Astrocytes as targets for Venezuelan equine encephalitis virus infection
Abstract
Venezuelan equine encephalitis virus (VEE) produces an acute infection in humans and induces a well-characterized cytopathic effect in neurons of the central nervous system (CNS). However, little is known about the role of glial cells in response to VEE infection of the CNS. Our results demonstrate that VEE is capable of a productive infection in primary astrocyte cultures and that this infection is cytotoxic. Further, there were significant differences in the growth kinetics comparing virulent and attenuated strains of VEE. Additionally, VEE infection of astrocyte cultures induced gene expression of two neuro-immune modulators, tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS). Assays for TNF-alpha protein and nitric oxide (NO) demonstrated high levels of TNF-alpha protein and low levels of NO in response to VEE infection of astrocytes. These observations suggest an important role of astrocytes in this virus-induced encephalitis, and that interactions between astrocytes, other glial cells, and neurons may be important in VEE pathogenesis. Such interactions, which could impact neuronal survival, may include loss of functional changes in astrocytes or, alternatively, their production of neurotoxic molecules.
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VEEV triggers neurological sequelae in survivors that can be characterized by cognitive, motor, and sensory deficits likely through direct neuronal and glial cell infection.
“It is well documented that VEEV triggers neurological sequelae in survivors that can be characterized by cognitive, motor, and sensory deficits likely through direct neuronal and glial cell infection [7,8].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [8]
The introduction (p. 2) describes neuronal infection and degeneration, and the Discussion (pp. 6–7) shows astrocyte infection in vitro and proposes that it could contribute to VEE encephalitis. The paper does not report neurological sequelae in survivors or characterize cognitive, motor, and sensory deficits, so it does not establish the claimed link between those deficits and neuronal or glial infection. (LLM, conf=0.88)
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V <scp>ENEZUELAN</scp> E <scp>QUINE</scp> E <scp>NCEPHALITIS</scp>
Weaver, S. C., Ferro, C., Barrera, R., Boshell, J., & Navarro, J.-C. (2004) · Annual Review of Entomology · doi:10.1146/annurev.ento.49.061802.123422 · Cited by 465 · see citing works
Steele, K., & Twenhafel, N. (2010) · Veterinary Pathology · doi:10.1177/0300985810372508 · Cited by 314 · see citing works
Host responses to alphavirus infection
Ryman, K. D., & Klimstra, W. B. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00670.x · Cited by 169 · see citing works
“Furthermore, VEEV (78) and SFV (127) can infect glial cells in vitro, and models in which the capacity of glial cell activation and inflammatory mediator release is limited exhibit reduced disease manifestations after infection with neurovirulent alphaviruses (77, 79).”
BackgroundLundberg, L., Pinkham, C., Baer, A., Amaya, M., Narayanan, A., Wagstaff, K., Jans, D., & Kehn-Hall, K. (2013) · Antiviral Research · doi:10.1016/j.antiviral.2013.10.004 · Cited by 170 · see citing works
Lindqvist, R., Mundt, F., Gilthorpe, J., Wölfel, S., Gekara, N., Kröger, A., & Överby, A. K. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0748-7 · Cited by 138 · see citing works
“Similar findings have been observed with other viral infections such as WNV, JEV, and Junin virus whereas infection with Venezuelan equine encephalitis virus infection induced cell death in cultured astrocytes [31, 37, 39, 85, 86] .”
ResultVaccines for Venezuelan equine encephalitis
Paessler, S., & Weaver, S. C. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.07.095 · Cited by 114 · see citing works
“Previous studies have demonstrated that the murine model is characterized by biphasic disease, which starts with the productive infection of lymphoid tissue and culminates in the destruction of the CNS by viral replication and a “toxic” neuroinflammatory response that is uniformly lethal [10–16].”
Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis
Salimi, H., Cain, M. D., & Klein, R. (2016) · Neurotherapeutics · doi:10.1007/s13311-016-0443-5 · Cited by 108 · see citing works
Sharma, A., & Knollmann-Ritschel, B. (2019) · Viruses · doi:10.3390/v11020164 · Cited by 88 · see citing works
“Infection of glia and oligodendrocytes by VEEV appears to follow the neuronal infection [99,107,108].”
BackgroundSchoneboom, B. A., Catlin, K. M. K., Marty, A. M., & Grieder, F. B. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(00)00290-3 · Cited by 86 · see citing works
“Materials and methods ly described (McCarthy and de Vellis, 1980; Schoneboom et al., 1999).”
