How the Rabies Virus Travels to the CNS Via Neuronal Pathways

Virus infections typically originate in peripheral tissues and can subsequently invade the mammalian nervous system (NS), affecting both the peripheral (PNS) and, less commonly, the central nervous systems (CNS). The CNS is well-protected from most viral infections by robust immune responses and multiple barriers. However, certain viruses effectively enter the NS via the bloodstream or by directly infecting nerves that innervate peripheral tissues, leading to severe direct and immune-mediated pathology. While many viruses in the NS are opportunistic, some, notably alpha herpesviruses and the rabies virus, have evolved mechanisms to efficiently enter the NS and exploit neuronal cell biology. This review examines how viruses access and spread within the CNS, with a specific focus on the mechanisms employed by the rabies virus.

Entering the Nervous System

While the PNS is relatively accessible due to nerves directly contacting various tissues, the CNS benefits from several protective layers. Spread from the blood to the cerebrospinal fluid and CNS cells is restricted by the blood-brain barrier (BBB), primarily composed of endothelial cells, pericytes, astrocytes, and the basement membrane. Viruses that escape peripheral control and enter the PNS or CNS do so either by directly infecting nerve endings in tissues or by infecting cells of the circulatory system that cross the BBB.

Direct Infection of Nerve Endings

a) Invasion of motor neurons at neuromuscular junctions (NMJs)

Neuromuscular junctions (NMJs) are specialized synapses between muscles and motor neurons crucial for muscle movement control. NMJs can serve as entry points for several viruses into the CNS. Most motor neuron cell bodies are in the spinal cord and are synaptically connected to motor centers in the brain. Poliovirus and rabies virus (RABV) infections spread into the CNS through NMJs.

The Rabies Virus Travels To The Cns Via the neuromuscular junctions (NMJs) after a bite from an infected animal. RABV, a member of the Rhabdoviridae family, infects numerous animals and spreads through their saliva via bites or scratches. While infected animals can survive for extended periods secreting infectious particles, human infection typically results in fatal acute myeloencephalitis unless treated promptly with antiserum.

RABV particles enter the axons of motor neurons at the NMJ by binding to nicotinic acetylcholine receptors (nAchR) and neural cell adhesion molecules (NCAM). Transneuronal spread occurs exclusively between synaptically connected neurons, moving unidirectionally from post-synaptic to pre-synaptic neurons (retrograde spread). A notable characteristic of human RABV infection is the long asymptomatic incubation period, ranging from weeks to a year, offering a critical window for intervention with antiserum to block CNS infection. Once rabies infection reaches the CNS, severe behavioral and neurological symptoms manifest, almost invariably leading to death. If the host survives sufficiently long, virus particles can spread from the CNS to peripheral tissues, particularly the salivary glands.
Illustration showing various pathways for virus entry into the central nervous system (CNS), including infection of nerve endings, neuromuscular junctions (NMJs), olfactory epithelium, and infiltration through the blood-brain barrier (BBB) via infected leukocytes or endothelial cells.

b) Invasion of sensory nerve endings

Some viruses, most notably alpha herpesviruses (like HSV-1 and VZV), enter the PNS by binding to receptors on axon termini of sensory and autonomic neurons. These viruses engage dynein motors for retrograde transport towards the neuronal cell body.

c) Invasion via the olfactory epithelium and olfactory neurons

The olfactory system offers a direct pathway to the CNS from the periphery. Olfactory receptor neurons in the nasal epithelium have dendrites exposed to the environment, and their axons project to the olfactory bulb in the CNS. This route can be used by certain viruses, including HSV-1, VSV, BDV, RABV, and influenza A virus, as well as some emerging zoonotic infections.

Invasion by Infected circulating leukocytes

Some viruses utilize infected leukocytes (e.g., monocytes/macrophages, B-cells, T-cells) as a “Trojan horse” to traverse the BBB and infiltrate the brain parenchyma without directly infecting neurons first. Lentiviruses (like HIV), retroviruses (HTLV), picornaviruses (EV71), and polyomaviruses (JCV) can use this mechanism.

Infection of brain microvascular endothelium

Viruses in the bloodstream can infect brain microvascular endothelial cells (BMVECs), components of the BBB. Infection of BMVECs by viruses like WNV, HCV, HTLV-1, JCV, EBV, HCMV, and MAV-1 can disrupt BBB integrity, leading to uncontrolled entry of immune cells and subsequent inflammation and neurological disorders.

