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From: TSS ()
Subject: Oral Transmissibility of Prion Disease Is Enhanced by Binding to Soil Particles "We observed an almost 700-fold difference"
Date: July 7, 2007 at 10:09 am PST

Soil particles found to boost prion’s capacity to infect
July 6, 2007

by Terry Devitt

The rogue proteins that cause chronic wasting disease (CWD) exhibit a
dramatic increase in their infectious nature when bound to common soil
particles, according to a new study.

Writing in the journal Public Library of Science (PLoS) Pathogens, a group
led by University of Wisconsin-Madison prion expert Judd Aiken reports that
prions, the protein agents of a family of fatal brain disorders, bind
tightly to a common soil mineral and significantly increase the oral
transmissibility of the agent.

The finding is important because it may help explain how chronic wasting
disease and scrapie persist in the environment and spread efficiently in
animal populations.

"We found a huge difference between infectious agent alone and infectious
agent bound to these soil particles," says Aiken, the senior author of the
new study and a professor of comparative biosciences in the UW-Madison
School of Veterinary Medicine. "We observed an almost 700-fold difference"
in the rate of infection.

Prions are an abnormal form of a protein produced normally by the body.
Tough as nails, they can persist in the environment for long periods of time
and retain their infectious capabilities. It is believed that prions may
persist in the soil around the carcasses of dead animals and other locations
where infected animals shed the protein in body fluids.

"These disease agents can stay out there for years and stay infectious,"
Aiken explains.

And herbivores such as deer and sheep, which are susceptible to prion
infection, tend to consume a fair amount of dirt daily as they graze and
forage. They are also known to consume soil as a source of minerals. Mineral
licks are frequented by many animals, raising the prospect that the agents
may become concentrated in the soil.

Relatively little is known about the routes of prion transmission in
animals, but the new Wisconsin study may help to resolve one puzzle: Oral
transmission of prions, says Aiken, tends not to be very efficient.

"This is a dichotomy in our field, and maybe (the new research) is part of
the answer."

In their studies, the Wisconsin researchers looked at the ability of prions
to bind to different types of common soil minerals. One, known as
montmorillonite, is a type of clay and prions seem to have a special
affinity for latching onto the microscopic particles.

"We expected the binding of the montmorillonite to be the highest among the
minerals we examined. However, we were surprised by the strength of the
binding," notes Joel Pedersen, a UW-Madison professor of soil science who
helped direct the new study.

The Wisconsin team also looked at the ability of the prion to bind to two
other common soil minerals: quartz and kaolinite, another common clay

"We found binding of the abnormal protein to all three," says Aiken, "but
the binding to montmorillonite was very avid, very tight. We found it very
difficult to remove the prions from the montmorillonite."

Feeding the prion-mineral mix to hamsters, a common animal model for prion
disease, Aiken's team expected to see a lower rate of infection than animals
dosed with pure agent. Surprisingly, prions bound to montmorillonite were
significantly more infectious than prions alone.

"We thought the binding might decrease infectivity," Aiken explains. "In
each case, you add montmorillonite and we get more animals sicker and
quicker than in the absence of montmorillonite clay."

What is occurring in soils in the woods and on the farm is unknown, says
Pedersen, but the new findings may help begin to answer some key questions
about how prions survive in the soil and retain their infectious nature,
sometimes for years.

In the case of scrapie, the prion disease of sheep, observations of sheep
pastures in the United Kingdom and Iceland have shown that animals
introduced into pastures that once held infected animals could become
infected. Infectivity of prions was also enhanced when they were bound to wh
ole soil.

"Since the 1940s it's been known that 'infected pastures' have the ability
to infect new animals," according to Aiken.

Pedersen notes that soils are a complex mixture of organic and inorganic
components that vary across the landscape and that scientists are just
beginning to tease out factors in soils that may contribute to
transmissibility. The new study implies, he says, "that some soils may
promote the transmission of the prion agent more readily than others."

