Increased susceptibility of transgenic mice expressing human PrP to experimental sheep bovine spongiform encephalopathy is not due to increased agent titre in sheep brain tissue

Abstract

Bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt–Jakob disease in humans have previously been shown to be caused by the same strain of transmissible spongiform encephalopathy agent. It is hypothesized that the agent spread to humans following consumption of food products prepared from infected cattle. Despite evidence supporting zoonotic transmission, mouse models expressing human prion protein (HuTg) have consistently shown poor transmission rates when inoculated with cattle BSE. Higher rates of transmission have however been observed when these mice are exposed to BSE that has been experimentally transmitted through sheep or goats, indicating that humans may potentially be more susceptible to BSE from small ruminants. Here we demonstrate that increased transmissibility of small ruminant BSE to HuTg mice was not due to replication of higher levels of infectivity in sheep brain tissue, and is instead due to other specific changes in the infectious agent.

Insights into Mechanisms of Transmission and Pathogenesis from Transgenic Mouse Models of Prion Diseases

“…In contrast, gene-targeted transgenic mice expressing human PrP were not susceptible to BSE prions [56]. However, these mice were susceptible to sheep-adapted BSE prions suggesting increased susceptibility of humans to BSE prions following passage through sheep [83], an effect that is unrelated to increased titer of BSE prions in sheep brain [84]. The effect of codon 129 heterozygosity on human prion susceptibility has been further examined in Tg mice co-expressing transgene arrays expressing HuPrP-M129 and HuPrP-V129 [85].…”

“…In contrast, the transmission efficiency of classical BSE and H-type isolates to transgenic mice expressing human PrP is relatively low [20, 68, 123]. Increased pathogenicity of sheep-passaged BSE occurred in Tg mice expressing porcine PrP [124] or human PrP [84] raising the possibility that BSE may gain virulence by passage in another species.…”

Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

“…Gene-targeted transgenic mouse lines expressing physiological levels of MM129, VV129 or MV129 human PrPs (HuMM, HuMV and HuVV) have been shown to be susceptible to infection with sporadic human prions, and to a lesser extent to vCJD, but were resistant to cattle BSE and CWD from cervids (Bishop et al, 2006(Bishop et al, , 2010Moda et al, 2012;Wilson et al, 2012). Interestingly, despite their lack of susceptibility to cattle BSE, HuMM transgenic mice were partially susceptible to sheep-passaged and goat-passaged BSE prions (Plinston et al, 2011(Plinston et al, , 2014Wilson et al, 2013).…”

“…Interestingly, despite their lack of susceptibility to cattle BSE, HuMM transgenic mice were partially susceptible to sheep-passaged and goat-passaged BSE prions (Plinston et al, 2011(Plinston et al, , 2014Wilson et al, 2013).…”

Path morphological alterations in sheep with scrapie: light and electron microscopy

“…Зараженная мясокостная мука интенсивно использовалась в кормах для КРС в странах Европейского союза и некоторых других странах для повышения прироста массы тела и надоев молока; она могла попадать также в корма овец и коз. Экспериментальное заражение овец и коз прионом ГЭП КРС показало, что эти животные чувствительны к данному возбудителю и, более того, прион, проходя пассаж через их организм, становится более вирулентным [7]; по клинической картине и гистологии болезнь не отличается от естественного скрепи. Учитывая зооантропонозность приона ГЭП КРС для людей, Евросоюз и другие страны усилили исследования случаев скрепи овец и коз, и естественная инфекция у коз подтвердилась [8,9].…”