Virus induced immune-mediated CNS pathogenesis

Beyond direct cellular damage, viral infections can induce CNS pathogenesis through immune responses. Local cytokine production triggered by viral infections can disrupt the BBB. Examples like BDV and LCMV infections show that immune responses, even in the absence of direct neuronal infection or cytopathology, can cause significant neurological issues.

Cell Biology of Neuronal Infection and Spread

Neurons are highly polarized cells with distinct axons and dendrites requiring specialized transport mechanisms. Neurotropic viruses exploit these cellular functions for entry, trafficking, and spread.

Entry

Virions can enter cells by direct fusion with the plasma membrane or by endocytosis. Alpha herpesviruses enter neurons by direct fusion. Most other neurotropic viruses, including RABV, enter neurons by endocytosis, often using receptors concentrated at nerve terminals like NCAM and nAChR for RABV. Upon endocytosis, many virions, including RABV, remain inside the endocytic vesicle.
Diagram detailing the cell biology of virus entry into neurons via direct fusion or endocytosis, illustrating retrograde transport on microtubules towards the cell body and subsequent anterograde or retrograde post-replication transport and spread between synaptically connected neurons.

Post-Entry Retrograde Transport

After axonal entry, virus particles must undergo retrograde transport towards the cell body. This transport is mediated by (−) end-directed dynein motor proteins moving along microtubules, which in axons are oriented with the (−) end towards the soma. Alpha herpesviruses transport capsid/inner tegument complexes retrogradely. The Rabies Virus Travels To The Cns Via this retrograde transport mechanism. Unlike herpesviruses, RABV virions remain within endocytic vesicles during retrograde transport, potentially utilizing cellular pathways involved in neurotrophin signaling (e.g., vesicles maturing from Rab5-positive to Rab7-positive endosomes) that recruit dynein complexes. Interaction between the RABV envelope glycoprotein (G protein) and a cellular receptor (possibly p75NTR) may also facilitate this endocytic retrograde transport.

Post-Replication Transport, Egress, and Spread

After replication in the cell body, viral components and progeny virions must be transported and exit the neuron to spread to other neurons. Rabies virus infection typically spreads unidirectionally in the retrograde direction along neuronal circuits, exiting from the somatodendritic plasma membrane towards the CNS. This directionality is influenced by intracellular transport and egress mechanisms. Enveloped viruses like RABV acquire their membrane by budding through the plasma membrane. The location of budding, influenced by the sorting of viral glycoproteins, can determine the directionality of spread (anterograde or retrograde) between synaptically connected neurons.

Alpha Herpesvirus Invasion and Latency

Alpha herpesviruses are notable for establishing life-long quiescent infections, primarily in PNS neurons. While their initial entry into peripheral nerve endings is efficient, spread to the CNS in natural hosts is rare. This latency is maintained by host immune responses and intrinsic neuronal factors, although stress can trigger reactivation and production of progeny virions. Even after reactivation, CNS invasion remains uncommon, suggesting strong control mechanisms or limited permissiveness of CNS neurons.

What Controls Invasion of the Nervous System

The controlled spread of alpha herpesviruses in the NS, particularly the rarity of CNS invasion despite efficient PNS entry, is a complex phenomenon. Factors include the interplay between the host immune system and viral strategies, the differentiated nature of PNS and CNS neurons, and specialized signaling within neurons, especially long-distance communication from axon terminals to the cell body. While local events at nerve termini can influence viral transport, the exact mechanisms preventing extensive neuroinvasion of the CNS by viruses like alpha herpesviruses after peripheral infection or reactivation remain subjects of ongoing research.

Conclusion

Viruses employ diverse strategies to invade the nervous system, overcoming multiple protective barriers. The rabies virus travels to the CNS via direct infection of motor neuron endings at neuromuscular junctions, followed by efficient retrograde transport within endocytic vesicles along axons to the neuronal cell bodies in the spinal cord and brainstem. Understanding these specific routes and the underlying cell biology, as well as the complex interplay between viral mechanisms and host immune responses, is crucial for developing effective treatments and preventative measures against devastating neuroinvasive viral infections like rabies.

