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Cited by 86Barrier Structure and Function StudiesMosquito-borne diseases and controlinterferon and immune responses

Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection

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Cain, Matthew D., Salimi, Hamid, Gong, Yongfeng, Yang, Lihua, Hamilton, Samantha L., Heffernan, James R., Hou, Jianghui, Miller, Mark J. +1 more·2017·Journal of Neuroimmunology
DOI 10.1016/j.jneuroim.2017.04.008PMC PMC5694394
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Abstract

Viral infections of the central nervous system (CNS) are often associated with blood-brain barrier (BBB) disruption, yet the impact of virus replication and immune cell recruitment on BBB integrity are incompletely understood. Using two-photon microscopy, we demonstrate that Venezuelan equine encephalitis virus (VEEV) strain TC83-GFP, a GFP expressing, attenuated strain with a G3A mutation within the 5' UTR that is associated with increased sensitivity to type I interferons (IFNs), does not directly impact BBB permeability. Following intranasal infection of both wild-type and IFN-induced protein with tetratricopeptide repeats 1 (IFIT1)-deficient mice, which fail to block TC83-specific RNA translation, virus spreads to the olfactory bulb and cortex via migration along axonal tracts of neurons originating from the olfactory neuroepithelium. Global dissemination of virus in the CNS by 2days post-infection (dpi) was associated with increased BBB permeability in the olfactory bulb, but not in the cortex or hindbrain, where permeability only increased after the recruitment of CX3CR1+ and CCR2+ mononuclear cells on 6 dpi, which corresponded with tight junction loss and claudin 5 redistribution. Importantly, despite higher levels of viral replication, similar results were obtained in IFIT1-deficient mice. These findings indicate that TC83 gains CNS access via anterograde axonal migration without directly altering BBB function and that mononuclear and endothelial cell interactions may underlie BBB disruption during alphavirus encephalitis.

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  • Activation of hippocampal astrocytes and microglia leads to encephalitis and neurological damage.

    “which is well characterized to lead to encephalitis and neurological damage (Cain et al., 2017; Sharma et al., 2011).”

    From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Cain et al., 2017

    Results §3.1 reports infection of astrocytes, and Results §3.3 reports microglial accumulation near blood–brain barrier disruption during infection. Methods §2.2 describes an encephalitis mouse model, but the paper does not establish that activation of hippocampal astrocytes and microglia causes encephalitis or neurological damage; its reported observations concern the olfactory bulb and cortex. (LLM, conf=0.83)

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Authors
Cain, M. D., Salimi, H., Gong, Y., Yang, L., Hamilton, S. L., Heffernan, J. R., Hou, J., Miller, M. J., & Klein, R. S.
Affiliations
Washington University in St. Louis (US)
Corresponding author
  • Miller, Mark J.
  • Klein, Robyn S.
ORCID
Venue
Journal of Neuroimmunology
Publisher
Elsevier BV
Published
2017-07
Volume
308
Pages
118-130
ISSN
0165-5728 (ISSN-L)
DOI
10.1016/j.jneuroim.2017.04.008
PMC
PMC5694394
OpenAlex
W2611233682
Cited by
86
References
37
Citations by year
2026: 6 · 2025: 8 · 2024: 17 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 10 · 2019: 14 · 2018: 6 · 2017: 1
FWCI
4.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroimmunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (U19 AI083019, R01 NS052632, R01DK084059, HDTRA11510032, R01 DK097, U01 AI095550, R01 AI077600)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR048335)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
Venezuelan equine encephalitis virus, alphavirus, blood-brain barrier disruption, olfactory bulb, CCR2+ monocytes, IFIT1, type I interferon, claudin-5, tight junctions, intranasal infection, encephalitis
MeSH terms
CX3C Chemokine Receptor 1, Animals, Animals, Newborn, Blood-Brain Barrier, Brain, Capillary Permeability, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Encephalitis Virus, Venezuelan Equine, Epithelial Cells, Gene Expression Regulation, Cricetinae, Mice, Inbred C57BL, Mice, Transgenic, Tumor Necrosis Factor-alpha, Virus Replication, Alphavirus Infections, Receptors, Chemokine, Adaptor Protein Complex 1, Mice, Virus Internalization

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