BackgroundInfluentialSelf-citationPaessler, S., Ni, H.-L., Petrakova, O., Fayzulin, R. Z., Yun, N., Anishchenko, M., Weaver, S., & Frolov, I. (2006) · Journal of Virology · doi:10.1128/jvi.80.6.2784-2796.2006 · Cited by 82 · see citing works
“By the time encephalitis has developed in an infected mouse, the infectious virus is usually absent from the peripheral organs and blood (12, 13, 15, 16, 39, 42, 43).”
BackgroundSharma, A., Bhattacharya, B., Puri, R., & Maheshwari, R. (2008) · BMC Genomics · doi:10.1186/1471-2164-9-289 · Cited by 62 · see citing works
“VEEV infection of the CNS has been shown to result in neurodegeneration, perivascular cuffing with infiltrating lymphocytes, gliosis, cerebral edema and apoptotic neurons associated with astrogliosis in the regions of the brain which is free of VEEV antigen [10].”
BackgroundSchoneboom, B., Lee, J. S., & Grieder, F. B. (2000) · Journal of Interferon and Cytokine Research · doi:10.1089/107999000312621 · Cited by 59 · see citing works
“(25) However, the role of microglia in VEE infection and disease induction is completely unknown.”
Self-citationBaer, A., Lundberg, L., Swales, D. A., Waybright, N., Pinkham, C., Dinman, J. D., Jacobs, J. L., & Kehn‐Hall, K. (2016) · Journal of Virology · doi:10.1128/jvi.02827-15 · Cited by 64 · see citing works
“As VEEV has been shown to productively infect astrocytes both in vitro and in vivo (14, 15), we chose astrocytes as our model of interest.”
MethodJulander, J., Siddharthan, V., Blatt, L., Schafer, K., Sidwell, R., & Morrey, J. (2007) · Virology · doi:10.1016/j.virol.2006.10.031 · Cited by 49
“It is interesting that viral antigen was not detected by IHC in astrocytes since the closely related Venezuelan equine encephalitis virus (VEEV) has been shown to infect primary astrocytes (Schoneboom et al., 1999).”
BackgroundSharma, A., & Maheshwari, R. (2009) · Journal of General Virology · doi:10.1099/vir.0.010280-0 · Cited by 46 · see citing works
“…against VEEV, but neurodegeneration following VEEV infection in the brain is also widely believed to be due to excessive inflammatory response to virus presence in the brain (Charles et al., 2001; Grieder & Vogel, 1999; Jackson et al., 1991; Schoneboom et al., 1999, 2000a, b; White et al., 2001).”
BackgroundImmunopathogenesis of alphaviruses
Baxter, V. K., & Heise, M. (2020) · Advances in Virus Research · doi:10.1016/bs.aivir.2020.06.002 · Cited by 45 · see citing works
Valero, N., Mosquera, J., Alcocer, S., Bonilla, E., Salazar, J., & Álvarez-Mon, M. (2015) · Brain Research · doi:10.1016/j.brainres.2015.06.034 · Cited by 42 · see citing works
Bohmwald, K., Soto, J., Andrade-Parra, C. A., Fernández-Fierro, A., Espinoza, J. A., Ríos, M., Eugenin, E., González, P., Opazo, M. C., Riedel, C., et al. (2020) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2020.09.021 · Cited by 40 · see citing works
Fragkoudis, R., Tamberg, N., Siu, R. W. C., Kiiver, K., Kohl, A., Merits, A., & Fazakerley, J. (2009) · Journal of Neurovirology · doi:10.1080/13550280802482583 · Cited by 40
“SV also infects neurons, whereas Eastern and Venezuelan equine encephalitis viruses infect neurons, oligodendrocytes, and astrocytes ( Schoneboom et al, 1999; Del Piero et al, 2001).”
BackgroundPineal hormone melatonin as an adjuvant treatment for COVID-19 (Review)
Vlachou, M., Siamidi, A., Dedeloudi, A., Konstantinidou, S., & Papanastasiou, I. P. (2021) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2021.4880 · Cited by 27 · see citing works
Schäfer, A., Whitmore, A., Konopka, J. L., & Johnston, R. (2009) · Journal of Virology · doi:10.1128/jvi.02383-08 · Cited by 27 · see citing works
“In general, the main target cells for alphavirus infection in the CNS are neurons, but infection of astrocytes by VEE also has been described (10, 21, 50).”
BackgroundKehn-Hall, K., & Bradfute, S. B. (2022) · Expert Review of Anti-Infective Therapy · doi:10.1080/14787210.2022.2141224 · Cited by 25 · see citing works
“Infection of astrocytes with VEEV results in increased production of TNF-alpha and low inducible nitric oxide synthase [51]; iNOS may play a role in VEEV pathogenesis in vivo [50].”
