High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses

Abstract

To clarify the mechanisms leading to the development of Creutzfeldt-Jakob disease in some recipients of pituitary-derived human growth hormone (hGH), we investigated the effects of repeated injections of low prion doses in mice. The injections were performed, as in hGH-treated children, by a peripheral route at short intervals and for an extended period. Twelve groups of 24 mice were intraperitoneally inoculated one, two, or five times per week for 200 days with 2 ؋ 10 ؊5 to 2 ؋ 10 ؊8 dilutions of brain homogenate containing the mouse-adapted C506M3 scrapie strain. Sixteen control mice were injected once a week for 200 days with a 2 ؋ 10 ؊4 dilution of normal brain homogenate. Of mice injected in a single challenge with a scrapie inoculum of a 2 ؋ 10 ؊4 , 2 ؋ 10 ؊5 , or 2 ؋ 10 ؊6 dilution, 2/10, 1/10, and 0/10 animals developed scrapie, respectively. Control mice remained healthy. One hundred thirty-five of 135 mice injected with repeated prion doses of a 2 ؋ 10 ؊5 or 2 ؋ 10 ؊6 dilution succumbed to scrapie. Of mice injected with repeated scrapie doses of a 2 ؋ 10 ؊7 or 2 ؋ 10 ؊8 dilution, 52/59 and 38/67 animals died of scrapie, respectively. A high incidence of scrapie was observed in mice receiving repeated doses at low infectivity, whereas there was no disease in mice that were injected once with the same doses. Repeated injections of low prion doses thus constitute a risk for development of prion disease even if the same total dose inoculated in a single challenge does not induce the disease.

Longitudinal Detection of Prion Shedding in Saliva and Urine by Chronic Wasting Disease-Infected Deer by Real-Time Quaking-Induced Conversion

“…4 to 6 and Tables 1 to 3). Perhaps exposure to repeated low prion doses in nature may in turn lead to more consistent prion shedding by animals so infected, as has previously been inferred for subinfectious doses of scrapie (35), although substantially more data would be needed to support this extrapolation. Additional information is needed to assess the infectivity of excreta deposited in the environment; however, prion shedding of this magnitude in a free-ranging species would seem to pose a substantial challenge to eradication of CWD.…”

Chronic Wasting Disease Prions in Elk Antler Velvet

“…Whereas oral transmission of rodent-adapted scrapie prions is known to be ≈5 orders of magnitude less efficient than transmission by intracerebral inoculation (14,15), the relative efficiency of oral CWD prion transmission is unknown. Multiple exposures to low levels of CWD prions in the environment (16,17), as well as increased infectivity when prions are bound to soil minerals (18), are factors that may influence transmission.…”

Prion transmission

“…87 100,101 in contrast, a second study found that repeated doses of low infectivity produced much higher incidences of disease than a single challenge with the same cumulative dose. 102 Given the unequivocal data showing that scrapie and CWD prions are secreted at low levels from multiple routes it seems imperative that the effects of repeat exposures to low levels of prion are investigated further. Given the results with scrapie-contaminated milk and CWD-contaminated saliva, it seems very likely that these low levels of prion in different secreta/excreta are capable of transmitting disease upon prolonged exposure, either through direct animal-to-animal contact or through environmental reservoirs of infectivity.…”