Chapter 10 Infectious Diseases of the Nervous System From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved.

Figure 1 An Egyptian stele thought to represent a polio victim, 18th dynasty (1403–1365 BC). Carving shows an Egyptian with a crippled leg, likely the result of poliomyelitis infection. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 2

Figure 2 Botox/B binding to both synaptotagmin and the ganglioside receptor on the membrane of cholinergic neuron. From Ref. 1. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 3

Figure 3 Model for the entry of Botulinum Neurotoxin (BoNT) into nerve cells. SNARE proteins mediate vesicular docking. Vesicular Synaptobrevin (Syb) and membrane Syntaxin (Syn) and SNAP-25 must interact (A) for vesicular docking on the cell membrane, which in turn allows vesicular release of acetylcholine (ACh) (A). Once released, ACh binds acetylcholine receptors (AChR), which mediates muscle contraction (C). The intra-vesicular parts of synaptic vesicle proteins become exposed on the plasma membrane as the vesicle integrates into the membrane (D). When BoNT is present it binds to a ganglioside molecule on the cell surface, which allows BoNT to access their protein receptor (exemplified here for synaptotagmin (Syt)) (E). After binding the protein receptor, the neurotoxins are endocytosed via retrieval of synaptic vesicles (F). The lumen of the recycling vesicles becomes acidified via the action of the vesicular proton pump (G). Acidification provokes a structural rearrangement in the neurotoxins, whereby the heavy-domain (HC and HN) forms a channel through the vesicular membrane (H). The light chain (L) passes through the channel due to partial unfolding and is released to the cytosol following reduction of the disulfide bond (I). Ultimately, the light chain cleaves its target SNARE(s), Syb, Syx, or SNAP-25, (J) and thus blocks the synaptic vesicle cycle, which it exploits for cellular entry. Preventing the further docking of ACh vesicles prevents ACh release and subsequent binding to AChR, leading to paralysis (K). The entry of BoNT into nerve cells requires the vesicular docking cycle to expose the appropriate protein receptor (here shown as Syt), hence the rate of toxin uptake is directly related to vesicular fusion and therefore directly related to synaptic activity. This results in more active muscle groups becoming paralyzed more quickly. Figure courtesy of Stephanie Robert and adopted from Ref. 4. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 4

Figure 4 The various botulinum toxins have specific presysnaptic targets, which are all involved in synaptic vesicle release. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 5

Figure 5 Gummas disfiguring the head and face of an individual with syphilis. Bust in Musée de l’Homme Paris. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 6

Centers for Disease Control and Prevention/Susan Lindsley. Figure 6 Cross-section of spinal cord showing loss of dorsal spinal neurons in the dorsal spinothalamic tracts (white areas encircled by dashed line) in a patient with neurosyphilis. Centers for Disease Control and Prevention/Susan Lindsley. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 7

Photo: WHO/P. Virot (UN News Center). Figure 7 Children with polio at the Amar Jyoti Research Center, Delhi, India. Photo: WHO/P. Virot (UN News Center). From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 8

Reproduced with permission from Ref. 8. Figure 8 Human immunodeficiency virus I budding from CD4 lymphocytes (left). Schematic of the structure of the viral particle (right). Reproduced with permission from Ref. 8. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 9

Figure 9 Human immunodeficiency virus infects microglia, which, in conjunction with astrocytes, exert toxic effects on neurons, causing indirect killing by the virus. From Ref. 11. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 10

Figure 10 A fluid level-attenuated inversion recovery magnetic resonance image of a patient with human immunodeficiency virus-induced dementia presenting with subcortical white matter abnormalities throughout the brain. These changes, visible as bright brain tissue within the otherwise gray-appearing brain tissue, are typically seen in the late stages of the disease and have become rare with aggressive antiviral treatment. From Ref. 9. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 11

Figure 11 Cellular pathology of Creutzfeld Jacobs disease (top), and Kuru (bottom). Each shows an abundance of vacuoles, giving the brain a sponge-like consistency. From Ref. 12. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 12

Reproduced with permission from Ref. 13. Figure 12 Three-dimensional shape of PrP and PrPsc illustrating the conversion from primarily a-helical to b-sheet structure. Reproduced with permission from Ref. 13. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 13

Figure 13 Isolated and cultured Naegleria fowleri trophozoites (top) at low (left) and high (right) magnification. The high-magnification image (top, right) shows the flagella with which the pathogens propel. Brain of a patient who died from primary amoebic meningoencephalitis (PAM), showing extensive hemorrhage and necrosis, mainly in the frontal cortex (bottom, right, arrow). Cerebral portion of the brain from a patient with PAM, stained with hematoxylin and eosin, showing large clusters of Naegleria fowleri trophozoites and destruction of the normal brain tissue architecture (bottom, right). Cysts are not seen (original magnification ×100). Inset: Higher magnification (×1000) of N. fowleri trophozoites (arrows) with the characteristic nuclear morphology. Centers for Disease Control and Prevention, http://www.cdc.gov/parasites/naegleria/naegleria-fowleri-images.html. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 14

Image provided by Dr Rajesh Sharma DMRD, MD. Figure 14 Coronal T2-weighted image of the brain reveal multiple cystic lesions throughout the entire brain. That are markedly hyperintense with a hypointense mural nodule. Image provided by Dr Rajesh Sharma DMRD, MD. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 15

Figure 15 Viruses suitable for gene delivery to the central nervous system. dsDNA, double-stranded DNA; ssDNA, single-stranded DNA. From Ref. 24. From Diseases of the Nervous System. Copyright © 2015 Elsevier Inc. All rights reserved. 16