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Righetto, I.; Gasparotto, M.; Casalino, L.; Vacca, M.; Filippini, F. Neurotropic Viruses in Mitochondria-Related CNS Disorders. Encyclopedia. Available online: https://encyclopedia.pub/entry/41467 (accessed on 23 April 2024).
Righetto I, Gasparotto M, Casalino L, Vacca M, Filippini F. Neurotropic Viruses in Mitochondria-Related CNS Disorders. Encyclopedia. Available at: https://encyclopedia.pub/entry/41467. Accessed April 23, 2024.
Righetto, Irene, Matteo Gasparotto, Laura Casalino, Marcella Vacca, Francesco Filippini. "Neurotropic Viruses in Mitochondria-Related CNS Disorders" Encyclopedia, https://encyclopedia.pub/entry/41467 (accessed April 23, 2024).
Righetto, I., Gasparotto, M., Casalino, L., Vacca, M., & Filippini, F. (2023, February 21). Neurotropic Viruses in Mitochondria-Related CNS Disorders. In Encyclopedia. https://encyclopedia.pub/entry/41467
Righetto, Irene, et al. "Neurotropic Viruses in Mitochondria-Related CNS Disorders." Encyclopedia. Web. 21 February, 2023.
Neurotropic Viruses in Mitochondria-Related CNS Disorders
Edit

The central nervous system (CNS) is known to be the most energy-demanding system in the human body. Mitochondria are crucial for CNS functionality. Neurotropic viruses such as Herpes, Rabies, West-Nile, and Polioviruses seem to hijack neuronal transport networks, commandeering the proteins that mitochondria typically use to move along neurites.

neurological disorder neurotropic virus mitochondria

1. Introduction

Mitochondria can prevent the abnormal increase in cytoplasmic calcium concentration; therefore, impaired mitochondrial transport into the presynaptic terminal is responsible for neurotransmission dysregulation [1]. Neurotropic viruses can alter calcium intracellular levels, as [Ca2+] activates fundamental pathways required for viral replication and provides a persistent infection [2]. The ER is a target for the virus, due to its intracellular calcium stores. Acting on ER channels, viruses make it possible for the release of a higher amount of Ca2+ in the cytoplasm, which is then used by mitochondria to boost ATP production to provide the higher energy cellular demands required for continuous viral replication. Moreover, a decrease of calcium concentration in the Golgi apparatus and ER fights the anti-viral response and the regulation of ER-[Ca2+] crosstalk may facilitate or prevent apoptosis [2]. Viral infections of the brain often cause death of neurons and astrocytes. Some neurotropic viruses, such as CHPV (Chandipura Virus) and JEV (Japanese Encephalitis Virus), share common host proteins modulating pathogenesis, as revealed by network analysis [3]. In this case, the DJ-1 protein is over-expressed in response to ROS generation and is able to modulate the viral replication and interferon responses along with low-density lipoprotein (LDL) receptor expression in neurons.

2. Poliovirus

Poliovirus (PV) is responsible for the destruction of motor neurons via apoptosis, leading to paralytic poliomyelitis. PV is able to induce a [Ca2+] cyt increase. This event takes place via inositol-1,4,5-triphosphate receptor (IP3R) and Ryanodine receptor (RyR) channels [4], resulting in a drop in membrane potential. Calcium from the ER is accumulated in the mitochondria through voltage-dependent anion channel-1 (VDAC), which is located on the outer mitochondrial membrane (OMM), and the mitochondrial calcium uniporter (MCU) that is located on the inner mitochondrial membrane (IMM). This results in mitochondrial dysfunction, apoptosis, and improved virus spreading. On the contrary, the non-structural protein 2B is responsible for the Ca2+ increase from extracellular sources, decreasing at the same time the [Ca2+] ER and [Ca2+] Golgi. This way, the host cell apoptosis is suppressed via the inhibition of caspase 3 activation, ensuring virus replication [5].

3. Herpes Virus

Herpes simplex virus (HSV) was found to increase [Ca2+] in neurons due to increased firing. This affects the interaction of mitochondrial protein Miro-1 with kinesin-1, resulting in the disruption of mitochondrial mobility and allowing viral spread. ND7/23 sensory neurons infected by HSV exhibit a modulation of [Ca2+] by T-type voltage gated calcium channels (VGCC) [6].
HSV-1 encephalitis (HSE) is the most common cause of viral encephalitis and a severe disease with high morbidity and mortality. Post-mortem human HSE brains show a high reduction in mitochondrial transcripts compared to controls, demonstrating that mitochondrial damage underlies the HSE phenotype, and this is confirmed in a primary human astrocyte HSV-1 infection model [7]. It is noteworthy that the same decrease in the expression of many genes important for mitochondrial function, observed with HSV infection, can also result in oxidative stress and neuronal damage leading to Alzheimer’s disease [8].

