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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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PrPres plaques and spongiform changes in mice infected with vCJD no. 4 late or early brain.(A) PrP plaques were visible, here in the cortex of late brain passage, after periodic acid-Schiff (PAS) and Congo red staining. Note that their morphology and the surrounding ring of vacuoles are typical of florid plaques, a pathological hallmark of vCJD in human. (B) Hematoxylin and eosin staining of brain sections from mice infected with late or early brain. Note the distinct regionalization of vacuolation among the two agents. Th; thalamus. Bars: (A) = 200 µm. (B) = 100 µm.
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pone-0001419-g003: PrPres plaques and spongiform changes in mice infected with vCJD no. 4 late or early brain.(A) PrP plaques were visible, here in the cortex of late brain passage, after periodic acid-Schiff (PAS) and Congo red staining. Note that their morphology and the surrounding ring of vacuoles are typical of florid plaques, a pathological hallmark of vCJD in human. (B) Hematoxylin and eosin staining of brain sections from mice infected with late or early brain. Note the distinct regionalization of vacuolation among the two agents. Th; thalamus. Bars: (A) = 200 µm. (B) = 100 µm.

Mentions: The distinct nature of abnormal PrP deposits was further assessed by light and fluorescent microscopy examination of fixed and frozen sections. Numerous plaques were present only in late brain passage (Figure S2). Their structure had a typical aspect arranged in peripheral radiating spicules (Figures 3A and S3). They were Congo red (Figure 3A) and thioflavin-S positive (Figure S3), indicating an amyloid fibrils organization. A large number of these dense deposits were surrounded by a ring of vacuoles (Figure 3A), a morphology typical of the florid plaques observed in vCJD-infected humans [1]. Examination of histopathologic lesions in several areas of the brain indicated that spongiosis was prominent in the thalamus of late brain passage, whereas striatum and cortex were mostly damaged in early brain passage (Figure 3B). Astrogliosis activation was important in the thalamus and cortex frequently at the vicinity of the plaques in late brain, whereas it was spatially unrelated to PrPres deposition in early mice (Figure S2). In one of the early brains, the observed PrP distribution suggested the presence of both PrPsCJD and PrPvCJD, consistent with the mixed PrPres electrophoretic pattern visible on the immunoblot (Figure S4).


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)

PrPres plaques and spongiform changes in mice infected with vCJD no. 4 late or early brain.(A) PrP plaques were visible, here in the cortex of late brain passage, after periodic acid-Schiff (PAS) and Congo red staining. Note that their morphology and the surrounding ring of vacuoles are typical of florid plaques, a pathological hallmark of vCJD in human. (B) Hematoxylin and eosin staining of brain sections from mice infected with late or early brain. Note the distinct regionalization of vacuolation among the two agents. Th; thalamus. Bars: (A) = 200 µm. (B) = 100 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001419-g003: PrPres plaques and spongiform changes in mice infected with vCJD no. 4 late or early brain.(A) PrP plaques were visible, here in the cortex of late brain passage, after periodic acid-Schiff (PAS) and Congo red staining. Note that their morphology and the surrounding ring of vacuoles are typical of florid plaques, a pathological hallmark of vCJD in human. (B) Hematoxylin and eosin staining of brain sections from mice infected with late or early brain. Note the distinct regionalization of vacuolation among the two agents. Th; thalamus. Bars: (A) = 200 µm. (B) = 100 µm.
Mentions: The distinct nature of abnormal PrP deposits was further assessed by light and fluorescent microscopy examination of fixed and frozen sections. Numerous plaques were present only in late brain passage (Figure S2). Their structure had a typical aspect arranged in peripheral radiating spicules (Figures 3A and S3). They were Congo red (Figure 3A) and thioflavin-S positive (Figure S3), indicating an amyloid fibrils organization. A large number of these dense deposits were surrounded by a ring of vacuoles (Figure 3A), a morphology typical of the florid plaques observed in vCJD-infected humans [1]. Examination of histopathologic lesions in several areas of the brain indicated that spongiosis was prominent in the thalamus of late brain passage, whereas striatum and cortex were mostly damaged in early brain passage (Figure 3B). Astrogliosis activation was important in the thalamus and cortex frequently at the vicinity of the plaques in late brain, whereas it was spatially unrelated to PrPres deposition in early mice (Figure S2). In one of the early brains, the observed PrP distribution suggested the presence of both PrPsCJD and PrPvCJD, consistent with the mixed PrPres electrophoretic pattern visible on the immunoblot (Figure S4).

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