The Generative Brain

Marin-Moreno A et al. 2020, Radical change in zoonotic abilities of atypical BSE prion strains as evidenced by crossing of sheep species barrier in transgenic mice (Emerg Infect Dis 26:1130-1139)

The current reference point for how far atypical BSE might reach towards people. Published by CDC in Emerging Infectious Diseases, original publication date 21 April 2020 and in the June 2020 issue, by a Spanish and French group from CISA-INIA near Madrid and the host pathogen interactions unit at the veterinary school in Toulouse. The authors put classical, L-type and H-type BSE isolates into transgenic mice carrying human prion protein with methionine, valine or both at codon 129, and then repeated the exercise after first passing one L-type and one H-type isolate through sheep prion protein mice. Three findings matter. L-type BSE infected every methionine 129 mouse on first passage, which classical BSE did not manage without a second passage, so in this model L-type looked the more efficient of the two. Valine 129 blocked L-type completely, including in the heterozygous line. H-type did not transmit to any human PrP line at all, but after passage through valine arginine glutamine sheep PrP mice it gained the ability to infect both the methionine and the valine lines, with a phenotype the authors describe as resembling sporadic CJD MM1, while sheep passaged L-type switched the other way and came to resemble sporadic CJD VV2. The authors are explicit that this does not establish a causal link with sporadic CJD and that results in mice overexpressing human prion protein should not be over-extrapolated. This entry is information only and says nothing about risk to any individual.