4. Rabies Virus

The Rabies virus (RABV) belongs to the lyssavirus genus of the Rhabdoviridae family and is the etiological agent of rabies with severe neurological symptoms and 100% mortality. RABV is able to induce apoptosis in vitro and in vivo. This virus carries a single non-segmented negative strand RNA genome. Five genes are encoded: the nucleoprotein (N), phosphoprotein (M), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L). Protein M plays a role in apoptosis induction as it partially targets mitochondria activating caspase-dependent and caspase-independent pathways at the late stage of infection. In particular, caspase-9 and caspase-3 are activated in a time-dependent manner, but not caspase-8. This phenomenon implies that the apoptosis induced by RABV involves the mitochondrial intrinsic pathway. At the late stage of infection, mitochondrial membrane potential is significantly dissipated, and the cytochrome c diffuses into the cytoplasm from mitochondria. Moreover, infection by RABV elicits the expression of the proapoptotic protein AIF, translocating into the nucleus of the infected cells [9]. RABV infection also leads to m-calpain upregulation, providing a proof of altered [Ca2+] m uptake. M-calpain cleaves Bid, activates calcineurin A, and stimulates killer kinases, thus leading to the cell death [10].

5. West-Nile Virus

West Nile virus (WNV) is a single stranded RNA flavivirus and a member of the JEV serocomplex. Even though WNV infections in humans most often result in mild illness, 0.5–1% of the patients may develop meningitis, encephalitis, acute flaccid paralysis, and death due to neurotropic invasion of the CNS and neuronal apoptosis [11]. Apoptosis is accompanied by the release of cytochrome c from the mitochondria and the formation of apoptosomes [12]. Neuro-2a cells (neuronal cells) show typical apoptotic characteristics when infected by WNV, e.g., Bax gene up-regulation [13]. Brain-derived T98G cells can undergo both extrinsic and intrinsic apoptotic pathways upon WNV infection, and Caspase-3-dependent neuronal death contributes to the pathogenesis of West Nile virus encephalitis [14][15].

6. Zika Virus

Zika virus infection can result in microcephaly in newborns, but serious neurological complications can also concern adults. Indeed, Zika virus is able to cause cell death in neural progenitor cells, astrocytes, and neurons. Studies in mice embryo brains showed that primary neurons in the cortico-striatal region exhibit an increased expression of the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and a [Ca2+] increase [16]. Excess [Ca2+] ER released from the lumen is then taken up by the mitochondria, leading to an increase in mtROS and the subsequent DNA damage [17].
The NS4B protein of Zika virus has been reported to recruit Bax to the mitochondria and induce Bax conformational activation. The overexpressed NS4B was localized to the mitochondria and induced cell apoptosis by activating the pro-apoptotic protein Bax [18]. Since astrocytes are targets of the Zika virus, iPSC-derived astrocytes were used as a model system to investigate key mechanisms and fates involved in the neurotoxicity of the virus, finding that Zika virus infection leads to mitochondrial failure, oxidative stress, and DNA damage [19].

