Prions spread via the autonomic nervous system from the gut to the central nervous system in cattle incubating bovine spongiform encephalopathy

Abstract

To elucidate the still-unknown pathogenesis of bovine spongiform encephalopathy (BSE), an oral BSE challenge and sequential kill study was carried out on 56 calves. Relevant tissues belonging to the peripheral and central nervous system, as well as to the lymphoreticular tract, from necropsied animals were analysed by highly sensitive immunohistochemistry and immunoblotting techniques to reveal the presence of BSE-associated pathological prion protein (PrP Sc )depositions. Our results demonstrate two routes involving the autonomic nervous system through which BSE prions spread by anterograde pathways from the gastrointestinal tract (GIT) to the central nervous system (CNS): (i) via the coeliac and mesenteric ganglion complex, splanchnic nerves and the lumbal/caudal thoracic spinal cord (representing the sympathetic GIT innervation); and (ii) via the Nervus vagus (parasympathetic GIT innervation). The dorsal root ganglia seem to be subsequently affected, so it is likely that BSE prion invasion of the non-autonomic peripheral nervous system (e.g. sciatic nerve) is a secondary retrograde event following prion replication in the CNS. Moreover, BSE-associated PrP Sc was already detected in the brainstem of an animal 24 months post-infection, which is 8 months earlier than reported previously. These findings are important for the understanding of BSE pathogenesis and for the development of new diagnostic strategies for this infectious disease.

Localization of Sympathetic, Parasympathetic and Sensory Neurons Innervating the Distal Ileum of the Cattle

“…Recently, the same result was demonstrated in the cattle after an oral challenge of PrP Sc [12]. After oral ingestion of scrapie agent in the hamster, initial infection of the brain occurred via the vagus nerve rather than by spread along the spinal cord [3].…”

“…Experimental time-course studies on the pathogenesis of PrP Sc in rodents strongly suggested that infection spread from the gastrointestinal tract via the splanchnic and vagus nerves to the spinal cord and brain after an intraperitoneal, intragastric or oral administration of PrP Sc [2,3,15,22,23]. Recently, the same result was demonstrated in the cattle after an oral challenge of PrP Sc [12].…”

“…There may be differences between the hamster and cattle in the pathways along which infection spreads from the intestine to the brain. On the other hand, it is demonstrated that the vagus nerve contributes to the transport of PrP Sc in the cattle [12]. The results of the present study suggest that the site of neuroinvasion to the vagus nerve may be in upper intestine.…”

TSE pathogenesis in cattle and sheep

“…In cattle experimentally infected with a high oral dose of BSE, infectivity was present in the ileum six months after oral infection [71,73] and in the tonsil ten months after oral infection (the latter only detectable using the more sensitive bovine transgenic mouse and cattle bioassay) [16,74]. In these animals PrP Sc was immunohistochemically detected in TBM of the ileal Peyer's patches but not in the tonsil [26,63,74]. Despite this apparently low involvement of the lymphoid system, neuroinvasion still occurs after a relatively long incubation period.…”

Approaches to investigating transmission of spongiform encephalopathies in domestic animals using BSE as an example

“…For BSE and scrapie some of these questions have been addressed partially [39,42,45,49,56,61]. It is possible that for novel TSE many of these questions will remain unanswered or unpursued, except by the most determined of researchers after the funding, stimulated by the public health and political aspects of BSE and vCJD, has dwindled.…”