BackgroundDahal, B., Lin, S.-C., Carey, B., Jacobs, J. L., Dinman, J. D., van Hoek, M. V., Adams, A. A., & Kehn-Hall, K. (2019) · Virology · doi:10.1016/j.virol.2019.10.016 · Cited by 25 · see citing works
“Cytopathic effects in primary astrocytes following VEEV infection has been shown in previous published studies (Peng et al., 2013; Schoneboom et al., 1999) .”
ResultValero, N., MarinaEspina, L., Bonilla, E., & Mosquera, J. (2007) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2006.00381.x · Cited by 25 · see citing works
“In addition, previous reports have shown elevated NO production and cytokines induction in VEE virus treated cultures of microglia [11] and astrocytes [35], suggesting an important role of neurons , astrocytes and microglia in the virus-induced encephalitis.”
BackgroundMouse model of neurological complications resulting from encephalitic alphavirus infection
Ronca, S. E., Smith, J., Koma, T., Miller, M. M., Yun, N., Dineley, K. T., & Paessler, S. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00188 · Cited by 22 · see citing works
“Alphaviruses have been described to infect astrocytes and the affect is cytotoxic (Schoneboom et al., 1999).”
BackgroundGupta, P., Sharma, A., Han, J., Yang, A. X., Bhomia, M., Knollmann-Ritschel, B., Puri, R., & Maheshwari, R. (2017) · BMC Infectious Diseases · doi:10.1186/s12879-017-2355-3 · Cited by 21 · see citing works
Astrocyte response to Junín virus infection.
Pozner, R., Collado, S., de Giusti, C., Ure, A., Biedma, M., Romanowski, V., Schattner, M., & Gómez, R. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.08.059 · Cited by 21 · see citing works
“Moreover, in Venezuelan equine virus-induced encephalitis, the inflammatory response is partially mediated by iNOS and TNF- and seems to contribute to neurodegeneration [24].”
BackgroundReiss, C. (2016) · Cambridge International Law Journal · doi:10.1007/978-3-319-33133-1 · Cited by 21
Neuroprotection in HIV‐Positive Drug Users: Implications for Antioxidant Therapy
Shor-Posner, G., Lecusay, R., Morales, G., Campa, A., & Míguez-Burbano, M. (2002) · Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/01.qai.0000028069.79472.6f · Cited by 20
Kafai, N. M., Jáňová, H., Cain, M. D., Alippe, Y., Muraro, S. P., Sariol, A., Elam-Noll, M., Klein, R. S., & Diamond, M. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112946 · Cited by 18 · see citing works
“…in the brain, VEEV primarily infects neurons but also targets other supporting cells, including astrocytes upon initial invasion via the BBB. 62 69–71 Although a prior study showed that Ldlrad3-deficient mice survived subcutaneous challenge with pathogenic VEEV strains, 42 the role of LDLRAD3…”
Keck, F., Khan, D. H., Roberts, B., Agrawal, N., Bhalla, N., & Narayanan, A. (2018) · Viruses · doi:10.3390/v10110606 · Cited by 19 · see citing works
Peng, B., Borisevich, V., Popov, V. L., Zacks, M. A., Estes, D. M., Campbell, G. A., & Paessler, S. (2013) · Veterinary Microbiology · doi:10.1016/j.vetmic.2012.11.021 · Cited by 17 · see citing works
“This observation is in contrast with previously described results obtained with rat astrocytes, in which apparently upregulation of potentially neurotoxic immunomodulators such as TNF-a and iNOS was reported, leading to the speculation that astrocytes may contribute in a negative way to pathology and apoptosis of neur…”
BackgroundResultValero, N., Espina, L. M., & Mosquera, J. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9098-7 · Cited by 19
“production and cytokines induction in VEE virus treated cultures of microglia [12] and astrocytes [29], suggesting an important role of neurons, astrocytes and”
BackgroundFatal Neurological Respiratory Insufficiency Is Common Among Viral Encephalitides
Wang, H., Siddharthan, V., Kesler, K. K., Hall, J., Motter, N. E., Julander, J., & Morrey, J. (2013) · Journal of Infectious Diseases · doi:10.1093/infdis/jit186 · Cited by 18 · see citing works
“broader tropism that includes glial cells [42].”
