Abstract
Transmissible spongiform encephalopathies (TSEs), or prion diseases, affecting human and animal species can be transmitted from TSE-infected individuals to naïve susceptible hosts during the long asymptomatic (years to decades) and symptomatic disease stages. The presence of infectious hematogenous prions in asymptomatic TSE-infected hosts demonstrates the highly infectious nature of blood-borne prions in hosts lacking overt clinical symptoms. It is currently unknown when and how infectious prions first enter the blood following initial exposure. We have previously shown that the whole-blood real-time quaking-induced conversion assay (wbRT-QuIC) possesses 100% specificity and >92% sensitivity, making it an ideal tool to address this question. Here, we use wbRT-QuIC to analyze whole blood collected from oral, extranasal or aerosol TSE-exposed hosts for blood-borne prions. Our results demonstrate that conversion competent prions in the inoculum are capable of crossing mucosal surfaces and entering the circulatory system within 30min—no matter the route of exposure. Detection of the inoculum minutes post exposure is followed by a steady decline in the detection of blood-borne prions up to 3 days which is followed by a progressive increase in the detection of nascent conversion competent prions between 1 and 17 months post exposure. These data provide the first evidence for the facile transport of mucosally acquired prions into the circulatory system, providing evidence for multiple routes of inter- and intra- host prion trafficking and shedding.