- Oral Transmissibility of Prion Disease Is Enhanced
by Binding to Soil Particles "We observed an almost 700-fold difference"
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- Soil Particles Found To
Boost Prion's Capacity To Infect
- By Terry Devitt
7-6-7
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- 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.
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- 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.
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- 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.
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- "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.
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- 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.
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- "These disease agents can stay out there for years
and stay infectious," Aiken explains.
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- 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.
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- 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.
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- "This is a dichotomy in our field, and maybe (the
new research) is part of the answer."
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- 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.
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- "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.
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- 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 mineral.
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- "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."
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- 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.
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- "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."
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- 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.
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- 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.
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- "Since the 1940s it's been known that 'infected
pastures' have the ability to infect new animals," according to Aiken.
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- 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."
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- 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.
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- Aiken emphasizes there's still much to learn about routes
of prion transmission, and the role of soil is just beginning to be explored.
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- "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."
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- 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.
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- http://www.news.wisc.edu/13918
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- Oral Transmissibility of Prion Disease Is Enhanced by
Binding to Soil Particles
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- Christopher J. Johnson1,2, Joel A. Pedersen3, Rick J.
Chappell4, Debbie McKenzie2, Judd M. Aiken1,2*
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- 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 America
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- 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.
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-
- snip...
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- Discussion These experiments address the critical question
of whether soil particlebound prions are infectious by an environmentally
relevant exposure route, namely, oral ingestion. Oral infectivity of soil
particlebound 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 PrPTSEMte 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.
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- 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.
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- 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 [4244]. Enhanced translocation of the
infectious agent from the gut lumen into the body may be responsible for
the observed increase in transmission efficiency.
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- 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.
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- 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.
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- 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 [5,79]. 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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- snip...full text is here:
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- http://pathogens.plosjournals.org/perlserv/?request=get-
document&doi=10.1371/journal.ppat.0030093
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- http://pathogens.plosjournals.org/perlserv/?request=get-
pdf&file=10.1371_journal.ppat.0030093-L.pdf
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- http://pathogens.plosjournals.org/perlserv/?request=get-
pdf&file=10.1371_journal.ppat.0030093-S.pdf
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- --TSS
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