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Review
. 2022 Mar 8;23(6):2909.
doi: 10.3390/ijms23062909.

Propagation and Dissemination Strategies of Transmissible Spongiform Encephalopathy Agents in Mammalian Cells

Stefanie-Elisabeth Heumüller  1 , Annika C Hornberger  1 , Alina S Hebestreit  1 , André Hossinger  1 , Ina M Vorberg  1   2
Affiliations
Review

Propagation and Dissemination Strategies of Transmissible Spongiform Encephalopathy Agents in Mammalian Cells

Stefanie-Elisabeth Heumüller et al. Int J Mol Sci. .

Abstract

Transmissible spongiform encephalopathies or prion disorders are fatal infectious diseases that cause characteristic spongiform degeneration in the central nervous system. The causative agent, the so-called prion, is an unconventional infectious agent that propagates by converting the host-encoded cellular prion protein PrP into ordered protein aggregates with infectious properties. Prions are devoid of coding nucleic acid and thus rely on the host cell machinery for propagation. While it is now established that, in addition to PrP, other cellular factors or processes determine the susceptibility of cell lines to prion infection, exact factors and cellular processes remain broadly obscure. Still, cellular models have uncovered important aspects of prion propagation and revealed intercellular dissemination strategies shared with other intracellular pathogens. Here, we summarize what we learned about the processes of prion invasion, intracellular replication and subsequent dissemination from ex vivo cell models.

Keywords: PrP; amyloid; prion; transmissible spongiform encephalopathies; virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prion infection mechanisms. Dissemination of PrPSc relies on different routes. PrPSc can be transmitted from a donor (brown) to a recipient (blue) cell. Most studies on prion uptake and infection have been performed with purified PrPSc or with crude brain homogenate containing prions. If PrPSc is “freely” released into the extracellular space is unknown. (a) Receptors for exogenously added PrPSc include heparan sulfate proteoglycans (HSPGs), Lrp1 or the 37 kDa/67 kDa laminin receptor (LRP/LR). (b) “Free” PrPSc can be internalized by different endocytosis routes or macropinocytosis. (c) In cellular systems, PrPSc can be released from donor cells via microvesicles shedding from the cell surface or in association with smaller extracellular vesicles (EVs) derived from multivesicular bodies (MVBs) that fuse with the cell membrane. EVs can be taken up by recipient cells by different pathways. Few EV ligands that mediate binding to target cells have been identified. Viral ligands present on PrPSc-containing EV can bind to recipient cells and facilitate subsequent infection. (d) PrPSc can also transmit to recipient cells within endosomal vesicles through tunneling nanotubes (TNTs). (e) Within target cells, the majority of internalized PrPSc is directed to the lysosome for degradation. (f) Newly formed PrPSc can be found on the cell surface, within the endocytic recycling pathway and the endo-lysosomal pathway. Productive infection requires PrPC expression but is determined by additional cellular factors and the prion strain. Created with BioRender.
Figure 2
Figure 2
L929 cells infected with 22L secrete PrPSc and prion infectivity in association with EVs. (a) EVs isolated from conditioned medium of L929 cells persistently infected with scrapie strain 22L (L92922L) were added to L929 cells. Recipient cells were passaged at least four times before PrPSc formation was monitored by Western blot. (b) Western blot detection of PrPSc in donor cells (L92922L) or PrPSc in EVs derived from donor cells or PrPSc in recipient cells after continuous culture. PrPSc present in proteinase K-treated lysates was detected using anti-PrP antibody 4H1. PrPSc runs as unglycosylated, monoglycosylated and diglycosylated bands.
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References

    1. Gallardo M.J., Delgado F.O. Animal prion diseases: A review of intraspecies transmission. Open Vet. J. 2021;11:707–723. doi: 10.5455/OVJ.2021.v11.i4.23. - DOI - PMC - PubMed
    1. Prusiner S.B. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136–144. doi: 10.1126/science.6801762. - DOI - PubMed
    1. Oesch B., Westaway D., Walchli M., McKinley M.P., Kent S.B., Aebersold R., Barry R.A., Tempst P., Teplow D.B., Hood L.E., et al. A cellular gene encodes scrapie PrP 27-30 protein. Cell. 1985;40:735–746. doi: 10.1016/0092-8674(85)90333-2. - DOI - PubMed
    1. Bessen R.A., Kocisko D.A., Raymond G.J., Nandan S., Lansbury P.T., Caughey B. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature. 1995;375:698–700. doi: 10.1038/375698a0. - DOI - PubMed
    1. Supattapone S. Cofactor molecules: Essential partners for infectious prions. Prog. Mol. Biol. Transl. Sci. 2020;175:53–75. doi: 10.1016/bs.pmbts.2020.07.009. - DOI - PMC - PubMed