Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease - PubMed (original) (raw)

Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease

Laura Manuelidis et al. Proc Natl Acad Sci U S A. 2003.

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.

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Figures

Figure 1

Figure 1

Interference ic with low-dose SY and FU (see text). Incubation of SY-only mice (SY), SY mice challenged with FU at 92 days (SY/FU), normal brain inoculated mice challenged with FU at 92 days (Nl/FU), and mice inoculated only with normal brain on day 0 (Nl). Each inoculated mouse is shown with found dead (fd) animals indicated by arrows. Old surviving mice were killed at 659 days. All of the Nl/FU mice showed clear clinical signs (cli+, dotted curve fit) that closely followed terminal signs (Nl/FU end), whereas SY-only and SY/FU-parallel mice survived >300 days longer, and many of these showed no clinical signs or pathology.

Figure 2

Figure 2

(A, C, and E) Neuropathology of representative mice inoculated ic with normal brain followed by FU challenge at 92 days (Nl/FU), terminal at 280–285 days, are shown, with those first inoculated with SY (SY/FU all killed at 659 days). The low-power images in A and B show widespread pathologic PrP (red) in Nl/FU but not protected SY/FU mice. Widespread activated microglia (keratin sulfate detection, C and D) also reveals widespread microglia only in the unprotected controls. Similarly, obvious vacuolar change amidst many red hypertrophic astrocytes (glial fibrillary acidic protein detection) is seen only in Nl/FU (E) but not in SY/FU (F) mice.

Figure 3

Figure 3

Western blot of representative 10% brain homogenates without PK digestion (left 7 lanes) and the same samples treated with PK (+PK lanes). Each sample was 5 μl. Only the Nl/FU controls at 280 days (FU) show strong PrP-res bands, and the normal (N), SY-only (SY), and SY/FU mice show no detectable PrP-res, including the mouse at 635 days with SY clinical signs. SYp lane shows PrP-res in the early-passage SY brain, and the last SY lane shows no PrP-res in SY brains at 90 days, just before FU challenge.

Figure 4

Figure 4

Box plot of incubation times with higher doses of FU and later passaged SY in WT and RAG-1 mice. Median is shown by line in each box, and the circle represents an outlier mouse. Interference is completely abolished except in the SY/FU wt mice above the median (see text).

Figure 5

Figure 5

Interference experiment using the i.v. route. Maximal doses (10% brain homogenates) of low-passage SY and FU (SY-1/FU-1) are 193 days longer (mean ± SEM) than unprotected FU-1 controls. They were even 73 longer than 100-fold dilutions of FU (FU-3), indicating a strong suppression of FU by the i.v. route. The SY-only controls (SY-1) with more surviving mice (at 698 days) were, however, somewhat longer-lived than the SY/FU mice.

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References

    1. Manuelidis L. Proc Natl Acad Sci USA. 1998;95:2520–2525. - PMC - PubMed
    1. Manuelidis L, Valley S, Manuelidis E E. Proc Natl Acad Sci USA. 1985;82:4263–4267. - PMC - PubMed
    1. Oesch B D, Westaway D, Wälchli M, McKinley M P, Kent S B, Aebersold R, Barry R A, Tempst P, Teplow D E, Hood L E, et al. Cell. 1985;40:735–746. - PubMed
    1. Manuelidis L. Ann NY Acad Sci. 1994;724:259–281. - PubMed
    1. Akowitz A, Sklaviadis T, Manuelidis L. Nucleic Acids Res. 1994;22:1101–1107. - PMC - PubMed

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