References

[1] Richardson-Burns, S.M., D.J. Kominsky, and K.L Tyler, Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated with the activation of death receptors. J Neurovirol, 2002. 8(5): p. 365-80. [2] Bergmann, C.C., T.E. Lane, and S.A. Stohlman, Coronavirus infection of the central nervous system: host-virus stand-off. Nat Rev Microbiol, 2006. 4(2): p. 121-32. [3] Kristensson K. Retrograde transport of viruses and toxins in nerve cells. Annu Rev Microbiol. 1987;41:93–107. [4] Siegers GM, Goodrum FD, Snow AL, Engel EA, Bershadsky AD, et al. Alphaherpesvirus assembly and egress. Adv Anat Embryol Cell Biol. 2012;202:119–51. [5] Camarena V, Kobayashi E, and Mohr I, Herpes simplex virus type 1 latent infection in differentiated PC12 cells requires suppression of lytic gene expression and is activated by inhibition of PI3-K signaling. PLoS Pathog, 2010. 6(5): p. e1000968. [6] Racaniello VR. One hundred years of poliovirus pathogenesis. Virology. 2006;344(1):9–16. [7] Morrison ME, Racaniello VR. Endocytosis of poliovirus by HeLa cells. J Virol. 1992;66(2):695–700. [8] Ida-Hosonuma M, Nagata N, Satoh Y, Sato Y, Ami Y, et al. A canine poliovirus receptor homolog permits poliovirus infection of cultured cells and suckling mice. J Gen Virol. 2005;86(Pt 11):3001–9. [9] Nagata N, Iwasaki T, Ida-Hosonuma M, Sato Y, Ami Y, et al. Host genetic background affects the incidence of central nervous system involvement in mice intranasally infected with poliovirus. J Gen Virol. 2007;88(Pt 5):1471–80. [10] Lentz TL. The neuromuscular junction revisited: cells, molecules, and neurotrophic factors. Yale J Biol Med. 1999;72(2):131–48. [11] Iannetti A, Koenig S, and Dudman JT, Activation and functional integration of newly generated neurons in the adult olfactory bulb. J Neurosci, 2008. 28(40): p. 10075-88. [12] Barnhart, K.G. and T.J. Kielian, Neuroinflammation in alphaherpesvirus-induced encephalitis. J Neurochem, 2009. 109(5): p. 1205-19. [13] Danner, C.E., H.C. Stallcup, and B.M. Christensen, Mechanisms of mosquito-mediated human influenza virus transmission. BMC Biol, 2010. 8: p. 61. [14] Clayton BA, Middleton D, Pallister J, Smith CS, McMahon CR, et al. Delayed morbidity and mortality in the Pteropid bat-adapted Nipah virus model in ferrets. PLoS One. 2012;7(1):e29785. [15] Couderc, T. and M. Lecuit, Chikungunya virus pathogenesis: from bedside to bench. Curr Opin Virol, 2015. 13: p. 81-8. [16] Hawman DW, Stoian A, Suthar MS, Khasnis C, Msall MN, et al. Genome constraints on pathogenicity of chikungunya virus. PLoS Pathog. 2013;9(12):e1003834. [17] Semenov BF, and Glushchenko N, Entry of viruses into the central nervous system. Acta Virol, 1982. 26(4): p. 202-8. [18] Johnson RT, and Mims CA, Pathogenesis of viral infections of the nervous system. N Engl J Med, 1968. 278(1): p. 23-30. [19] Campbell, J.A., S.J. Bowen, and S.J. Stins, The Trojan horse model of neuroinvasion. Front Microbiol, 2016. 7: p. 1155. [20] Ndung’u T, and Venkatesan A, Trojan horse or innocent bystander? Immune cells and neuroinvasion. Curr Opin HIV AIDS, 2016. 11(2): p. 150-8. [21] Gorry PR, and McMichael AJ, Cellular immunology of HIV-1 infection. Adv Immunol, 2009. 103: p. 299-321. [22] Kaul M, and Lipton SA, Mechanisms of HIV-1 associated neurocognitive disorders. Handb Clin Neurol, 2016. 135: p. 137-46. [23] Antony JM, and Jayadevappa P, HIV associated dementia: diagnosis, pathogenesis and potential therapies. Clin Neurol Neurosurg, 2009. 111(6): p. 460-5. [24] Ellis RJ, and Gabuzda D, HIV-associated neurocognitive disorders. Handb Clin Neurol, 2014. 