Independent amplification of co-infected long incubation period low conversion efficiency prion strains

Eckland, Thomas; Shikiya, Ronald A.; Bartz, Jason C.

doi:10.1371/journal.ppat.1007323

Cited by 18 publications

(11 citation statements)

References 72 publications

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“…3). These data suggest that soil-bound PrP Sc can compete for PrP C , which is thought to be the limiting factor in strain interference (43, 49). We hypothesize that the PrP C binding site on PrP Sc is different from the site at which PrP Sc binds to the soil surface, allowing adequate conversion activity during the initial round of PMCAsi, when PrP Sc exists largely in the adsorbed state (50, 51).…”

Section: Discussionmentioning

confidence: 95%

Alteration of Prion Strain Emergence by Nonhost Factors

Holec

Yuan

Bartz

2019

mSphere

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Prions can persist in the environment for extended periods of time after adsorption to surfaces, including soils, feeding troughs, or fences. Prion strain- and soil-specific differences in prion adsorption, infectivity, and response to inactivation may be involved in strain maintenance or emergence of new strains in a population. Extensive proteinase K (PK) digestion of Hyper (HY) and Drowsy (DY) PrPSc resulted in a greater reduction in the level of DY PrPSc than of HY PrPSc. Use of the PK-digested material in protein misfolding cyclic amplification strain interference (PMCAsi) resulted in earlier emergence of HY PrPSc than of undigested controls. This result established that strain-specific alteration of the starting ratios of conversion-competent HY and DY PrPSc can alter strain emergence. We next investigated whether environmentally relevant factors such as surface binding and weathering could alter strain emergence. Adsorption of HY and DY PrPSc to silty clay loam (SCL), both separately and combined, resulted in DY interfering with the emergence of HY in PMCAsi in a manner similar to that seen with unbound controls. Similarly, repeated cycles of wetting and drying of SCL-bound HY and DY PrPSc did not alter the emergence of HY PrPSc compared to untreated controls. Importantly, these data indicate that prion strain interference can occur when prions are bound to surfaces. Interestingly, we found that drying of adsorbed brain homogenate on SCL could restore its ability to interfere with the emergence of HY, suggesting a novel strain interference mechanism. Overall, these data provide evidence that the emergence of a strain from a mixture can be influenced by nonhost factors. IMPORTANCE The prion strain, surface type, and matrix containing PrPSc can influence PrPSc surface adsorption. The cumulative effect of these factors can result in strain- and soil-specific differences in prion bioavailability. Environmental weathering processes can result in decreases in PrPSc conversion efficiency and infectivity. Little is known about how incomplete inactivation of surface-bound PrPSc affects transmission and prion strain emergence. Here, we show that strain interference occurs with soil-bound prions and that altering the ratios of prion strains by strain-specific inactivation can affect strain emergence. Additionally, we identify a novel mechanism of inhibition of prion conversion by environmental treatment-induced changes at the soil-protein interface altering strain emergence. These novel findings suggest that environmental factors can influence strain emergence of surface-bound prions.

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Section: Discussionmentioning

confidence: 95%

Alteration of Prion Strain Emergence by Nonhost Factors

Holec

Yuan

Bartz

2019

mSphere

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“…The delayed disease then usually has the clinical presentation and PrP Sc of the faster strain. Alternatively, mixed infections can result in independent replication of both strains 37 .…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that certain combinations of strain do not compete, and animals have the pathology and PrP Sc of the shorter incubation strain without delay in incubation periods 35 – 37 . In addition, the two coinfecting strains can replicate independently, where an animal has the pathology of the shorter incubation strain without delay, but PrP Sc is a mixture of both strains 23 , 36 – 38 .…”

Section: Introductionmentioning

confidence: 99%

BSE can propagate in sheep co-infected or pre-infected with scrapie

Chong

Foster

Goldmann

et al. 2021

Sci Rep

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To understand the possible role of mixed-prion infections in disease presentation, the current study reports the co-infection of sheep with bovine spongiform encephalopathy (BSE) and scrapie. The bovine BSE agent was inoculated subcutaneously into sheep with ARQ/ARQ or VRQ/ARQ PRNP genotypes either at the same time as subcutaneous challenge with scrapie, or three months later. In addition, VRQ/VRQ sheep naturally infected with scrapie after being born into a scrapie-affected flock were challenged subcutaneously with BSE at eight or twenty one months-of-age. Sheep were analysed by incubation period/attack rate, and western blot of brain tissue determined the presence of BSE or scrapie-like PrPSc. Serial protein misfolding cyclic amplification (sPMCA) that can detect very low levels of BSE in the presence of an excess of scrapie agent was also applied to brain and lymphoreticular tissue. For VRQ/ARQ sheep challenged with mixed infections, scrapie-like incubation periods were produced, and no BSE agent was detected. However, whilst ARQ/ARQ sheep developed disease with BSE-like incubation periods, some animals had a dominant scrapie western blot phenotype in brain, but BSE was detected in these sheep by sPMCA. In addition, VRQ/VRQ animals challenged with BSE after natural exposure to scrapie had scrapie-like incubation periods and dominant scrapie PrPSc in brain, but one sheep had BSE detectable by sPMCA in the brain. Overall, the study demonstrates for the first time that for scrapie/BSE mixed infections, VRQ/ARQ sheep with experimental scrapie did not propagate BSE but VRQ/VRQ sheep with natural scrapie could propagate low levels of BSE, and whilst BSE readily propagated in ARQ/ARQ sheep it was not always the dominant PrPSc strain in brain tissue. Indeed, for several animals, a dominant scrapie biochemical phenotype in brain did not preclude the presence of BSE prion.

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“…Pre‐infecting mice with a slow‐incubating strain could severely delay or completely block subsequent infection by a fast strain. Bessen, Bartz and colleagues reported similar findings in golden Syrian hamsters (Bartz et al ., ; Eckland et al ., ). It was argued that the blockage in propagation was not immunological in origin but was caused by competition for resources at a common replication site.…”

Section: Introductionmentioning

confidence: 97%

Forms and abundance of chaperone proteins influence yeast prion variant competition

King

2019

Molecular Microbiology

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Summary [PSI+] variants are different infectious conformations of the same Sup35 protein. We show that when [PSI+] variants VK and VL co‐infect a dividing host, only one prevails in the end and the host genetic background is involved in winner selection. In the 5V‐H19 background, the VK variant dominates over the VL variant. The order of dominance is reversed in the 74‐D694 background, where VL can coexists with VK for a short period, but will eventually take over. Differential interaction of chaperone proteins with distinct prion variant conformations can influence the outcome of competition. Expanding the Glycine/Methionine‐rich domain of Sis1, an Hsp40 protein, helps the propagation of VL. Over‐expression of the Hsp70 protein Ssa2 lowers the number of prion particles (propagons) in the cell. There is more reduction for VK than VL, causing the latter to dominate in some of the 5V‐H19 and all of the 74‐D694 cells tested. Consistently, depleting Ssa1 in 74‐D694 strengthens VK. Swapping chromosomal alleles of SSA1/2 and SIS1 between 5V‐H19 and 74‐D694, including cognate promoters, is not sufficient to change the native dominance order of each background, suggesting there exist additional polymorphic factors that modulate [PSI+] competition.

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Independent amplification of co-infected long incubation period low conversion efficiency prion strains

Cited by 18 publications

References 72 publications

Alteration of Prion Strain Emergence by Nonhost Factors

Alteration of Prion Strain Emergence by Nonhost Factors

BSE can propagate in sheep co-infected or pre-infected with scrapie

Forms and abundance of chaperone proteins influence yeast prion variant competition

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