Why that's the case is unknown, Pedersen explains, but the Wisconsin team is
exploring several hypotheses: that the soil particles might somehow protect
the prion from degradation in the digestive system, that prions bound to
clay might change the route or degree of uptake of the agent, or that the
mineral somehow alters the size of prion aggregates, which have been shown
to be more infectious than prions alone.

Aiken emphasizes there's still much to learn about routes of prion
transmission, and the role of soil is just beginning to be explored.

"Soil is a very complex medium and we don't know what the agent is binding
to" in natural or agricultural settings, Aiken says. "We do know that soil
is not the only way it transmits. Animal-to-animal transmission is
important, too."

In addition to Aiken and Pedersen, authors of the PLoS Pathogens paper
include Christopher J. Johnson, Rick J. Chappell and Debbie McKenzie. The
work was supported by a grant from the U.S. Department of Defense.

Oral Transmissibility of Prion Disease Is Enhanced by Binding to Soil

Christopher J. Johnson1,2, Joel A. Pedersen3, Rick J. Chappell4, Debbie
McKenzie2, Judd M. Aiken1,2*

1 Program in Cellular and Molecular Biology, University of
Wisconsin-Madison, Madison, Wisconsin, United States of America, 2
Department of Comparative Biosciences, School of Veterinary Medicine,
University of Wisconsin-Madison, Madison, Wisconsin, United States of
America, 3 Department of Soil Science and Molecular and Environmental
Toxicology Center, University of Wisconsin-Madison, Madison, Wisconsin,
United States of America, 4 Biostatistics and Medical Informatics,
University of Wisconsin Medical School, Madison, Wisconsin, United States of

Soil may serve as an environmental reservoir for prion infectivity and
contribute to the horizontal transmission of prion diseases (transmissible
spongiform encephalopathies [TSEs]) of sheep, deer, and elk. TSE infectivity
can persist in soil for years, and we previously demonstrated that the
disease-associated form of the prion protein binds to soil particles and
prions adsorbed to the common soil mineral montmorillonite (Mte) retain
infectivity following intracerebral inoculation. Here, we assess the oral
infectivity of Mte- and soil-bound prions. We establish that prions bound to
Mte are orally bioavailable, and that, unexpectedly, binding to Mte
significantly enhances disease penetrance and reduces the incubation period
relative to unbound agent. Cox proportional hazards modeling revealed that
across the doses of TSE agent tested, Mte increased the effective infectious
titer by a factor of 680 relative to unbound agent. Oral exposure to
Mte-associated prions led to TSE development in experimental animals even at
doses too low to produce clinical symptoms in the absence of the mineral. We
tested the oral infectivity of prions bound to three whole soils differing
in texture, mineralogy, and organic carbon content and found soil-bound
prions to be orally infectious. Two of the three soils increased oral
transmission of disease, and the infectivity of agent bound to the third
organic carbon-rich soil was equivalent to that of unbound agent. Enhanced
transmissibility of soil-bound prions may explain the environmental spread
of some TSEs despite the presumably low levels shed into the environment.
Association of prions with inorganic microparticles represents a novel means
by which their oral transmission is enhanced relative to unbound agent.


These experiments address the critical question of whether soil
particle–bound prions are infectious by an environmentally relevant exposure
route, namely, oral ingestion. Oral infectivity of soil particle–bound
prions is a conditio sine qua non for soil to serve as an environmental
reservoir for TSE agent. The maintenance of infectivity and enhanced
transmissibility when TSE agent is bound to the common soil mineral Mte is
remarkable given the avidity of the PrPTSE–Mte interaction [22]. One might
expect the avid interaction of PrPTSE with Mte to result in the mineral
serving as a sink, rather than a reservoir, for TSE infectivity. Our results
demonstrate this may not be the case. Furthermore, sorption of prions to
complex whole soils did not diminish bioavailability, and in two of three
cases promoted disease transmission by the oral route of exposure. While
extrapolation of these results to environmental conditions must be made with
care, prion sorption to soil particles clearly has the potential to increase
disease transmission via the oral route and contribute to the maintenance of
TSE epizootics.