References

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  2. Zhou, Y.; Frey, T.K.; Yang, J.J. Viral Calciomics: Interplays between Ca2+ and Virus. Cell Calcium. 2009, 46, 1–17.
  3. Ghosh, S.; Mukherjee, S.; Sengupta, N.; Roy, A.; Dey, D.; Chakraborty, S.; Chattopadhyay, D.; Banerjee, A.; Basu, A. Network Analysis Reveals Common Host Protein/s Modulating Pathogenesis of Neurotropic Viruses. Sci. Rep. 2016, 6, 32593.
  4. Brisac, C.; Téoulé, F.; Autret, A.; Pelletier, I.; Colbère-Garapin, F.; Brenner, C.; Lemaire, C.; Blondel, B. Calcium Flux between the Endoplasmic Reticulum and Mitochondrion Contributes to Poliovirus-Induced Apoptosis. J. Virol. 2010, 84, 12226–12235.
  5. Campanella, M.; de Jong, A.S.; Lanke, K.W.H.; Melchers, W.J.G.; Willems, P.H.G.M.; Pinton, P.; Rizzuto, R.; van Kuppeveld, F.J.M. The Coxsackievirus 2B Protein Suppresses Apoptotic Host Cell Responses by Manipulating Intracellular Ca2+ Homeostasis. J. Biol. Chem. 2004, 279, 18440–18450.
  6. Zhang, Q.; Hsia, S.; Martin-Caraballo, M. Regulation of T-type Ca2+ Channel Expression by Interleukin-6 in Sensory-like ND7/23 Cells Post-herpes Simplex Virus (HSV-1) Infection. J. Neurochem. 2019, 151, 238–254.
  7. Wnęk, M.; Ressel, L.; Ricci, E.; Rodriguez-Martinez, C.; Guerrero, J.C.V.; Ismail, Z.; Smith, C.; Kipar, A.; Sodeik, B.; Chinnery, P.F.; et al. Herpes Simplex Encephalitis Is Linked with Selective Mitochondrial Damage; a Post-Mortem and in Vitro Study. Acta Neuropathol. 2016, 132, 433–451.
  8. Polansky, H.; Goral, B. How an Increase in the Copy Number of HSV-1 during Latency Can Cause Alzheimer’s Disease: The Viral and Cellular Dynamics According to the Microcompetition Model. J. Neurovirol. 2021, 27, 895–916.
  9. Zan, J.; Liu, J.; Zhou, J.-W.; Wang, H.-L.; Mo, K.-K.; Yan, Y.; Xu, Y.-B.; Liao, M.; Su, S.; Hu, R.-L.; et al. Rabies Virus Matrix Protein Induces Apoptosis by Targeting Mitochondria. Exp. Cell Res. 2016, 347, 83–94.
  10. Ubol, S.; Kasisith, J.; Pitidhammabhorn, D.; Tepsumethanol, V. Screening of Pro-Apoptotic Genes Upregulated in an Experimental Street Rabies Virus-Infected Neonatal Mouse Brain. Microbiol. Immunol. 2005, 49, 423–431.
  11. Peng, B.H.; Wang, T. West Nile Virus Induced Cell Death in the Central Nervous System. Pathogens 2019, 8, 215.
  12. Kleinschmidt, M.C.; Michaelis, M.; Ogbomo, H.; Doerr, H.-W.; Cinatl, J. Inhibition of Apoptosis Prevents West Nile Virus Induced Cell Death. BMC Microbiol. 2007, 7, 49.
  13. del Carmen Parquet, M.; Kumatori, A.; Hasebe, F.; Morita, K.; Igarashi, A. West Nile Virus-Induced Bax-Dependent Apoptosis. FEBS Lett. 2001, 500, 17–24.
  14. Shrestha, B.; Gottlieb, D.; Diamond, M.S. Infection and Injury of Neurons by West NileEncephalitisVirus. J. Virol. 2003, 77, 13203–13213.
  15. Samuel, M.A.; Morrey, J.D.; Diamond, M.S. Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis. J. Virol. 2007, 81, 2614–2623.
  16. Olmo, I.G.; Carvalho, T.G.; Costa, V.V.; Alves-Silva, J.; Ferrari, C.Z.; Izidoro-Toledo, T.C.; da Silva, J.F.; Teixeira, A.L.; Souza, D.G.; Marques, J.T.; et al. Zika Virus Promotes Neuronal Cell Death in a Non-Cell Autonomous Manner by Triggering the Release of Neurotoxic Factors. Front. Immunol. 2017, 8, 1016.
  17. Doñate-Macián, P.; Jungfleisch, J.; Pérez-Vilaró, G.; Rubio-Moscardo, F.; Perálvarez-Marín, A.; Diez, J.; Valverde, M.A. The TRPV4 Channel Links Calcium Influx to DDX3X Activity and Viral Infectivity. Nat. Commun. 2018, 9, 2307.
  18. Han, X.; Wang, J.; Yang, Y.; Qu, S.; Wan, F.; Zhang, Z.; Wang, R.; Li, G.; Cong, H. Zika Virus Infection Induced Apoptosis by Modulating the Recruitment and Activation of Proapoptotic Protein Bax. J. Virol. 2021, 95, e01445-20.
  19. Ledur, P.F.; Karmirian, K.; Pedrosa, C.d.S.G.; Souza, L.R.Q.; Assis-de-Lemos, G.; Martins, T.M.; Ferreira, J.d.C.C.G.; de Azevedo Reis, G.F.; Silva, E.S.; Silva, D.; et al. Zika Virus Infection Leads to Mitochondrial Failure, Oxidative Stress and DNA Damage in Human IPSC-Derived Astrocytes. Sci. Rep. 2020, 10, 1218.
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