Key facts

  • Thirteen authors are listed, first author Alba Marin-Moreno and last author Juan Maria Torres, across two affiliations: Centro de Investigacion en Sanidad Animal (CISA-INIA) in Madrid and Interactions Hote Agent Pathogene at the Ecole Nationale Veterinaire de Toulouse; a co-author, Patricia Aguilar-Calvo, is listed with a current affiliation at the University of California San Diego.
  • The paper is Emerging Infectious Diseases 26(6):1130-1139, doi 10.3201/eid2606.181790, PMID 32441630, PMC7258450, open access under a CC BY licence, with an original publication date of 21 April 2020 and first indexing in Europe PMC on 23 May 2020.
  • Three human PrP mouse lines were used, all on a mouse PrP null background and all expressing human prion protein at about four times the level in human brain: TgMet129 (HuPrP-Tg340), TgVal129 (HuPrP-Tg361) and TgMet/Val129 (HuPrP-Tg351, the F1 cross of the other two). The supporting lines were TgVRQ (OvPrP-Tg338, sheep VRQ allele at 8 to 10 times sheep brain level), TgARQ (OvPrP-TgShXI, sheep ARQ allele at 3 to 4 times) and TgBo (BoPrP-Tg110, bovine).
  • Mice were inoculated into the brain at 6 to 7 weeks of age with the equivalent of 2 mg of brain from a 10 percent homogenate in 5 percent glucose, and followed to clinical disease or to about 700 days after inoculation.
  • In TgMet129 mice all three L-type isolates infected every animal on first passage: L1 at 607 plus or minus 13 days (7 of 7), L2 at 629 plus or minus 35 days (7 of 7) and L3 at 541 plus or minus 70 days (7 of 7). Second passage gave 487 plus or minus 116 days (4 of 4) and 508 plus or minus 97 days (5 of 5) for L1 and L2, so the incubation period shortened only modestly.
  • The three classical BSE isolates needed a second passage in the same line: C-BSE0 went from 1 of 6 on first passage to 6 of 6 at 633 plus or minus 32 days, C-BSE2 from 0 of 9 to 3 of 4 at 572 plus or minus 37 days, and C-BSE3 from 2 of 6 to 6 of 6 at 615 plus or minus 95 days.
  • None of the three H-type isolates (H1, H2, H3) produced disease or protease resistant prion protein in any of the three human PrP lines within about 700 days.
  • No isolate of any type, classical, L-type or H-type, transmitted to the TgVal129 or TgMet/Val129 lines on direct inoculation, which is the basis for the paper's statement that valine 129 is a strong protective variant against L-type BSE even in heterozygous form.
  • In sheep PrP mice, isolate L2 reached 6 of 6 in TgVRQ at 438 plus or minus 20 days on first passage and 168 plus or minus 22 days on second, and in TgARQ went from 2 of 6 to 6 of 6 at 155 plus or minus 8 days. Isolate H3 infected 1 of 6 TgVRQ mice at 801 days on first passage and all 6 at 408 plus or minus 44 days on second, and never transmitted in TgARQ past 700 days.
  • After VRQ sheep passage the two atypical agents changed places. VRQ adapted L-BSE lost the ability to replicate in TgMet129 but reached a full attack rate with short incubation in TgVal129, with a protease resistant prion protein profile and deposition pattern resembling sporadic CJD VV2; VRQ adapted H-BSE reached full attack rates in both TgMet129 and TgVal129 with features resembling sporadic CJD MM1.
  • Back transmission to bovine PrP mice shows how far the H-type change went. The parent isolates both gave 6 of 6 in TgBo, L2 at 263 plus or minus 31 days and H3 at 382 plus or minus 74 days, and sheep passaged L2 stayed bovine transmissible at 221 plus or minus 3 and 240 plus or minus 18 days. VRQ passaged H3 gave 0 of 6 in TgBo over two serial passages, which the authors read as an irreversible alteration of the H-BSE strain.
  • The funders named are the UK Food Standards Agency (FS231051), the Spanish Ministerio de Economia, Industria y Competitividad (RTA2012-00004, AGL2016-78054-R, BES-2010-040922), Fundacio La Marato de TV3 (201821-31), INIA (INIA-FPI-SGIT-2015-02), the Alliance BioSecure research foundation (FABS FRM-2014) and Interreg POCTEFA EFA148/16, which is the grant number of the REDPRION project; the article states that the funders had no role in the study.
  • The paper cites 32 works, among them both 2004 reports that defined the atypical bovine phenotypes (Biacabe for H-type and Casalone for the amyloidotic L-type form), the two 2008 studies of atypical BSE and L-type BASE in human PrP mice (Beringue and Kong), the 2014 ovine scrapie zoonotic potential paper from the same two laboratories, a 2017 paper on valine 129 protection, a 2011 paper on sheep and goat BSE in human PrP mice and a 2016 paper on L-BSE transmitted to sheep.
  • The authors' own reading is cautious. They do not claim a causal link with sporadic CJD, offer phenotypic convergence as one explanation for the resemblance, argue for keeping the ban on recycling meat and bone meal and for continued active surveillance, note that atypical BSE appears to arise sporadically so a cattle to sheep to human route is unlikely, and warn that transgenic mouse results need careful extrapolation.
  • Europe PMC listed 17 citing records on 21 October 2026, most of them on chronic wasting disease or on how prion protein expression and host genotype shape host range, and none of them a regulatory assessment of this paper.
  • An independent result points the same way on the sheep step. Cassmann and colleagues at the USDA National Animal Disease Center in Ames, with the Friedrich-Loeffler-Institut, published electronically on 8 October 2020 that bovine adapted transmissible mink encephalopathy passaged through VRQ/VRQ sheep produced an L-BSE like phenotype while passage through VRQ/ARQ sheep did not, and concluded that sheep host genotype shapes the strain that comes out.

Timeline

  1. 2020Original publication date given on the CDC article page, ahead of the print issue.
  2. 2020First indexed in Europe PMC, with the PMC deposit under PMC7258450.
  3. 2020Appears in the June 2020 issue of Emerging Infectious Diseases, volume 26 issue 6, pages 1130 to 1139.
  4. 2020Cassmann and colleagues publish a convergent result on the effect of sheep VRQ and ARQ genotype on an L-BSE like agent.
  5. 2021Pritzkow and colleagues publish a review of prion dissemination through the environment and medical practice that cites this paper.
  6. 2023Tranulis and Tryland publish a review of the zoonotic potential of chronic wasting disease that cites this paper.
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