Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients

Christina D. Orrù; Katrin Soldau; Christian Cordano; Jorge Llibre-Guerra; Ari J. Green; Henry Sanchez; Bradley R. Groveman; Steven D. Edland; Jiri G. Safar; Jonathan H. Lin; Byron Caughey; Michael D. Geschwind; Christina J. Sigurdson

doi:10.1128/mBio.02095-18

mBio (Dec 2018)

Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients

Christina D. Orrù,
Katrin Soldau,
Christian Cordano,
Jorge Llibre-Guerra,
Ari J. Green,
Henry Sanchez,
Bradley R. Groveman,
Steven D. Edland,
Jiri G. Safar,
Jonathan H. Lin,
Byron Caughey,
Michael D. Geschwind,
Christina J. Sigurdson

Affiliations

Christina D. Orrù: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, USA
Katrin Soldau: Department of Pathology, University of California, San Diego, La Jolla, California, USA
Christian Cordano: Department of Neurology, Multiple Sclerosis Center, University of California, San Francisco (UCSF), San Francisco, California, USA
Jorge Llibre-Guerra: Cognitive and Behavioral Research Unit, National Institute of Neurology, Havana, Cuba
Ari J. Green: Department of Neurology, Multiple Sclerosis Center, University of California, San Francisco (UCSF), San Francisco, California, USA
Henry Sanchez: Department of Pathology, University of California, San Francisco (UCSF), San Francisco, California, USA
Bradley R. Groveman: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, USA
Steven D. Edland: Department of Family Medicine & Public Health, University of California, San Diego, La Jolla, California, USA
Jiri G. Safar: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
Jonathan H. Lin: Department of Pathology, University of California, San Diego, La Jolla, California, USA
Byron Caughey: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Hamilton, Montana, USA
Michael D. Geschwind: Department of Neurology, Memory and Aging Center, University of California, San Francisco (UCSF), San Francisco, California, USA
Christina J. Sigurdson: Department of Pathology, University of California, San Diego, La Jolla, California, USA

DOI: https://doi.org/10.1128/mBio.02095-18
Journal volume & issue: Vol. 9, no. 6

Abstract

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ABSTRACT Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard. IMPORTANCE Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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