1. Introduction
Prion diseases are fatal transmissible neurodegenerative diseases thought to be caused by conformational conversion of cellular prion protein (PrPC) to pathological prion protein (PrPD) and its accumulation in both humans and animals [
1]. In humans, prion diseases are categorized into three different forms: sporadic, genetic and acquired [
2,
3]. While sporadic Creutzfeldt–Jakob disease (sCJD) is the most prevalent form of human prion diseases, the acquired forms have generated a lot of fear, in particular over concern of zoonotic transmission through consumption of infected animals. The animal prion diseases comprise scrapie in small ruminants [
1,
4], bovine spongiform encephalopathy (BSE) in cattle [
5], transmissible mink encephalopathy (TME) in mink [
6], feline spongiform encephalopathy (FSE) in cats [
7], spongiform encephalopathy in camels [
8] and chronic wasting disease (CWD) in cervids [
9].
Zoonotic transmission is a theoretical concern for all prion diseases, but, to date, the only documented transmission to humans has been from BSE-infected cattle. In the late 1980s, the outbreak of BSE (or mad cow disease) in cattle, and its transmission to humans through the food supply, resulted in a new form of prion disease, called variant CJD (vCJD), and caused 231 human deaths [
10,
11]. This has raised a concern for zoonotic transmission of other animal prion diseases, in particular CWD, as prevalence of this prion disease is rising.
CWD was first described in 1967 in a captive mule deer and later identified in black-tailed deer and Rocky Mountain elk in wild-life farms in Colorado and Wyoming [
9,
12]. In 2001, CWD was described in white-tailed deer in Nebraska and Dakota [
13], and, in 2005, it was described in moose in Colorado [
14]. Recently, CWD was also described in reindeer in Norway [
15].
As the most infectious and contagious of all prion diseases, CWD is efficiently transmitted among cervids by both direct and environmental contacts [
11]. Unlike BSE, CWD prions (PrPCWD) are distributed throughout the body of the diseased animal, including the peripheral and central nervous system, muscles, antler velvet and blood [
16]. PrPCWD is also shed in saliva, feces and urine [
11,
17] and can persist in the environment for many years, increasing exposure risk to all animal species within the ecosystem. This shedding, plus the fact that CWD occurs in wild migrating animals, makes its management more challenging than BSE, where banning specific risk material or contaminated feed was sufficient to reduce cases [
18,
19]. Attempts to control CWD spread include non-selective culling of the animals in endemic areas, regulations on the number of animals to be raised in a farm, guidance on carcass handling, mandatory testing of hunter harvested animals, feed bans, and prohibitions in importing cervids [
20]. Despite these measures, CWD incidence continues to rise.
A major concern for human exposure to CWD comes through direct consumption of venison, but also consumption of other ruminants that might be reservoirs of adapted CWD prions [
21,
22]. Fortunately, there is a strong species barrier in most prion diseases, largely dependent on the degree of homology of PrP amino acid sequence between donor and recipient species. The barrier is not absolute though; it can be influenced by PRNP polymorphisms and different prion strains [
23,
24]. This is highly relevant, as studies are demonstrating the existence of several different CWD strains, each of which may have unique transmission properties towards humans.
As an added challenge, we do not know what the signs and symptoms of CWD would look like in humans. It might resemble sporadic CJD or present as something unlike any known human prion disease. In cervids, clinical signs of CWD include weight loss, isolation, and loss of fear towards humans. Polyuria, polydipsia, excessive drooling, ataxia and tremors are observed during the later stages of the disease [
25,
26]. Among cervids, the incubation period varies from 2 to 4 years [
27]; if transmitted to humans, it could be decades.
In this article, we will review factors that could influence the transmission of CWD to humans, including risk of exposure, the influence of PRNP polymorphism and CWD strain on the species barrier, and transmission data from theoretical, experimental, and real-world scenarios. We will also present current surveillance data on human cases of prion disease and discuss how we might detect human presentations of CWD, should they arise.
2. Risk of Exposure
Whether humans will succumb to CWD transmission depends, in part, on the risk of humans encountering CWD in the real world. Human exposure to high levels of CWD prions is most likely to occur through direct handling of infected cervid carcasses or meat byproducts and through consumption of venison, velvet or other cervid byproducts [
28]. Unlike BSE, where prions existed primarily in brain and spinal cord, prions in CWD are found at higher titers in tissues that are more highly consumed, such as skeletal muscle, and have been detected in cervids that are still sub-clinical and therefore more likely to be consumed [
16,
29]. Environmental exposure of humans to CWD prions is also possible, given that PrPCWD is shed into the environment where it may remain infectious for decades. For these reasons, the prevalence of CWD and its geographical footprint are important factors.
Since the first description of CWD in the 1960s, there has been increasing geographic spread, with CWD now found in 26 states in the U.S., three provinces in Canada, South Korea, Norway, Sweden, and Finland [
27,
30]. In North America, the prevalence of CWD is variable, affecting up to 30% of free ranging animals in some areas, and as many as 80–90% of animals in captivity [
26,
27,
31]. In Wisconsin, where prevalence of CWD is among the highest in the world, CWD cases in white-tailed deer doubled between 2010 and 2016, and male deer populations had prevalence of infection up to 40–50% with females at 20–30% [
32]