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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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Western blots analysis of PrPres in the brains and spleens of tg650 mice infected with sporadic and variant CJD by intracerebral route.(A) Electrophoretic pattern of PrPres in the brain (upper panel) and spleen (lower panel) upon primary transmission. Note that vCJD case no. 4 shows either a typical vCJD or sCJD-like pattern in the brains of mice succumbing late or early with disease, respectively, while a vCJD-like pattern is consistently observed in the spleens. The PrPres profiles of variant and sporadic CJD in the brain of affected human patients are shown on the sides (left and right, respectively) of both immunoblots for comparison. (B) Ratio of diglycosylated and monoglycosylated PrPres species in the brains of mice following serial transmission of sporadic or variant CJD cases (data plotted as means±SEM). PrPvCJD and PrPsCJD patterns are represented by brown and grey colors, respectively. Variant CJD cases no. 1, 2, 3 and 4 are represented as diamond, circle, square, and triangle; sCJD cases no. 1, 2, 3 and 4 as polygon, star, ellipse, and rectangle. Secondary transmissions (when available) are represented by the same, unfilled symbols. Note the distinct glycoform ratio between early (grey triangle) and late brains upon transmission of vCJD case no. 4. (C) In early succumbing mice, the size of the PrPres fragments is higher in the brain (Br) than in the spleen (Sp), whereas in late succumbing it remains similar, as shown after deglycosylation by PNGase treatment. MM: molecular markers. (D) Electrophoretic pattern of PrPres in the brain and spleen upon secondary transmission. tg650 mice were inoculated with brain or spleen homogenates from either sCJD or vCJD case 4 late or early mice. The brain PrPres profile of human vCJD is shown on the left side of the gel for comparison.
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pone-0001419-g001: Western blots analysis of PrPres in the brains and spleens of tg650 mice infected with sporadic and variant CJD by intracerebral route.(A) Electrophoretic pattern of PrPres in the brain (upper panel) and spleen (lower panel) upon primary transmission. Note that vCJD case no. 4 shows either a typical vCJD or sCJD-like pattern in the brains of mice succumbing late or early with disease, respectively, while a vCJD-like pattern is consistently observed in the spleens. The PrPres profiles of variant and sporadic CJD in the brain of affected human patients are shown on the sides (left and right, respectively) of both immunoblots for comparison. (B) Ratio of diglycosylated and monoglycosylated PrPres species in the brains of mice following serial transmission of sporadic or variant CJD cases (data plotted as means±SEM). PrPvCJD and PrPsCJD patterns are represented by brown and grey colors, respectively. Variant CJD cases no. 1, 2, 3 and 4 are represented as diamond, circle, square, and triangle; sCJD cases no. 1, 2, 3 and 4 as polygon, star, ellipse, and rectangle. Secondary transmissions (when available) are represented by the same, unfilled symbols. Note the distinct glycoform ratio between early (grey triangle) and late brains upon transmission of vCJD case no. 4. (C) In early succumbing mice, the size of the PrPres fragments is higher in the brain (Br) than in the spleen (Sp), whereas in late succumbing it remains similar, as shown after deglycosylation by PNGase treatment. MM: molecular markers. (D) Electrophoretic pattern of PrPres in the brain and spleen upon secondary transmission. tg650 mice were inoculated with brain or spleen homogenates from either sCJD or vCJD case 4 late or early mice. The brain PrPres profile of human vCJD is shown on the left side of the gel for comparison.

Mentions: The nervous and lymphoid tissues were examined for the presence of proteinase K (PK)-resistant PrP (PrPres) by immunoblotting. PrPres was readily detected in the brains of all the vCJD- and sCJD-infected mice analyzed. A typical PrPvCJD banding pattern, characterized by low size fragments and prominent diglycoform species, was observed in vCJD no. 1 to 3-challenged mice and in vCJD no. 4 late mice (23/23 and 9/9 mouse brains analyzed, respectively, Figure 1A–B), a signature that was maintained in the brain of secondary inoculated mice (6/6 analyzed; Figure 1B, D). vCJD no. 4 early mice, however, showed a clearly distinct PrPres profile with predominantly monoglycosylated, higher size fragments (6/6; Figure 1A–C). Such a signature, termed PrPsCJD because of its similarity with that in sCJD-challenged mice was conserved on subsequent passage (35/35 analyzed; Figure 1A, B, D).


