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Infectious Prion Proteins Found to be Transmitted Extraneurally Cross-species: What Does that Mean for Public Health?

Talan, Jamie

doi: 10.1097/
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French researchers injected disease-causing prions from elk, hamsters, and cattle into the brains of mice genetically engineered to express sheep or humanized forms of infectious prion proteins and found evidence of cross-species transmission not only in their brains but in their spleens as well.

In the decade since bovine spongiform encephalopathy (BSE) jumped from cows to humans, it was thought that BSE-transmitted prions only target the brain. But a new study by French researchers suggests that infectious prion proteins may have a penchant for the spleen following cross-species transmission. In some strains, according to the study published in the Jan. 27 Science, the spleen is more permissive than the brain.

The findings are based on a series of experiments with transgenic animals. The scientists and others who study variant Creutzfeldt-Jakob disease (vCJD) worry that infectious prions may be latent in the spleens of unsuspecting people in the United Kingdom who may have been exposed to contaminated beef products. There have been around 200 confirmed cases of vCJD worldwide.

So-called prion protein, PrP, causes all known mammalian prion diseases. The endogenous, properly folded, form is denoted PrPC (for common or cellular) while the disease-linked, misfolded form is denoted PrPSc — for scrapie, after one of the diseases first linked to prions and neurodegeneration.

Until the BSE epidemic — dubbed “mad cow disease” — it was not known that an animal prion disease could be transmitted to the human species.

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Vincent Béringue, PhD, head of a laboratory in the virology immunology department of the French National Institute of Agricultural Research National Institute — Institut National de la Recherche Agronomique (INRA) — and his colleagues have been interested in cross-species transmission of prions for years. Their latest series of experiments identified some strains of the prion protein that have an easier time breaking the transmission barrier than others do, but specifically in the spleen.

“We know that cross-species transmission of the prion protein is a public health threat,” said Dr. Béringue. “These findings suggest we now have to be more careful than we have been. We need to understand why and whether this will have implications for disease in humans. For the moment, we don't know.”

The possibility that people may be silent carriers of an infectious pathogen that could trigger vCJD raises concern for the potential to pass on the disease through blood transfusions or during surgery. There are now studies underway in the UK looking at 300,000 samples of lymphoid tissue culled during surgical procedures.

Until recently, most studies only looked for infectious prions in the CNS. The French investigators used mice genetically engineered to express sheep or humanized forms of PrP. Then they injected disease-causing prions from elk, hamsters, and cattle into their brains and checked them for signs of disease throughout their life. At death, they collected and analyzed the tissue from the central nervous system and spleen.



If there were signs of disease, they considered the transmission barrier low; if there were no clinical or histopathological signs of infection, they assumed that the transmission barrier was high.

When Dr. Béringue and his colleagues looked outside of the brain to the spleen they were surprised — and worried. They found that while three of the 43 mice had detectable levels of prion in the brain, 26 of 41 of their spleens tested positive for prions. None of these mice showed clinical evidence of BSE.

The scientists concluded that for some strains lymphoid tissue was more permissive an environment than the CNS even though they infected the animal directly into the brain.

“As shown here, prions could persist silently for nearly a third of a host's life span before being detectable extraneurally by conventional diagnostic methods,” they said, adding that this “provides a transmission barrier that is more than sevenfold leakier in the spleen than in the brain.”

Dr. Béringue added: “If this is happening in humans, you can imagine that there are more people infected subclinically in lymphoid tissue who may never develop the disease.”

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Is that latency a potential threat to public health? Possibly, says one prion disease expert. These patients could infect others through blood transfusion, organ donation and surgery, and that worries John Collinge, MD, director of the Medical Research Council Prion Unit at University College London. In an accompanying editorial in Science, he wrote: “Concerns have persisted of a silent infection rate in the community because of the range of incubation periods in human prion diseases [partly genetically determined and which can exceed 50 years] and the possibility of subclinical carrier states.

“These data may also mean that apparent prevalence of subclinical prion infection will increase in BSE-exposed cohorts because it may take years to develop to a point detectable by these methods. All efforts should be made to assess the prevalence of prion infection in the UK population by analyzing surgical and autopsy LRS [lymphoreticular: spleen, lymph nodes, tonsil, appendix, and other gut-associated lymphoid tissues] and neural tissues, and investigating whether blood-based tests for vCJD can detect silent infection, both to assess prevalence of infection in donors, and if necessary, to ensure safety of blood and blood products and to avoid iatrogenic transmission during surgical and medical procedures.”

He added: “From a public health perspective, transmission barriers to infection, and not disease, matter for risk management as iatrogenic transmission will occur from healthy individuals, not those identified already as posing a risk by virtue of their clinical diagnosis of prion disease.”

What's more, multiple strains with different phenotypic traits can replicate in the same host, Dr. Collinge said.

Dr. Collinge said that efforts should be made to see how common prion infection is in the UK and to identify these people so that they do not give blood or donate organs.

He is overseeing the studies in the UK looking at the tissue samples from surgical procedures (mainly appendectomies). In two recent small studies, they reported that as many as one in 4,000 people in the UK could be carriers of infectious prions. That, said Dr. Collinge, could be as many as 20,000 people incubating the disease.

“This work is very important,” said Simon Mead, MD, PhD, a consultant neurologist at the UK National Prion Clinic based at the National Hospital for Neurology and Neurosurgery. “It suggests we should reconsider the meaning of the term ‘species barrier’ for prion propagation. We have relied on this barrier to protect us from epidemic animal prion diseases such as BSE and chronic wasting disease (CWD).”



“What Dr. Béringue and his colleagues have shown is that transmission across species barriers is much easier when you measure infection in lymphoreticular tissues rather than by brain tissue or clinical disease,” Dr. Mead explained. “In the study, infection rates across species barriers were remarkably high in lymphoid tissue, but rarely caused clinical disease or infection in the brain. Indeed, they showed that the prion strains — comparable with strains of influenza or tuberculosis — that grow in the lymphoreticular tissue of the inoculated animals are different from those in the brain.”

There is a big difference between finding PrPSc in lymphoreticular tissue/spleen of infected mice and development of clinical disease, said Kenneth L. Tyler, MD, the Reuler-Lewin Family Professor of Neurology, professor of medicine and microbiology and immunology, and chair of the neurology department at the University of Colorado-Denver School of Medicine.

“The species barrier idea — that prion diseases from one species were difficult to transmit to others — was based on detecting clinical disease,” said Dr. Tyler, who is also an associate editor of Neurology Today. “More recent studies suggest that in some cases prions are transmitted but disease doesn't seem to develop — in some cases even despite even accumulation of large number of PrPSc in brain; this suggests that the species barrier idea is more complex than we originally thought.

“It isn't always that prions fail to transmit, but in some cases they transmit and even replicate but disease doesn't occur. This study extends that a bit by noting that there may also be organ specific differences in which organs prions can replicate in after cross-species transmission.”

The implication for populations exposed to BSE is that there may be many more people infected by BSE prions in lymphoid tissues than have clinical disease, said Dr. Mead. “These people pose risks for public health as they may be blood donors and have operations without precautions being taken.” Dr. Mead's lab has developed a blood-based assay that might be used to look at the prevalence of prion infection in the UK population. Other groups are also developing blood tests for prion infection.

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• Béringue V, Herzog L, Laude H, et al. Facilitated cross-species transmission of prions in extraneural tissue. Science 2012;335(6067):472-475.
    • Collinge J. Cell biology. The risk of prion zoonoses. Science 2012;335(6067):411-413.
      ©2012 American Academy of Neurology