Bakovic, A., Bhalla, N., Kortchak, S., Sun, C.-Q., Zhou, W.-D., Ahmed, A., Risner, K. H., Klimstra, W., & Narayanan, A. (2020) · Viruses · doi:10.3390/v12091021 · Cited by 17
“As we previously demonstrated an interaction between IKKβ and nsP3 [31], we first confirmed nsP3 phosphorylation using U-87MG astrocytes, as these cells are susceptible to VEEV infection in vitro [43].”
MethodBakovic, A., Bhalla, N., Alem, F., Campbell, C., Zhou, W.-D., & Narayanan, A. (2021) · Viruses · doi:10.3390/v13081533 · Cited by 13 · see citing works
“The toxicity of selected inhibitors was assessed at multiple concentrations in U-87MG astrocytes [40,41].”
BackgroundPERK Is Critical for Alphavirus Nonstructural Protein Translation
Dahal, B., Lehman, C., Akhrymuk, I., Bracci, N. R., Panny, L., Barrera, M. D., Bhalla, N., Jacobs, J. L., Dinman, J. D., & Kehn-Hall, K. (2021) · Viruses · doi:10.3390/v13050892 · Cited by 8
RetractedWeaver, S. C., & Paessler, S. (2009) · Elsevier eBooks · doi:10.1016/b978-0-12-369408-9.00021-4 · Cited by 11 · see citing works
CHAPTER 20 – Equine Alphaviruses
Long, M., & Gibbs, E. (2007) · doi:10.1016/b978-1-4160-2406-4.50025-9 · Cited by 8
Inactivation of Venezuelan Equine Encephalitis Virus Genome Using Two Methods
Behnia, M., Baer, A., Skidmore, A. M., Lehman, C., Bracci, N. R., Kehn-Hall, K., & Bradfute, S. B. (2022) · Viruses · doi:10.3390/v14020272 · Cited by 4
The fine line between protection and pathology in neurotropic flavivirus and alphavirus infections
Ong, R.-Y., Lum, F., & Ng, L. (2014) · Future Virology · doi:10.2217/fvl.14.6 · Cited by 4 · see citing works
Fongsaran, C., Dineley, K. T., Paessler, S., & Cisneros, I. E. (2024) · Pathogens · doi:10.3390/pathogens13050397 · Cited by 3 · see citing works
“It is well documented that VEEV triggers neurological sequelae in survivors that Pathogens 2024 , 13 , 397 2 of 15 can be characterized by cognitive, motor, and sensory deficits likely through direct neuronal and glial cell infection [7,8].”
BackgroundRole of angiotensin II in experimental Venezuelan equine encephalitis in rats
Bermúdez, J., Valero, N., Mosquera, J., Vargas, R., Hernandez-Fonseca, J. P., Quiroz, Y., & Godoy, R. (2015) · Archives of Virology · doi:10.1007/s00705-015-2521-0 · Cited by 3 · see citing works
“This infection has been shown to result in perivascular cuffing with infiltrating lymphocytes, gliosis, activation of glial cells, cerebral edema, neurodegeneration, and apoptosis associated with astrogliosis [4, 5].”
BackgroundEncephalitic Development in Alphaviral Infection
Paessler, S., & Taylor, K. G. (2011) · InTech eBooks · doi:10.5772/24175 · Cited by 2 · see citing works
Valero-Cedeño, N., Durán, A., & Mosquera, J. A. (2026) · Reviews in Medical Virology · doi:10.1002/rmv.70165
Animal Models of Viral Encephalitis
Steele, K. (2013) · CRC Press eBooks · doi:10.1201/b13907-8
- Authors
- Schoneboom, B. A., Fultz, M. J., Miller, T. H., McKinney, L. C., & Grieder, F. B.
- Affiliations
- Uniformed Services University of the Health Sciences (US)
- Walter Reed National Military Medical Center (US)
- Venue
- Journal of Neurovirology
- Published
- 1999-01
- Volume
- 5
- Issue
- 4
- Pages
- 342-354
- ISSN
- 1355-0284 (ISSN-L)
- 1538-2443
- OpenAlex
- W2098000094
- Cited by
- 58
- References
- 0
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 2 · 2014: 1 · 2013: 6 · 2012: 1
- FWCI
- 1.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of NeuroVirology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Uniformed Services University of the Health Sciences
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- Venezuelan equine encephalitis virus, astrocytes, productive infection, cytotoxicity, virus growth kinetics, TNF-α, inducible nitric oxide synthase, nitric oxide, neuron-glia interactions
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Encephalitis Virus, Venezuelan Equine, Encephalomyelitis, Venezuelan Equine, Tumor Necrosis Factor-alpha, Virulence, Virus Replication, Rats, Sprague-Dawley, Nitric Oxide Synthase, Rats, Nitric Oxide Synthase Type II
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