title: PrPSc formation and clearance as determinants of prion tropism.
abstract: Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation. We found that similar to the lymphotropic strain HY TME, DY TME crosses mucosal epithelia, enters draining lymphatic vessels in underlying laminae propriae, and is transported to LRS tissues. Since DY TME causes disease once it enters the peripheral nervous system, the restriction in DY TME pathogenesis is due to its inability to establish infection in LRS tissues, not a failure of transport. To determine if LRS tissues can support DY TME formation, we performed protein misfolding cyclic amplification using DY PrPSc as the seed and spleen homogenate as the source of PrPC. We found that the spleen environment can support DY PrPSc formation, although at lower rates compared to lymphotropic strains, suggesting that the failure of DY TME to establish infection in the spleen is not due to the absence of a strain-specific conversion cofactor. Finally, we provide evidence that DY PrPSc is more susceptible to degradation when compared to PrPSc from other lymphotrophic strains. We hypothesize that the relative rates of PrPSc formation and clearance can influence prion tropism.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Ronald A
authors.identifier: 0000-0002-3607-0276
authors.initials: RA
authors.lastname: Shikiya
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Langenfeld
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Eckland
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Jonathan
authors.identifier: 0000-0002-2063-8672
authors.initials: J
authors.lastname: Trinh
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Sara A M
authors.identifier: 0000-0003-0800-1115
authors.initials: SAM
authors.lastname: Holec
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Candace K
authors.identifier: 0000-0002-5920-4556
authors.initials: CK
authors.lastname: Mathiason
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.|Department of Pharmacy Science, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Kincaid
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, Nebraska, United States of America.
authors.forename: Jason C
authors.identifier: 0000-0003-4081-7886
authors.initials: JC
authors.lastname: Bartz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006224:Cricetinae; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D008647:Mesocricetus; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology*; D011328:Prions
chemical_list: D018620:PrPSc Proteins; D011328:Prions