The Glycosylation Status of PrPCIs a Key Factor in Determining Transmissible Spongiform Encephalopathy Transmission between Species

Abstract

ABSTRACTThe risk of transmission of transmissible spongiform encephalopathies (TSE) between different species has been notoriously unpredictable because the mechanisms of transmission are not fully understood. A transmission barrier between species often prevents infection of a new host with a TSE agent. Nonetheless, some TSE agents are able to cross this barrier and infect new species, with devastating consequences. The host PrPCmisfolds during disease pathogenesis and has a major role in controlling the transmission of agents between species, but sequence compatibility between host and agent PrPCdoes not fully explain host susceptibility. PrPCis posttranslationally modified by the addition of glycan moieties which have an important role in the infectious process. Here, we showin vivothat glycosylation of the host PrPChas a significant impact on the transmission of TSE between different host species. We infected mice carrying different glycosylated forms of PrPCwith two human agents (sCJDMM2 and vCJD) and one hamster strain (263K). The absence of glycosylation at both or the first PrPCglycosylation site in the host results in almost complete resistance to disease. The absence of the second site of N-glycan has a dramatic effect on the barrier to transmission between host species, facilitating the transmission of sCJDMM2 to a host normally resistant to this agent. These results highlight glycosylation of PrPCas a key factor in determining the transmission efficiency of TSEs between different species.IMPORTANCEThe risks of transmission of TSE between different species are difficult to predict due to a lack of knowledge over the mechanisms of disease transmission; some strains of TSE are able to cross a species barrier, while others do not. The host protein, PrPC, plays a major role in disease transmission. PrPCundergoes posttranslational glycosylation, and the addition of these glycans may play a role in disease transmission. We infected mice that express different forms of glycosylated PrPCwith three different TSE agents. We demonstrate that changing the glycosylation status of the host can have profound effects on disease transmission, changing host susceptibility and incubation times. Our results show that PrPCglycosylation is a key factor in determining risks of TSE transmission between species.