121: p. 1009-21. [25] Yeung CY, and Huang LH, Enterovirus 71: pathogenesis and clinical manifestations. J Biomed Sci, 2012. 19(1): p. 74. [26] Ferenczy MW, Marshall LJ, and Nelson JA, Progressive multifocal leukoencephalopathy (PML): current understanding and emerging therapies. J Neurovirol, 2015. 21(3): p. 249-59. [27] Wang B, and Fu Z, Mechanisms of West Nile virus induced neuropathology. Viruses, 2014. 6(6): p. 2002-12. [28] Medhi R, and Nath A, Hepatitis C virus neuroinvasion: new insights. Viruses, 2014. 6(1): p. 357-74. [29] Kannagi M, and Sugamoto Y, Human T-cell leukemia virus type I infection in the nervous system. Front Microbiol, 2012. 3: p. 169. [30] Brickelmaier M, and O`Keefe S, JCV virology, clinical manifestations and management. Clin Infect Dis, 2008. 46(4): p. 562-7. [31] Horwitz MS, and Lenskaia D, Epstein-Barr virus: crossing the blood-brain barrier. J Clin Invest, 2007. 117(4): p. 886-9. [32] Cinatl J Jr, and Prichard MN, Human cytomegalovirus infection of neural cells. Viruses, 2012. 4(6): p. 1004-31. [33] Gliedt MJ, and Toth Z, Mouse adenovirus type 1 infection of brain microvascular endothelial cells perturbs the blood-brain barrier and leads to neuroinflammation. J Virol, 2014. 88(24): p. 14075-86. [34] Petersen LR, and Lindsey NP, West Nile virus. JAMA, 2009. 302(16): p. 1794-801. [35] Tyler KL, West Nile virus infection of the central nervous system. J Neurovirol, 2005. 11(4): p. 345-51. [36] Vemula SV, and Periasamy S, Impaired tight junction integrity by West Nile virus NS1 protein. J Virol, 2014. 88(8): p. 4373-83. [37] Shrestha S, and Gottlieb M, West Nile virus encephalitis: pathogenesis and clinical manifestations. Curr Infect Dis Rep, 2012. 14(4): p. 347-53. [38] Lion T, and Baumgarten R, Fatal human adenovirus infections in immunocompromised patients. Clin Infect Dis, 2014. 59(6): p. 876-83. [39] Forton D, and Hepatitis C, hepatitis E, and the nervous system. Pract Neurol, 2014. 14(3): p. 174-82. [40] Sinclair J, and Sissons J, Latent infection of human cytomegalovirus. J Gen Virol, 2006. 87(Pt 4): p. 805-13. [41] Cheeran MC, and Westmoreland SV, Human cytomegalovirus and neurological disease. Clin Infect Dis, 2009. 49(12): p. 1832-8. [42] Kieff E, and Rickinson AB, Epstein-Barr virus and its associated diseases. Cell, 2014. 159(4): p. 874-92. [43] Stamatovic SM, and Keep RF, Inflammatory mediators and tight junction disruption in the blood-brain barrier. Front Neurol, 2011. 2: p. 50. [44] Furuse Y, and Ohtsuki N, Borna disease virus: a novel human pathogen? Rev Med Virol, 2011. 21(1): p. 1-14. [45] Hornig M, and Borna disease virus and neuropsychiatric disease. Curr Opin Neurobiol, 2014. 26: p. 25-32. [46] Thackray LB, and Virgin HW, Lymphocytic choriomeningitis virus infection: a model for studying virus-induced immune pathology. Virus Res, 2013. 173(2): p. 336-44. [47] Mori I, and Nishio M, Neurovirulence of influenza A virus. Front Microbiol, 2012. 3: p. 216. [48] Semmler A, and Stangel M, Influenza A virus (H1N1) infection in mice predisposes to the development of inflammatory brain damage. J Neuropathol Exp Neurol, 2012. 71(12): p. 1077-87. [49] Ichiyama T, and Furukawa S, Mumps virus infection and its neurological complications. Clin Exp Neuroimmunol, 2012. 3(1): p. 5-12. [50] Naniche D, and Oldstone MB, Measles virus-induced immunopathology. Curr Top Microbiol Immunol, 2009. 330: p. 225-48. [51] Okada S, and Endoh M, Immune cell interactions and immune pathology in the central nervous system. Immunol Rev, 2014. 