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Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD.

Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, Perret-Liaudet A, Haïk S, Vilotte JL, Fontés M, Laude H - PLoS ONE (2008)

Bottom Line: We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathological phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions.They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

View Article: PubMed Central - PubMed

Affiliation: Institut Scientifique de Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France. vincent.beringue@jouy.inra.fr

ABSTRACT

Background: The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Methodology/principal findings: Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.

Conclusion/significance: Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathological phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

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Regional distribution of PrPres in the brains of tg650 mice infected with vCJD and sCJD.The distribution of PrPres deposits in the brains of tg650 mice infected with vCJD no. 4 late or early brain, vCJD (case no. 1), and sCJD (case no. 2) or non-TSE material (mock) is shown on representative histoblots in 4 different antero-posterior sections. Note the differing size and distribution of PrPres deposits between late and early brain, and their similarity to that observed with vCJD and sCJD, respectively.
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pone-0001419-g002: Regional distribution of PrPres in the brains of tg650 mice infected with vCJD and sCJD.The distribution of PrPres deposits in the brains of tg650 mice infected with vCJD no. 4 late or early brain, vCJD (case no. 1), and sCJD (case no. 2) or non-TSE material (mock) is shown on representative histoblots in 4 different antero-posterior sections. Note the differing size and distribution of PrPres deposits between late and early brain, and their similarity to that observed with vCJD and sCJD, respectively.

Mentions: To confirm that the biological and molecular disparities observed after transmission of vCJD no. 4 reflected the propagation of two distinct prion strains, we examined the regional distribution of abnormal PrP and spongiform lesions in the brain, which are known to exhibit strain-dependant variations. We first performed histoblots analyses on antero-posterior coronal frozen sections to compare the distribution of PrPres in the brains of mice inoculated with late or early brain. In late brain passage, abundant and large, plaque-like PrP deposits were scattered throughout the brain, predominantly in the cerebral cortex, corpus callosum, several nuclei of the thalamus, optic tract and brain stem, a distribution similar to that seen in vCJD 1–3 brains (Figure 2; Table S1). In sharp contrast, PrP deposition in early brain passage was absent in most of these regions (Figure 2; Table S1). The staining was much less intense, rather diffuse, but nevertheless specific as compared to mock-infected mice (Figure 2). It was restricted to the ventral pallidum, dorsolateral geniculate, lateral posterior and mediodorsal nuclei of the thalamus and external cortex of the inferior colliculus, resembling that in sCJD 1–3 brains (Figure 2; Table S1).


Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD.

Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, Perret-Liaudet A, Haïk S, Vilotte JL, Fontés M, Laude H - PLoS ONE (2008)

Regional distribution of PrPres in the brains of tg650 mice infected with vCJD and sCJD.The distribution of PrPres deposits in the brains of tg650 mice infected with vCJD no. 4 late or early brain, vCJD (case no. 1), and sCJD (case no. 2) or non-TSE material (mock) is shown on representative histoblots in 4 different antero-posterior sections. Note the differing size and distribution of PrPres deposits between late and early brain, and their similarity to that observed with vCJD and sCJD, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171367&req=5

pone-0001419-g002: Regional distribution of PrPres in the brains of tg650 mice infected with vCJD and sCJD.The distribution of PrPres deposits in the brains of tg650 mice infected with vCJD no. 4 late or early brain, vCJD (case no. 1), and sCJD (case no. 2) or non-TSE material (mock) is shown on representative histoblots in 4 different antero-posterior sections. Note the differing size and distribution of PrPres deposits between late and early brain, and their similarity to that observed with vCJD and sCJD, respectively.
Mentions: To confirm that the biological and molecular disparities observed after transmission of vCJD no. 4 reflected the propagation of two distinct prion strains, we examined the regional distribution of abnormal PrP and spongiform lesions in the brain, which are known to exhibit strain-dependant variations. We first performed histoblots analyses on antero-posterior coronal frozen sections to compare the distribution of PrPres in the brains of mice inoculated with late or early brain. In late brain passage, abundant and large, plaque-like PrP deposits were scattered throughout the brain, predominantly in the cerebral cortex, corpus callosum, several nuclei of the thalamus, optic tract and brain stem, a distribution similar to that seen in vCJD 1–3 brains (Figure 2; Table S1). In sharp contrast, PrP deposition in early brain passage was absent in most of these regions (Figure 2; Table S1). The staining was much less intense, rather diffuse, but nevertheless specific as compared to mock-infected mice (Figure 2). It was restricted to the ventral pallidum, dorsolateral geniculate, lateral posterior and mediodorsal nuclei of the thalamus and external cortex of the inferior colliculus, resembling that in sCJD 1–3 brains (Figure 2; Table S1).

Bottom Line: We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathological phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions.They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

View Article: PubMed Central - PubMed

Affiliation: Institut Scientifique de Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France. vincent.beringue@jouy.inra.fr

ABSTRACT

Background: The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Methodology/principal findings: Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.

Conclusion/significance: Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathological phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.

Show MeSH
Related in: MedlinePlus