founder stock developed
in FY2005 and bioassays performed in FY2006.

Elk in potentially contaminated facility monitored in every year of the
project.

The potential for transmission of BSE through the placenta of
experimentally infected sheep will be evaluated (FY2005).

4. What were the most significant accomplishments this past year?
A. Genetics can be an important component of TSE control programs if
some polymorphisms in the prion gene are associated with reduced disease
incidence. In conjunction with Colorado State University, private
landowners (the Richard Edwards family), the Canadian Food Inspection
Agency, and the Nebraska Department of Game and Parks, the Animal
Disease Research Unit identified susceptible prion genotypes in elk,
white tailed deer and mule deer, characterized the first reported prion
pseudogene in placental mammals, and developed protocols for
differentiating between the functional gene and the pseudogene. We
demonstrated that all reported genotypes of mule deer are susceptible,
identified the single genotype in white tailed deer associated with a
reduced susceptibility to disease and demonstrated that elk of the most
resistant genotype can be affected by disease under some farm
conditions. This accomplishment supports the state and federal
regulatory agencies' control programs, and allows research laboratories
to correctly genotype cervid livestock.

B. Diagnostic testing is performed on a limited number of tissues and
correct identification of the most appropriate target tissue for each
species is critical for accurate surveillance. In collaboration with
Colorado State University, the Canadian Food Inspection Agency, and the
Nebraska Division of Game and Parks, the Animal Disease Research Unit
described the distribution of PrP-Sc in large populations of captive elk
and free ranging white tailed deer. This study demonstrated that the
most accurate testing of elk requires examination of the both the brain
and the retropharyngeal lymph node but testing of white tailed deer can
be accomplished by examination of the retropharyngeal lymph node alone.
This work provides the scientific basis for tissue selection for
diagnostic testing of elk and white tailed deer, complementing the
previous study on mule deer testing.

2) Although the transmission routes of CWD are unknown, placentas shed
by infected deer or elk are potential sources of environmental
contamination. Testing of reproductive tissues for assessing prion
contamination is performed in collaboration with Colorado State
University and the University of Idaho. These studies have shown no
evidence that CWD is transmitted by contact with the placenta of
infected females, as is seen in sheep scrapie.

3) Large and small carnivores feed on dead deer and elk in the CWD
endemic area. If these animals are susceptible to a TSE following oral
exposure to the agent in the tissues of dead deer or elk, they represent
another reservoir of disease. Under a cooperative agreement with the
University of Washington, mink were exposed to tissues from CWD-positive
elk. The incubation period is expected to exceed 18 months and results
are expected in FY2005.

C. Significant activities that support special target populations.

None

D. Progress Report opportunity to submit additional programmatic
information to your Area Office and NPS (optional for all in-house (¿D¿)
projects and the projects listed in Appendix A; mandatory for all other
subordinate projects).

None

5. Describe the major accomplishments over the life of the project,
including their predicted or actual impact.
Diagnostic test development: Postmortem diagnostic test methodology was
developed and transferred to the regulatory agencies for use in the U.S.
The test was modified for use in live deer, although the test requires
general anesthesia and re-trapping of deer found to be positive.
Monoclonal antibodies useful in assays on routinely formalin fixed
tissue from infected sheep, deer, elk, cattle, humans, mink, domestic
cats and a wide variety of captive wildlife potentially exposed to prion
diseases were developed. The technology was transferred to USDA, Animal
Plant Health Inspection Service, which contracts with a network of 20
veterinary diagnostic laboratories to provide surveillance for CWD in
the US. Gold standard testing of cattle for BSE is conducted only at the
National Veterinary Services Laboratory in Ames, IA. The technology and
antibodies are also used by the Canadian Food Inspection Agency in
Nepean, Ontario, and the Foreign Animal Disease Diagnostic Laboratory in
Winnipeg.

CWD genetics: We provided the first report of a processed prion
pseudogene in livestock, allowing research laboratories and wildlife
managers to correctly identify the prion functional gene in wildlife.
Using the appropriate testing technology, we demonstrated that none of
the reported genotypes of cervids are associated with disease resistance
and genetic measures cannot be a component of the federal CWD control
program. However, one genotype in elk is associated with very low
disease prevalence and it is possible that selection for this genotype
in captive elk with very minor potential exposure to CWD would reduce
the disease incidence.

6. What science and/or technologies have been transferred and to whom?
When is the science and/or technology likely to become available to the
end-user (industry, farmer, other scientists)? What are the constraints,
if known, to the adoption and durability of the technology products?
The antiprion monoclonal antibodies have been licensed to private
companies for development of immunohistochemistry and enzyme linked
immunosorbent assays. An IHC test for BSE using one of the monoclonal
antibodies is licensed and marketed internationally. In the US, TSE
testing is conducted by the federal government or by federally approved
laboratories. All the IHC testing performed in the US for livestock TSEs
is performed with the technology and antibody reagents developed by this
project.

7. List your most important publications in the popular press and
presentations to organizations and articles written about your work.
1. BSE diagnostic testing in the US. Invited presentation to the 12th
Annual Food Safety Farm to Table Conference, May 2004, Moscow, ID

2. BSE Testing Technology. Invited presentation to the Beef Industry
Food Safety Council Industry Summit on Bovine Spongiform Encephalopathy,
Fort Worth, TX, April 26, 2004

3. Is BSE in sheep at threat to the US sheep industry? Invited
presentation to the Sheep and Goat Health Committee Seminar, National
Institute for Animal Agriculture, April 4, 2004, Salt Lake City, UT

4. Prion susceptibility genetics in three cervid species, invited
presentation to the Annual meeting of the American College of Veterinary
Pathologists, Banff, Canada, November 15, 2003

Review Publications
O'Rourke, K.I., Spraker, T.R., Hamburg, L.K., Besser, T.E., Brayton,
K.A., Knowles, D.P. 2004. Polymorphisms in the prion precursor
functional gene but not the pseudogene are associated with susceptibilty
to chronic wasting disease in white-tailed deer. Journal of General
Virology. 85:1339-1346.


Brayton, K.A., O'Rourke, K.I., Lyda, A.K., Miller, M.W., Knowles, D.P. A
processed pseudogene contributes to apparent mule deer prion gene
heterogeneity. Gene. 2003. v. 326. p. 167-173.

Hamir, A.N., Miller, J.M., O'Rourke, K.I., Bartz, J.C., Stack, M.J.,
Chaplin, M.J. 2004. Transmission of transmissible mink encephalopathy
(TME) to raccoons (Procyon lotor) by intracerebral inoculation. Journal
of Veterinary Diagnostic Investigation. 16(1):57-63.


http://www.ars.usda.gov/research/projects/projects.htm?ACCN_NO=404978&fy=2004

TSS

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