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Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD
Vincent Béringue1, Annick Le Dur, Philippe Tixador
1Institut Scientifique de Recherche Agronomique (INRA), UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France. vincent.beringue@jouy.inra.fr
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.
Insights
Variant Creutzfeldt-Jakob disease (vCJD) prions can establish lifelong, asymptomatic infections in lymphoid tissues. This highlights the risk of vCJD transmission and potential for alternative disease phenotypes in humans.
Area of Science:
- Neuroscience
- Infectious Diseases
- Prion Biology
Background:
- Predicting the variant Creutzfeldt-Jakob disease (vCJD) epidemic is challenging due to unknown infection prevalence and potential for asymptomatic or sporadic-like disease.
- vCJD shares the methionine at codon 129 human prion protein allele with affected patients.
Purpose of the Study:
- To investigate vCJD prion transmission and strain characteristics in a mouse model.
- To analyze the efficiency of vCJD prion infection via different routes and its persistence in lymphoid tissues.
Main Methods:
- Transgenic mice overexpressing human prion protein (Met129) were infected with vCJD and sporadic CJD (sCJD) prions.
- Infection routes included intracerebral and intraperitoneal inoculation.
- Transmission efficiency and prion strain phenotypes were assessed in brain and spleen.
Main Results:
- The mouse model accurately reproduced key vCJD infection features, including significant lymphoid tissue involvement.
- Intracerebral vCJD prion inoculation resulted in either vCJD or sCJD-like prion propagation in the brain, but invariably vCJD prion in the spleen.
- Peripheral vCJD prion exposure led to inefficient neuroinvasion but established persistent, asymptomatic splenic infections.
Conclusions:
- Human-to-human vCJD transmission may result in diverse neuropathological phenotypes.
- Examination of sporadic CJD cases' lymphoid tissues could identify vCJD-type prion infections.
- vCJD prions readily establish long-term, subclinical infections in lymphoreticular tissues, increasing iatrogenic transmission risks.
