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PrP^CWD lymphoid cell targets in early and advanced chronic wasting disease of mule deer

Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1671, USA¹
Colorado Division of Wildlife, Wildlife Research Center, 317 West Prospect Road, Fort Collins, CO 80526-2097, USA²
Prionics AG, Wagistrasse 27a, 8952 Schlieren, Switzerland³
Institute for Animal Science and Health (ID-Lelystad), Edelhertweg 15, 8219 PH Lelystad, The Netherlands⁴

Author for correspondence: Edward Hoover. Fax +1 970 491 0523. e-mail ehoover{at}lamar.colostate.edu

Up to 15% of free-ranging mule deer in northeastern Colorado and southeastern Wyoming, USA, are afflicted with a prion disease, or transmissible spongiform encephalopathy (TSE), known as chronic wasting disease (CWD). CWD is similar to a subset of TSEs including scrapie and variant Creutzfeldt–Jakob disease in which the abnormal prion protein isoform, PrP^CWD, accumulates in lymphoid tissue. Experimental scrapie studies have indicated that this early lymphoid phase is an important constituent of prion replication interposed between mucosal entry and central nervous system accumulation. To identify the lymphoid target cells associated with PrP^CWD, we used triple-label immunofluorescence and high-resolution confocal microscopy on tonsils from naturally infected deer in advanced disease. We detected PrP^CWD primarily extracellularly in association with follicular dendritic and B cell membranes as determined by frequent co-localization with antibodies against membrane bound immunoglobulin and CD21. There was minimal co-localization with cytoplasmic labels for follicular dendritic cells (FDC). This finding could indicate FDC capture of PrP^CWD, potentially in association with immunoglobulin or complement, or PrP^C conversion on FDC. In addition, scattered tingible body macrophages in the germinal centre contained coarse intracytoplasmic aggregates of PrP^CWD, reflecting either phagocytosis of PrP^CWD on FDC processes, apoptotic FDC or B cells, or actual PrP^CWD replication within tingible body macrophages. To compare lymphoid cell targets in early and advanced disease, we also examined: (i) PrP^CWD distribution in lymphoid cells of fawns within 3 months of oral CWD exposure and (ii) tonsil biopsies from preclinical deer with naturally acquired CWD. These studies revealed that the early lymphoid cellular distribution of PrP^CWD was similar to that in advanced disease, i.e. in a pattern suggesting FDC association. We conclude that in deer, PrP^CWD accumulates primarily extracellularly and associated with FDCs and possibly B cells – a finding which raises questions as to the cells responsible for pathological prion production.

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