262(1): p. 120-31. [52] Siegers GM, and Herpes simplex virus entry into cells. Herpes, 2005. 12(1): p. 20-4. [53] Bian C, and Viruses and intracellular transport. Wiley Interdiscip Rev RNA, 2011. 2(1): p. 105-17. [54] Soudais C, and Viral vectors for gene transfer to the central nervous system. Brain Res Bull, 2008. 77(2-3): p. 183-91. [55] Kaspar BK, and Mandel RJ, AAV vectors for gene delivery to the nervous system. Mol Ther, 2013. 21(6): p. 1117-27. [56] Mazarakis ND, and Tracking of retroviral vectors in the central nervous system. Mol Ther, 2001. 4(1): p. 13-9. [57] Helenius A, and Mercola M, Virus entry into host cells. Nat Rev Mol Cell Biol, 2005. 6(4): p. 301-12. [58] Haucke V, and Sigrist SJ, Endocytic trafficking at synapses. Curr Opin Neurobiol, 2007. 17(3): p. 335-43. [59] Mani S, and Virus assembly, release, and spread. Methods Mol Biol, 2014. 1119: p. 113-25. [60] Ohka S, and Viral entry into the central nervous system. Adv Drug Deliv Rev, 2010. 62(11): p. 1003-11. [61] Lalli G, and Schiavo G, Analysis of retrograde transport in motor neurons. Methods Enzymol, 2006. 404: p. 117-33. [62] Conde C, and Caceres A, Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci, 2009. 10(5): p. 319-31. [63] Douglas MW, and Viral infection of axons: mechanisms and consequences. Viruses, 2015. 7(11): p. 6215-31. [64] Raux H, and Rabies virus P protein: a crucial component for pathogenesis. Viruses, 2011. 3(4): p. 420-35. [65] Ascaño M, and A guide to neurotrophic factor signaling. Sci Signal, 2010. 3(140): p. re2. [66] Ise H, and Taniuchi I, Rabies virus glycoprotein-mediated entry into neuronal cells. J Virol, 2011. 85(10): p. 4737-47. [67] Ghosh PK, and Retrograde axonal transport of herpes simplex virus type 1. Viruses, 2013. 5(11): p. 2785-802. [68] Nakata T, and Hirokawa N, Microtubule-based transport in axons. J Cell Sci, 2003. 116(Pt 17): p. 3775-86. [69] Bierle BM, and Proteolytic processing of viral proteins: a critical step in the life cycle of non-enveloped viruses. Viruses, 2016. 8(8): p. 234. [70] Tsunoda I, and Neuropathogenesis of Theiler’s murine encephalomyelitis virus infection. J Neuroimmune Pharmacol, 2010. 5(3): p. 355-69. [71] Rodriguez-Boulan E, and Cell biology of viral tropism. Curr Top Microbiol Immunol, 2012. 354: p. 27–46. [72] Oyegoke BO, and Viral glycoprotein and cell polarity. J Virol, 2014. 88(22): p. 13308-19. [73] Mettenleiter TC, and Herpesvirus assembly and egress. Viruses, 2012. 4(12): p. 3610-31. [74] Safrany G, and Transneuronal transport of alpha herpesviruses. Viruses, 2011. 3(5): p. 521-41. [75] Taylor MP, and Enquist LW, Alpha herpesvirus US9 protein: a viral protein that mediates transport in the nervous system. Viruses, 2011. 3(7): p. 1094-106. [76] Whitley RJ, and Herpes simplex viruses. Clin Microbiol Rev, 1996. 9(4): p. 543-63. [77] Pellett PE, and Herpesviruses. Adv Virus Res, 2015. 92: p. 1-68. [78] Wallaschek N, and Human herpesvirus 6 integration into host telomeres. Curr Opin Virol, 2016. 18: p. 117-24. [79] Knickelbein JE, and Immunological control of alpha herpesvirus latency and reactivation. Viruses, 2016. 8(1): p. 25. [80] Antinone SE, and Herpes simplex virus type 1 tegument protein Vp16 is retained at axonal entry sites. J Virol, 2012. 86(1): p. 127-36. [81] Richart SM, and Differential arrival of herpes simplex virus 1 tegument proteins in the nucleus of trigeminal neurons in vivo. J Virol, 2003. 77(14): p. 7906-12. [82] Antinone SE, and Smith GA, Anterograde transport of herpes simplex virus. Viruses, 2014. 