Abstract
We previously showed that intracerebral (ic) inoculation of the attenuated SY strain of Creutzfeld-Jakob disease in mice could delay clinical signs and widespread neuropathology evoked by subsequent ic challenge with the more virulent FU strain. Using lower doses of SY and FU ic, we here demonstrate that mice can be protected well into old age without demonstrable neuropathology or pathologic prion protein (PrP-res). In contrast, parallel FU only controls became terminally diseased 1 year earlier. To determine whether factors elaborated in response to SY might be part of this effect, we evaluated brain and serum samples from additional parallel mice at 90 days after SY infection and just before FU challenge. The infectivity of FU preparations was significantly reduced by mixing with these fresh SY brain homogenates but not by mixing with SY serum samples, suggesting that brain cells were elaborating labile inhibitory factors that were part of the protective response. SY infectivity was too low to be detected in these brain homogenates. Although suppression could be overcome by higher FU doses ic, strong protection against maximal doses of FU was observed by using i.v. inoculations. Because myeloid microglia are infectious and also elaborate many factors in response to the foreign Creutzfeld-Jakob disease agent, it is likely that innate immunity underlies the profound protection shown here. In principle, it should be possible to artificially stimulate relevant myeloid pathways to better prevent and/or delay the clinical and pathological sequelae of these infections.