Two of three tested soils potentiated oral prion disease transmission. The
reason for increased oral transmissibility associated with some, but not
all, of the soils remains to be elucidated. One possibility is that
components responsible for enhancing oral transmissibility were present at
higher levels in the Elliot and Bluestem soils than in the Dodge soil. The
major difference between the Dodge soil and the other two soils was the
extremely high natural organic matter content of the former (34%, [22]). The
Dodge and Elliot soils contained similar levels of mixed-layer
illite/smectite, although the contribution of smectite layers was higher in
the Dodge soil (14%–16%, [22]). The organic matter present in the Dodge soil
may have obstructed access of PrPTSE to sorption sites on smectite (or other
mineral) surfaces.

The mechanism by which Mte or other soil components enhances the oral
transmissibility of particle-bound prions remains to be clarified.
Aluminosilicate minerals such as Mte do not provoke inflammation of the
intestinal lining [39]. Although such an effect is conceivable for whole
soils, soil ingestion is common in ruminants and other mammals [25]. Prion
binding to Mte or other soil components may partially protect PrPTSE from
denaturation or proteolysis in the digestive tract [22,40] allowing more
disease agent to be taken up from the gut than would otherwise be the case.
Adsorption of PrPTSE to soil or soil minerals may alter the aggregation
state of the protein, shifting the size distribution toward more infectious
prion protein particles, thereby increasing the specific titer (i.e.,
infectious units per mass of protein) [41]. In the intestine, PrPTSE
complexed with soil particles may be more readily sampled, endocytosed
(e.g., at Peyer's patches), or persorbed than unbound prions.
Aluminosilicate (as well as titanium dioxide, starch, and silica)
microparticles, similar in size to the Mte used in our experiments, readily
undergo endocytotic and persorptive uptake in the small intestine [42–44].
Enhanced translocation of the infectious agent from the gut lumen into the
body may be responsible for the observed increase in transmission

Survival analysis indicated that when bound to Mte, prions from both BH and
purified PrPTSE preparations were more orally infectious than unbound agent.
Mte addition influenced the effective titer of infected BH to a lesser
extent than purified PrPTSE. Several nonmutually exclusive factors may
explain this result: (1) other macromolecules present in BH (e.g., lipids,
nucleic acids, other proteins) compete with PrPTSE for Mte binding sites;
(2) prion protein is more aggregated in the purified PrPTSE preparation than
in BH [45], and sorption to Mte reduces PrPTSE aggregate size, increasing
specific titer [41]; and (3) sorption of macromolecules present in BH to Mte
influences mineral particle uptake in the gut by altering surface charge or
size, whereas the approximately 1,000-fold lower total protein concentration
in purified PrPTSE preparations did not produce this effect.

We previously showed that other inorganic microparticles (kaolinite and
silicon dioxide) also bind PrPTSE [22]. All three types of microparticles
are widely used food additives and are typically listed as bentonite (Mte),
kaolin (kaolinite), and silica (silicon dioxide). Microparticles are
increasingly included in Western diets. Dietary microparticles are typically
inert and considered safe for consumption by themselves, do not cause
inflammatory responses or other pathologies, even with chronic consumption,
and are often sampled in the gut and transferred from the intestinal lumen
to lymphoid tissue [39,46,47]. Our data suggest that the binding of PrPTSE
to dietary microparticles has the potential to enhance oral prion disease
transmission and warrants further investigation.

In conclusion, our results provide compelling support for the hypothesis
that soil serves as a biologically relevant reservoir of TSE infectivity.
Our data are intriguing in light of reports that naïve animals can contract
TSEs following exposure to presumably low doses of agent in the environment
[5,7–9]. We find that Mte enhances the likelihood of TSE manifestation in
cases that would otherwise remain subclinical (Figure 3B and 3C), and that
prions bound to soil are orally infectious (Figure 5). Our results
demonstrate that adsorption of TSE agent to inorganic microparticles and
certain soils alter transmission efficiency via the oral route of exposure.

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