Aerosol Transmission of Chronic Wasting Disease in White-Tailed Deer

Denkers, Nathaniel D.; Hayes-Klug, Jeanette; Anderson, Kelly; Seelig, Davis; Haley, Nicholas J.; Dahmes, Sallie J.; Osborn, David A; Miller, Karl V.; Warren, Robert J.; Mathiason, Candace K.; Hoover, Edward A.

doi:10.1128/jvi.02852-12

Cited by 64 publications

(67 citation statements)

References 32 publications

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“…This quantitative approach allows application of RT-QuIC to diverse biological materials and enables better understanding of peripheral prion accumulation during the course of infection. Moreover, quantification of the level of infectivity present in excreta could shed light on the spread of CWD though elk and deer populations, and give a more accurate picture of the reservoirs of infectious agent present in the environment and level of exposure required to transmit disease (Almberg et al, 2011;Angers et al, 2009;Denkers et al, 2011Denkers et al, , 2012Haley et al, 2009Haley et al, , 2011Jennelle et al, 2009;Mathiason et al, 2006;Miller et al, 2004;Perrott et al, 2012;Saunders et al, 2008;Sigurdson et al, 1999;Spraker et al, 1997;Tamgüney et al, 2009;Williams & Young, 1980, 1982. levels based on end-point dilution of seed.…”

Section: Discussionmentioning

confidence: 99%

“…All appropriate intuitional protocols for animal handling and treatment were followed. All animals with 800-series ID numbers were aerosol-exposed and received two 1 ml doses of a 5 % CWD+ brain homogenate intranasally (Denkers et al, 2012). All deer with 700-series ID numbers were inoculated per os and received a single 1 g dose of CWD+ brain orally.…”

Section: Methodsmentioning

confidence: 99%

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Quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion

Henderson

Davenport

Haley

et al. 2015

Journal of General Virology

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107

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Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving the templated conversion of the normal cellular prion protein (PrP C ) to a pathogenic misfolded conformation. Templated conversion has been modelled in several in vitro assays, including serial protein misfolding amplification, amyloid seeding and real-time quakinginduced conversion (RT-QuIC). As RT-QuIC measures formation of amyloid fibrils in real-time, it can be used to estimate the rate of seeded conversion. Here, we used samples from deer infected with chronic wasting disease (CWD) in RT-QuIC to show that serial dilution of prion seed was linearly related to the rate of amyloid formation over a range of 10 "3 to 10 "8 mg. We then used an amyloid formation rate standard curve derived from a bioassayed reference sample (CWD+ brain homogenate) to estimate the prion seed concentration and infectivity in tissues, body fluids and excreta. Using these methods, we estimated that urine and saliva from CWD-infected deer both contained 1-5 LD 50 per 10 ml. Thus, over the 1-2 year course of an infection, a substantial environmental reservoir of CWD prion contamination accumulates.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion

Henderson

Davenport

Haley

et al. 2015

Journal of General Virology

Self Cite

107

134

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“…Specific details of the transmission of these diseases are not known, but there is evidence for the horizontal transmission of PrP Sc that has been excreted into the environment (7,8). The natural route(s) of entry for the infectious agent in the animal TSEs is not known, but there is experimental evidence for both oral (9)(10)(11)(12)(13) and nasal (14)(15)(16)(17)(18)(19) routes of infection. Whether the infectious agent is ingested or inhaled, it must cross an epithelium to enter the body, where prion conversion occurs prior to the onset of disease.…”

mentioning

confidence: 99%

Specificity, Size, and Frequency of Spaces That Characterize the Mechanism of Bulk Transepithelial Transport of Prions in the Nasal Cavities of Hamsters and Mice

