The effect of PrPSc accumulation on inflammatory gene expression within sheep peripheral lymphoid tissue

Anton G Gossner,John Hopkins

doi:10.1016/j.vetmic.2015.10.013

Abstract

Accumulation of the misfolded prion protein, PrPSc in the central nervous system (CNS) is strongly linked to progressive neurodegenerative disease. For many transmissible spongiform encephalopathies (TSEs), peripheral lymphoid tissue is an important site of PrPSc amplification but without gross immunological consequence. Susceptible VRQ homozygous New Zealand Cheviot sheep were infected with SSBP/1 scrapie by inoculation in the drainage area of the prescapular lymph nodes. The earliest time that PrPSc was consistently detected by immunohistology in these nodes was D50 post infection. This transcriptomic study of lymph node taken before (D10) and after (D50) the detection of PrPSc, aimed to identify the genes and physiological pathways affected by disease progression within the nodes as assessed by PrPSc detection. Affymetrix Ovine Gene arrays identified 75 and 80 genes as differentially-expressed at D10 and D50, respectively, in comparison with control sheep inoculated with uninfected brain homogenate. Approximately 70% of these were repressed at each time point. RT-qPCR analysis of seven genes showed statistically significant correlation with the array data, although the results for IL1RN and TGIF were different between the two technologies. The ingenuity pathway analysis (IPA) and general low level of repression of gene expression in lymphoid tissue, including many inflammatory genes, contrasts with the pro-inflammatory and pro-apoptotic events that occur within the CNS at equivalent stages of disease progression as assessed by PrPSc accumulation.

Highlights

Sheep scrapie is a transmissible spongiform encephalopathy (TSE), a group of fatal neurodegenerative diseases of the central nervous system (CNS)
A key feature of TSEs is the conversion of the host-encoded prion protein PrPC to disease-associated PrPSc (Prusiner, 1982); the replication of pathological PrPSc from physiological PrPC is a critical component of the disease (Prusiner et al, 1999)
The essential role of PrPC in TSE disease is confirmed by the resistance of PrPnull mice to disease (Bueler et al, 1993); by the reciprocal relationship of PrP gene (PRNP) copy number and incubation period (Bueler et al, 1993; Manson et al, 1994), and by the fact that resistance to sheep scrapie is influenced by polymorphisms of PRNP at codons 136 (V or A), 154 (R or H) and 171 (R or Q) (Goldmann et al, 1994)

Summary

Introduction

Sheep scrapie is a transmissible spongiform encephalopathy (TSE), a group of fatal neurodegenerative diseases of the central nervous system (CNS). The essential role of PrPC in TSE disease is confirmed by the resistance of PrPnull mice to disease (Bueler et al, 1993); by the reciprocal relationship of PrP gene (PRNP) copy number and incubation period (Bueler et al, 1993; Manson et al, 1994), and by the fact that resistance to sheep scrapie is influenced by polymorphisms of PRNP at codons 136 (V or A), 154 (R or H) and 171 (R or Q) (Goldmann et al, 1994). The CNS is the major target organ for TSE disease and neurodegeneration is associated with the accumulation of PrPSc within neurons (Mallucci et al, 2003). PrPSc replicates in follicular dendritic cells (FDC) in spleen and lymph node germinal centres (Jeffrey et al, 2000; McCulloch et al, 2011) and interference of this prolongs the incubation period. In contrast to neurons, PrPSc replication by FDC does not lead to their degeneration or the inhibition of gross immunological functions (Heikenwalder et al, 2005)

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