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Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function
Open accessAbstract
Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS. SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.
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“Influenza infection may enter the brain through several routes [122,123] or send deleterious signals to the brain via sensory neurons [124] and trigger neuroinflammation or associated chronic alterations in the CNS [125].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [125]
In the citing paper
“There is a precedent for acute viral infections causing long-term inflammation and dysfunction that predisposes individuals to neurodegenerative disease44,45”
From Dysregulation of brain and choroid plexus cell types in severe COVID-19 (2021) · cites this paper as [44]
In the citing paper
“Cognitive impairment may be caused by viral infections associated with direct invasion of the central nervous system [11, 24], or as an indirect effect of systemic infections not typically causing CNS infection (e.g. cytokine storm, neuro-inflammation, hypercoagulability) [11, 24].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [11]
In the citing paper
“Mechanisms underlying viral pathogenesis in these conditions may include a direct viral effect or indirect mechanisms, such as inflammation, epigenetic changes, and hypercoagulable changes, that may impact on brain structure and function in healthy or in cognitively impaired individuals [6, 11–15].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [11]
In the citing paper
“The H1N1 strain of influenza, which is not neuroinvasive in mouse models, causes acute elevation in CNS cytokines, hippocampal microglial reactivity, and impaired performance in cognitive behavioral tests (Hosseini et al., 2018; Jurgens et al., 2012).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Hosseini et al., 2018
In the citing paper
“Other viral syndromes such as influenza can cause microglial reactivity, elevated CNS cytokine levels, and impair cognitive function, even in the absence of neuroinvasion (Hosseini et al., 2018; Jurgens et al., 2012).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Hosseini et al., 2018
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Metadata
- Authors
- Hosseini, S., Wilk, E., Michaelsen-Preusse, K., Gerhauser, I., Baumgärtner, W., Geffers, R., Schughart, K., & Korte, M.
- Affiliations
- Helmholtz Centre for Infection Research (DE)
- University of Veterinary Medicine Hannover, Foundation (DE)
- University of Tennessee Health Science Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2018-02-27
- Volume
- 38
- Issue
- 12
- Pages
- 3060-3080
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6596076
- OpenAlex
- W2788200071
- Cited by
- 236
- References
- 101
- Citations by year
- 2026: 26 · 2025: 31 · 2024: 36 · 2023: 37 · 2022: 37 · 2021: 31 · 2020: 25 · 2019: 8 · 2018: 5
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digitale Bibliothek Braunschweig (Verbundzentrale Göttingen (VZG)) (submittedVersion)
- HZI (Helmholtz Centre for Infection Research) (submittedVersion, cc-by-nc-sa)
- LeoPARD - TU Braunschweig Publications And Research Data
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- influenza A virus, neuroinflammation, hippocampus, dendritic spine loss, H7N7, H3N2, H1N1, microglial activation, long-term potentiation, spatial memory impairment, neuronal morphology, transcriptome, cognitive impairment, viral encephalitis
- MeSH terms
- Animals, Female, Hippocampus, Inflammation, Mice, Inbred C57BL, Orthomyxoviridae Infections, Dendritic Spines, Mice, Influenza A Virus, H1N1 Subtype, Influenza A Virus, H3N2 Subtype, Influenza A Virus, H7N7 Subtype
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