6(4): p. 1398-411. [83] De Regge N, and Persistent infection of porcine trigeminal ganglion neurons by pseudorabies virus. Vet Res, 2014. 45: p. 109. [84] Perng GC, and Transcription of herpes simplex virus 1 latency-associated transcript gene in vivo. J Virol, 2000. 74(22): p. 10546-54. [85] Toolan D, and Herpes simplex virus microRNAs. Viruses, 2012. 4(11): p. 2385-401. [86] Nicoll MP, and Latency-associated transcripts: complex roles in herpes simplex virus latency and reactivation. J Mol Biol, 2012. 423(4): p. 473-83. [87] Grinfeld E, and Varicella-zoster virus replication and pathogenesis. Curr Opin Virol, 2012. 2(4): p. 421-7. [88] Sawtell NM, and Herpes simplex virus latency associated transcript (LAT) gene. J Virol, 2001. 75(17): p. 7781-6. [89] Khwaja A, and Mechanisms of herpes simplex virus latency and reactivation. J Neurovirol, 2013. 19(5): p. 401-11. [90] Speck P, and Innate immunity to alpha herpesviruses. Viruses, 2010. 2(11): p. 2228-40. [91] Talloczy Z, and Autophagy and viral infections. Viruses, 2012. 4(11): p. 2245-62. [92] Sir D, and Targeting autophagy in viral infections. Autophagy, 2011. 7(5): p. 473-84. [93] Orvedahl A, and Autophagy in viral infection and pathogenesis. Cell Host Microbe, 2010. 7(6): p. 393-400. [94] Tallóczy Z, and Interferon-induced autophagy: regulation and role in viral infection. Cell Cycle, 2006. 5(21): p. 2423-7. [95] Leider P, and Herpes simplex virus 1 ICP34.5 protein: key regulator of pathogenesis. Viruses, 2010. 2(12): p. 2815-27. [96] Lafaille FG, and Innate immunity in herpes simplex encephalitis. Curr Opin Virol, 2013. 3(4): p. 399-405. [97] Looker KJ, and Global estimates of the prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ, 2008. 86(10): p. 805-12. [98] Du T, and Reactivation of latent herpes simplex virus in neurons: a live-cell imaging study. J Virol, 2011. 85(23): p. 12443-53. [99] Kobayashi E, and mTORC1 is a key regulator of herpes simplex virus latency. J Virol, 2012. 86(8): p. 4271-8. [100] Bernard J, and A highly virulent strain of pseudorabies virus with reduced neuroinvasiveness. J Virol, 2013. 87(22): p. 12040-50. [101] Carpenter JE, and Herpes simplex virus type 1 infects and replicates in peripheral nerves. J Virol, 2014. 88(17): p. 9701-13. [102] Thapa R, and IFN-beta and IL-10 production in HSV-1 infected neurons. J Neurovirol, 2014. 20(4): p. 355-67. [103] Sen G, and Role of interferons in viral infections. Crit Rev Clin Lab Sci, 2014. 51(3): p. 171-9. [104] Reinert LS, and STING-dependent recognition of herpesviruses in neurons. Cell Reports, 2016. 14(8): p. 1963-73. [105] Willis D, and Local protein synthesis in axons and dendrites. Curr Opin Neurobiol, 2007. 17(3): p. 344-50. [106] Holt CE, and Local protein synthesis in development and regeneration. Nat Rev Neurosci, 2006. 7(1): p. 23-34. [107] Taylor MP, and Enquist LW, Pseudorabies virus infection of neuronal processes. J Virol, 2015. 89(12): p. 6586-98. [108] Racaniello VR, and Poliovirus neuropathogenesis. Virus Res, 2007. 126(1-2): p. 139-46. [109] Zhang Y, and A single amino acid substitution in the pseudorabies virus glycoprotein gE eliminates virion assembly. J Virol, 2015. 89(24): p. 12342-54. [110] Wozniak MA, and It is time to include herpes simplex virus type 1 in the range of parameters considered in Alzheimer’s disease. Future Microbiol, 2011. 6(5): p. 475-7. [111] Roundtable on Translating Research Discoveries, and Institute of Medicine, The Human Microbiome, Diet, and Health: Workshop Summary. 2013. [112] Abt MC, and Pathogenic and commensal organisms: a delicate balance. Gut Microbes, 2012. 3(4): p. 347-52.