Pathogenesis of bovine spongiform encephalopathy in sheep

Abstract

The pathogenesis of bovine spongiform encephalopathy (BSE) in sheep was studied by immunohistochemical detection of scrapie-associated prion protein (PrP(Sc)) in the gastrointestinal, lymphoid and neural tissues following oral inoculation with BSE brain homogenate. First accumulation of PrP(Sc) was detected after 6 months in the tonsil and the ileal Peyer's patches. At 9 months postinfection, PrP(Sc) accumulation involved all gut-associated lymphoid tissues and lymph nodes as well as the spleen. At this time point, PrP(Sc) accumulation in the peripheral neural tissues was first seen in the enteric nervous system of the caudal jejunum and ileum and in the coeliac-mesenteric ganglion. In the central nervous system, PrP(Sc) was first detected in the dorsal motor nucleus of the nervus Vagus in the medulla oblongata and in the intermediolateral column in the spinal cord segments T7-L1. At subsequent time points, PrP(Sc) was seen to spread within the lymphoid system to also involve all non-gut-associated lymphoid tissues. In the enteric nervous system, further spread of PrP(Sc) involved the neural plexi along the entire gastrointestinal tract and in the CNS the complete neuraxis. These findings indicate a spread of the BSE agent in sheep from the enteric nervous system through parasympathetic and sympathetic nerves to the medulla oblongata and the spinal cord.

Fig. 1

Schematic representation of PrP^Sc accumulation (in red) in the lymphoid tissues, ENS and CNS of ARQ/ARQ sheep orally infected with BSE after a 6 months b 9 months c 12–13 months d 15 months e 17 months and f 19 months and after the onset of clinical disease. Abbreviations: DMNV dorsal motor nucleus of the vagus; IMLC intermediolateral column; C, T and L cervical, thoracic and lumbal segments of the spinal cord; GN ganglion nodosus; GMCC ganglion mesentericum cranialis/coeliacum; GS ganglia spinalis; O oesophagus; R rumen; Re reticulum; Om omasum; Ab abomasum; Du duodenum; Je jejunum; Il ileum; Ca caecum; Co colon; Rec rectum; GALT gut-associated lymphoid tissues; GALT Lnn lymph nodes draining from GALT tissues. Only the efferent motor fibers of the autonomic nervous system are shown

Fig. 1

Schematic representation of PrP^Sc accumulation (in red) in the lymphoid tissues, ENS and CNS of ARQ/ARQ sheep orally infected with BSE after a 6 months b 9 months c 12–13 months d 15 months e 17 months and f 19 months and after the onset of clinical disease. Abbreviations: DMNV dorsal motor nucleus of the vagus; IMLC intermediolateral column; C, T and L cervical, thoracic and lumbal segments of the spinal cord; GN ganglion nodosus; GMCC ganglion mesentericum cranialis/coeliacum; GS ganglia spinalis; O oesophagus; R rumen; Re reticulum; Om omasum; Ab abomasum; Du duodenum; Je jejunum; Il ileum; Ca caecum; Co colon; Rec rectum; GALT gut-associated lymphoid tissues; GALT Lnn lymph nodes draining from GALT tissues. Only the efferent motor fibers of the autonomic nervous system are shown

Fig. 2

BSE-infected sheep 6 months after oral inoculation. PrP^Sc immunostaining of a palatine tonsil and b Peyer’s patches of the ileum. PrP^Sc accumulations are present in tingible body macrophages of the lymphoid follicles. Bar 50 μm

Fig. 3

BSE-infected sheep 9 months after oral inoculation. PrP^Sc immunostaining in a the Peyer’s patches of the ileum b the myenteric plexus of the ileum c IMLC of the spinal cord segment T10 and d DMNV at the obex. Note the sparse neuronal cell labelling in the IMLC (inlay in c) and the ventral part of the DMNV (inlay in d). aBar 50 μm; bbar 20 μm; c and d bar 500 μm

Fig. 4

BSE-infected sheep 12 months after oral inoculation. PrP^Sc immunostaining in a the Peyer’s patches of the ileum b marginal zone in the spleen c IMLC of the spinal cord segment T5 and d DMNV at the obex . Note the colocalization of PrP^Sc (blue) and marginal zone macrophages (red) in the inlay in b (arrow). CA central arteriole; GC germinal center; MZ marginal zone. aBar 100 μm; bbar 100 μm; cbar 500 μm; dbar 500 μm