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Unraveling prions: the complexities between the prion protein, complement, and B cells in diverse pathogenic settings

Date

2017

Authors

Kane, Sarah, author
Zabel, Mark, advisor
Bamburg, James, committee member
Tjalkens, Ronald, committee member
Avery, Anne, committee member

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Abstract

Prions diseases affect numerous mammalian species and may arise spontaneously, from genetic predisposition of the prion protein PrPC to misfold and aggregate, or from contacted with prion-contaminated materials. The first described prion disease, Scrapie, manifests in sheep, and records date back to the 18th century. Other mammalian species susceptible to prion diseases include humans, cats, mink, cervids (deer, elk, and moose), and cattle. The term Transmissible Spongiform Encephalopathy (TSE) arose to describe this new class of infectious diseases which exhibit spongiform degeneration in the central nervous system (CNS). TSEs are invariably fatal diseases, and only herd culling or breeding resistance mitigate disease spreading. However, chronic wasting disease (CWD) in cervids represents the first known TSE to occur in free-ranging wildlife, and the apparent facile spread demands strategies to halt its spread and prevent species eradication. Human prion disease characterization dates back to the 1920s. However, the bovine spongiform encephalopathy (BSE or mad cow disease) outbreak and subsequent transmission into a small number of humans in the 1980s and 90s pressed the need to understand the TSE agent. Many researchers since the 1960s postulated protein at least partially comprised the agent, but Stanley Prusiner provided the first scientific evidence of protein composition correlating with infectivity. Further, he coined the term proteinaceous particle, or prion. Follow-up research elegantly highlighted a host protein requisite to cause disease. Researchers now broadly accept the disease mechanism involves prions perverting the cellular prion protein to alter its conformation and join the highly stable growing prion aggregate. Upon peripheral exposure, most prion strains propagate in the lymphoreticular system prior to invading the CNS. Many elegant studies reveal the Complement system promotes initial prion trafficking and propagation in spleen and lymph nodes because mice deficient in various Complement proteins or receptors exhibit delayed or no disease. Once in the LRS, many postulate prions retrogradely infect the brain via sympathetic nerve fibers and the spinal cord. Once in the brain, prions provoke astrogliosis, neurodegeneration, and invariable death. While prion researchers made great strides in characterizing TSEs within a short few decades, many fundamental questions remain unaddressed. For example: what additional host factors foster prion pathogenesis? What is the normal function of the properly-folded, cellular prion protein? Lastly, do prion binding partners provide therapeutic targets? Data presented in this dissertation highlight crucial roles for Complement regulatory protein Factor H and Complement receptor CD21 in Scrapie pathogenesis, suggest C1q may strain-specifically impact prion disease, highlight PrPC as a crucial mediator in the adaptive immune system, and provide potential therapeutic tools and targets to combat prion disease.

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