Lesion Profiling and Subcellular Prion Localization of Cervid Chronic Wasting Disease in Domestic Cats

Abstract

Chronic wasting disease (CWD) is an efficiently transmitted, fatal, and progressive prion disease of cervids with an as yet to be fully clarified host range. While outbred domestic cats (Felis catus) have recently been shown to be susceptible to experimental CWD infection, the neuropathologic features of the infection are lacking. Such information is vital to provide diagnostic power in the event of natural interspecies transmission and insights into host and strain interactions in interspecies prion infection. Using light microscopy and immunohistochemistry, we detail the topographic pattern of neural spongiosis (the “lesion profile”) and the distribution of misfolded prion protein in the primary and secondary passage of feline CWD (FelCWD). We also evaluated cellular and subcellular associations between misfolded prion protein (PrPD) and central nervous system neurons and glial cell populations. From these studies, we (1) describe the novel neuropathologic profile of FelCWD, which is distinct from either cervid CWD or feline spongiform encephalopathy (FSE), and (2) provide evidence of serial passage-associated interspecies prion adaptation. In addition, we demonstrate through confocal analysis the successful co-localization of PrPD with neurons, astrocytes, microglia, lysosomes, and synaptophysin, which, in part, implicates each of these in the neuropathology of FelCWD. In conclusion, this work illustrates the simultaneous role of both host and strain in the development of a unique FelCWD neuropathologic profile and that such a profile can be used to discriminate between FelCWD and FSE.

Assessing Transmissible Spongiform Encephalopathy Species Barriers with an <em>In Vitro</em> Prion Protein Conversion Assay

“…It is to be noted that in a previous study, however, we found the CER assay resulted in a similar pattern of PrP res formation as that of PMCA 15 . The results presented here also indicate that the CER assay correctly predicts the species barriers for transmission of various TSEs to laboratory mice (Figure 3) and suggest that bobcats may have susceptibility to CWD (Figure 4), in agreement with reports that domestic cats (Felis catus) can acquire prion disease after experimental CWD challenge 26,27 . Studies using the CER assay could compliment PrP sequencing efforts to understand wildlife susceptibility to CWD 28 .…”

Molecular Mechanisms of Chronic Wasting Disease Prion Propagation

“…Studies by the late Dr. Richard Marsh in the mid-1980s at the University of Wisconsin demonstrated that the CWD agent transmitted poorly to Syrian golden hamsters, ferrets, and mink (Sigurdson et al 2008; Bartz et al 1998; Marsh et al 2005). Other susceptible species include several species of voles, white-footed mice, deer mice, cats, raccoons, and squirrel monkeys (Hamir et al 2003, 2007b; Race et al 2009a, 2014; Mathiason et al 2013; Di Bari et al 2013; Heisey et al 2010; Seelig et al 2015). While non-Tg mice have been reported to be resistant to CWD infection (Browning et al 2004), limited infection of the VM/Dk inbred strain of mice with elk CWD prions has been reported (Lee et al 2013).…”

Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

“…TSEs differ from other protein misfolding neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease in that they are transmissible from one individual to another [ 1 ]. Interspecies transmission of TSEs remains an active area of research [ 2 – 5 ], and may demonstrate that other TSEs could transmit to humans, but transmission of BSE to humans as variant CJD (vCJD) (reviewed in [ 6 ]) has resulted in the death of over 200 individuals worldwide.…”