Kincaid

Ayers

Bartz

2016

J Virol

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Inhalation of infected brain homogenate results in transepithelial transport. Bulk transepithelial transport in the nasal cavity has not been studied to date. In the present study, we characterized the frequency, size, and specificity of the intercellular spaces that mediate the bulk transport of inhaled prions between cells of mice or hamsters following extranasal inoculation with mock-infected brain homogenate, different strains of prion-infected brain homogenate, or brain homogenate mixed with India ink. Infected or mock-infected inoculum was identified within lymphatic vessels of the lamina propria and in spaces of >5 m between a small number of cells of the nasal mucosa in >90% of animals from 5 to 60 min after inhalation. The width of the spaces between cells, the amount of the inoculum within the lumen of lymphatic vessels, and the timing of the transport indicate that this type of transport was taking place through preexisting spaces in the nasal cavity that were orders of magnitude wider than what is normally reported for paracellular transport. The indiscriminate rapid bulk transport of brain homogenate in the nasal cavity results in immediate entry into nasal cavity lymphatics following inhalation. This novel mechanism may underlie the recent report of the early detection of prions in blood following inhalation and has implications for horizontal prion transmission. IMPORTANCEThe results of these studies demonstrate that the nasal mucosa of mice and hamsters is not an absolute anatomical barrier to inhaled prion-infected or uninfected brain homogenate. Relatively large amounts of infected and uninfected brain homogenate rapidly cross the nasal mucosa and enter the lumen of lymphatic vessels following inhalation. These bulk transepithelial transport events were relatively rare but present in >90% of animals 5 to 60 min following inhalation. This novel mechanism of bulk transepithelial transport was seen in experimental and control hamsters and mice, indicating that it was not species specific or in response to prion exposure. The indiscriminate bulk intercellular transport of inhaled pathogens across the nasal mucosa followed by entry into the lymphatic system may be a mechanism that underlies the entry and spread of other toxins and pathogens in olfactory system-driven animals.T ransmissible spongiform encephalopathies (TSEs) are a group of fatal neurological disorders affecting a variety of animal species, including humans. TSEs have relatively long incubation periods, and although they are rare in humans, they are relatively common in some animal populations. The TSEs affecting animals include scrapie in sheep and goats and chronic wasting disease (CWD) in deer, elk, and moose. The infectious agent is thought to consist largely if not entirely of PrP Sc , a misfolded conformation of the naturally occurring prion protein (PrP), designated PrP C (1-6). Specific details of the transmission of these diseases are not known, but there is evidence for the horizontal transmission of PrP Sc that has...

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“…Consequently, since its initial identification in northern Colorado and southeastern Wyoming, the disease has spread inexorably among North American states and provinces (3). To minimize the incidence of and ultimately to eliminate CWD, extensive surveillance and research projects have been developed (4,5). The ability to study the biology of CWD prions has been enhanced by the development of transgenic mice which overexpress cervid PrP on a mouse null PrP background (6)(7)(8).…”

mentioning

confidence: 99%

Assessing the Susceptibility of Transgenic Mice Overexpressing Deer Prion Protein to Bovine Spongiform Encephalopathy

Vickery

Lockey

Holder

et al. 2014

J Virol

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cSeveral transgenic mouse models have been developed which facilitate the transmission of chronic wasting disease (CWD) of cervids and allow prion strain discrimination. The present study was designed to assess the susceptibility of the prototypic mouse line, Tg(CerPrP)1536 ؉/؊ , to bovine spongiform encephalopathy (BSE) prions, which have the ability to overcome species barriers. Tg(CerPrP)1536 ؉/؊ mice challenged with red deer-adapted BSE resulted in 90% to 100% attack rates, and BSE from cattle failed to transmit, indicating agent adaptation in the deer.

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Aerosol Transmission of Chronic Wasting Disease in White-Tailed Deer

Cited by 64 publications

References 32 publications

Quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion

Quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion

Specificity, Size, and Frequency of Spaces That Characterize the Mechanism of Bulk Transepithelial Transport of Prions in the Nasal Cavities of Hamsters and Mice

Assessing the Susceptibility of Transgenic Mice Overexpressing Deer Prion Protein to Bovine Spongiform Encephalopathy

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