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Hidden CJD is new threat to thousands
By Nigel Hawkes, Health Editor
March 27, 2006
THOUSANDS of people in Britain may be infected with variant CJD, the human equivalent of mad cow disease, without knowing it, research suggests.
Experiments have confirmed that it is possible for a much wider group of people than had been assumed to be infected with the incurable brain condition. The presence in the population of undetected carriers of the infection has serious implications for the safety of the blood supply, and it increases the risk of passing on vCJD to others through infected surgical instruments.
It could make it much harder to eliminate the human infection, even though cattle no longer carry it. Potentially it could linger for generations, or for ever. The team behind the
research suggested that their finding represented a significant public
health issue.
Independent experts said that the work highlighted the need for a national autopsy programme for people who died of causes other than vCJD, to determine the extent of latent infection among those with no symptoms. So far, 161 cases of vCJD have been reported in Britain, 18 in France, and 12 in other parts of the world. These figures are much lower than some early estimates suggested, but the new data indicate that complacency is unjustified.
Up to 14,000 people may be carrying the rogue prion proteins that cause the disease without symptoms, the study indicates. Many scientists believe most of these will die of other causes before developing vCJD, but the length of the incubation period remains uncertain and it is possible they could account for a second wave of deaths from the disease.
In the study, published in The Lancet Neurology, a team led by Jean Manson, of the Institute for Anim
al Health, used genetically engineered mice to investigate the transmission of vCJD
.
The disease --known as BSE in cattle and vCJD in humans --is caused by a rogue version of the prion protein that curls itself up into the wrong shape. In the brain this leads to extensive damage, producing spongy voids that cause progressive symptoms and lead to an early death. There are no proven treatments.
Prions vary slightly from person to person according to genetic make-up, which influences how susceptible an individual is to catching the disease from meat.
Like all proteins, prions consist of a chain of amino acids. At a certain point on the chain there is a variation that occurs according to your genes. Some people have two copies of the amino acid valine at this position, some have one copy of valine and another copy of a different acid, methionine, while others have two copies of methionine. This creates three potential genetic types, known as VV, MV and MM.
So far, e
very singlecase of vCJD caught from beef has been in MM individuals, who make up about 40 per cent of t
he population. It has appeared that VV and MV individuals are protected from catching it, at least in this way, by genetic chance.
To check this, the Edinburgh team made three versions of the genetically modified mice, giving them the human genes to produce MM, VV, and MV prions. They also made mice with prion genes from a cow. They then injected BSE or vCJD into the mice's brains and waited for the results.
They found that BSE transmitted to the mice with cow prions, but not to mice with human prions --confirming what experience has taught us: that there is a fairly stiff species barrier preventing humans getting BSE. If this barrier had been lower the vCJD toll might have been as high as some early estimates suggested, and it is largely luck that it was not.
But they also found that vCJD transmitted to all three of the human lines: MM, as expected, but also MV and, to
a lesser extent, VV.
The implications are that when it comes to horizontal transmission of vCJD, all human bei
ngs --not just 40 per cent --are vulnerable. While the species barrier makes it hard to get BSE, it comes down for vCJD. Nobody is immune.
Interestingly, however, while brain tests of prions showed that MM and MV mice were equally easily infected, the MV mice did not develop any clinical signs of the disease within their lifetimes.
They died of something else, such as old age, before the brain disease could kill them.
Predicting susceptibility and incubation time of human-to-human transmission of vCJD
Summary
Background
Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encepha
lopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility.
Methods
Mice were produced to express
human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbr*d lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease.
Findings
BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV.
Interpretation
Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there see
ms to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary trans
mission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.
Affiliations
a. National CJD Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh, UK
b. Institute for Animal Health, Neuropathogenesis Unit, King's Buildings, Edinburgh, UK
Lancet Neurology (free registration required)
By Nigel Hawkes, Health Editor
March 27, 2006
THOUSANDS of people in Britain may be infected with variant CJD, the human equivalent of mad cow disease, without knowing it, research suggests.
Experiments have confirmed that it is possible for a much wider group of people than had been assumed to be infected with the incurable brain condition. The presence in the population of undetected carriers of the infection has serious implications for the safety of the blood supply, and it increases the risk of passing on vCJD to others through infected surgical instruments.
It could make it much harder to eliminate the human infection, even though cattle no longer carry it. Potentially it could linger for generations, or for ever. The team behind the
research suggested that their finding represented a significant public
health issue.
Independent experts said that the work highlighted the need for a national autopsy programme for people who died of causes other than vCJD, to determine the extent of latent infection among those with no symptoms. So far, 161 cases of vCJD have been reported in Britain, 18 in France, and 12 in other parts of the world. These figures are much lower than some early estimates suggested, but the new data indicate that complacency is unjustified.
Up to 14,000 people may be carrying the rogue prion proteins that cause the disease without symptoms, the study indicates. Many scientists believe most of these will die of other causes before developing vCJD, but the length of the incubation period remains uncertain and it is possible they could account for a second wave of deaths from the disease.
In the study, published in The Lancet Neurology, a team led by Jean Manson, of the Institute for Anim
al Health, used genetically engineered mice to investigate the transmission of vCJD
.
The disease --known as BSE in cattle and vCJD in humans --is caused by a rogue version of the prion protein that curls itself up into the wrong shape. In the brain this leads to extensive damage, producing spongy voids that cause progressive symptoms and lead to an early death. There are no proven treatments.
Prions vary slightly from person to person according to genetic make-up, which influences how susceptible an individual is to catching the disease from meat.
Like all proteins, prions consist of a chain of amino acids. At a certain point on the chain there is a variation that occurs according to your genes. Some people have two copies of the amino acid valine at this position, some have one copy of valine and another copy of a different acid, methionine, while others have two copies of methionine. This creates three potential genetic types, known as VV, MV and MM.
So far, e
very singlecase of vCJD caught from beef has been in MM individuals, who make up about 40 per cent of t
he population. It has appeared that VV and MV individuals are protected from catching it, at least in this way, by genetic chance.
To check this, the Edinburgh team made three versions of the genetically modified mice, giving them the human genes to produce MM, VV, and MV prions. They also made mice with prion genes from a cow. They then injected BSE or vCJD into the mice's brains and waited for the results.
They found that BSE transmitted to the mice with cow prions, but not to mice with human prions --confirming what experience has taught us: that there is a fairly stiff species barrier preventing humans getting BSE. If this barrier had been lower the vCJD toll might have been as high as some early estimates suggested, and it is largely luck that it was not.
But they also found that vCJD transmitted to all three of the human lines: MM, as expected, but also MV and, to
a lesser extent, VV.
The implications are that when it comes to horizontal transmission of vCJD, all human bei
ngs --not just 40 per cent --are vulnerable. While the species barrier makes it hard to get BSE, it comes down for vCJD. Nobody is immune.
Interestingly, however, while brain tests of prions showed that MM and MV mice were equally easily infected, the MV mice did not develop any clinical signs of the disease within their lifetimes.
They died of something else, such as old age, before the brain disease could kill them.
Predicting susceptibility and incubation time of human-to-human transmission of vCJD
Summary
Background
Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encepha
lopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility.
Methods
Mice were produced to express
human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbr*d lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease.
Findings
BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV.
Interpretation
Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there see
ms to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary trans
mission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.
Affiliations
a. National CJD Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh, UK
b. Institute for Animal Health, Neuropathogenesis Unit, King's Buildings, Edinburgh, UK
Lancet Neurology (free registration required)