Abstract
BackgroundPrions, composed of a misfolded protein designated PrPSc, are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrPSc aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system.MethodsC57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG35-55 in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co-induced animals were reactivated and subsequently injected into naïve mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrPSc deposition were next evaluated.ResultsWe first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrPSc. Next, we present evidence that mice infected with activated prion-experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrPSc aggregates in white matter areas in brains and spinal cords.ConclusionsOur results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrPSc in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products.
Highlights
Prions, composed of a misfolded protein designated PrPSc, are infectious agents causing fatal neurodegenerative diseases
Acceleration of prion disease by experimental autoimmune encephalomyelitis may depend on spleen PrPSc levels Regardless of the route of prion infection, PrPSc is first accumulated in immune organs such as the spleen and lymph nodes and appears in the infected brains much later in the incubation period [22,23]
We have shown in this work that acceleration of prion disease by central nervous system (CNS) inflammation, as is the case for EAE induction, requires the presence of substantial levels of PrPSc in the immune cells of prion-infected mice
Summary
Prions, composed of a misfolded protein designated PrPSc, are infectious agents causing fatal neurodegenerative diseases. Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease and kuru in humans, bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, and chronic wasting disease in deer [1]. This group of diseases is caused by shown by the fact that both infectivity and accumulation of PrPSc are initially detected in the spleens of the infected animals [5,6,7,8]. In the presence of inflammatory conditions affecting peripheral organs, activated lymphoreticular cells induce deposition of PrPSc and prion infectivity in the sites of infiltration in prioninfected animals [16]. Mastitis in sheep results in deposition of PrPSc in the inflamed mammary glands [17]
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