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)

Western blots analysis of PrPres in the brains and spleens of tg650 mice infected with sporadic and variant CJD by intracerebral route.(A) Electrophoretic pattern of PrPres in the brain (upper panel) and spleen (lower panel) upon primary transmission. Note that vCJD case no. 4 shows either a typical vCJD or sCJD-like pattern in the brains of mice succumbing late or early with disease, respectively, while a vCJD-like pattern is consistently observed in the spleens. The PrPres profiles of variant and sporadic CJD in the brain of affected human patients are shown on the sides (left and right, respectively) of both immunoblots for comparison. (B) Ratio of diglycosylated and monoglycosylated PrPres species in the brains of mice following serial transmission of sporadic or variant CJD cases (data plotted as means±SEM). PrPvCJD and PrPsCJD patterns are represented by brown and grey colors, respectively. Variant CJD cases no. 1, 2, 3 and 4 are represented as diamond, circle, square, and triangle; sCJD cases no. 1, 2, 3 and 4 as polygon, star, ellipse, and rectangle. Secondary transmissions (when available) are represented by the same, unfilled symbols. Note the distinct glycoform ratio between early (grey triangle) and late brains upon transmission of vCJD case no. 4. (C) In early succumbing mice, the size of the PrPres fragments is higher in the brain (Br) than in the spleen (Sp), whereas in late succumbing it remains similar, as shown after deglycosylation by PNGase treatment. MM: molecular markers. (D) Electrophoretic pattern of PrPres in the brain and spleen upon secondary transmission. tg650 mice were inoculated with brain or spleen homogenates from either sCJD or vCJD case 4 late or early mice. The brain PrPres profile of human vCJD is shown on the left side of the gel for comparison.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001419-g001: Western blots analysis of PrPres in the brains and spleens of tg650 mice infected with sporadic and variant CJD by intracerebral route.(A) Electrophoretic pattern of PrPres in the brain (upper panel) and spleen (lower panel) upon primary transmission. Note that vCJD case no. 4 shows either a typical vCJD or sCJD-like pattern in the brains of mice succumbing late or early with disease, respectively, while a vCJD-like pattern is consistently observed in the spleens. The PrPres profiles of variant and sporadic CJD in the brain of affected human patients are shown on the sides (left and right, respectively) of both immunoblots for comparison. (B) Ratio of diglycosylated and monoglycosylated PrPres species in the brains of mice following serial transmission of sporadic or variant CJD cases (data plotted as means±SEM). PrPvCJD and PrPsCJD patterns are represented by brown and grey colors, respectively. Variant CJD cases no. 1, 2, 3 and 4 are represented as diamond, circle, square, and triangle; sCJD cases no. 1, 2, 3 and 4 as polygon, star, ellipse, and rectangle. Secondary transmissions (when available) are represented by the same, unfilled symbols. Note the distinct glycoform ratio between early (grey triangle) and late brains upon transmission of vCJD case no. 4. (C) In early succumbing mice, the size of the PrPres fragments is higher in the brain (Br) than in the spleen (Sp), whereas in late succumbing it remains similar, as shown after deglycosylation by PNGase treatment. MM: molecular markers. (D) Electrophoretic pattern of PrPres in the brain and spleen upon secondary transmission. tg650 mice were inoculated with brain or spleen homogenates from either sCJD or vCJD case 4 late or early mice. The brain PrPres profile of human vCJD is shown on the left side of the gel for comparison.
Mentions: The nervous and lymphoid tissues were examined for the presence of proteinase K (PK)-resistant PrP (PrPres) by immunoblotting. PrPres was readily detected in the brains of all the vCJD- and sCJD-infected mice analyzed. A typical PrPvCJD banding pattern, characterized by low size fragments and prominent diglycoform species, was observed in vCJD no. 1 to 3-challenged mice and in vCJD no. 4 late mice (23/23 and 9/9 mouse brains analyzed, respectively, Figure 1A–B), a signature that was maintained in the brain of secondary inoculated mice (6/6 analyzed; Figure 1B, D). vCJD no. 4 early mice, however, showed a clearly distinct PrPres profile with predominantly monoglycosylated, higher size fragments (6/6; Figure 1A–C). Such a signature, termed PrPsCJD because of its similarity with that in sCJD-challenged mice was conserved on subsequent passage (35/35 analyzed; Figure 1A, B, D).

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