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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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Lin, Y.-S., Wang, H., Huang, D.-F., Hsieh, P.-F., Lin, M.-Y., Chou, C., Wu, I.-J., Huang, G., Gau, S. S., & Huang, H. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164164 · Cited by 84 · cited 1×
“Dysfunction of these genes has been identified in several neurodevelopmental and neuropsychiatric disorders such as autism, schizophrenia, and cognitive impairments (Demyanenko et al., 2014; Lee et al., 2016; Lin et al., 2016).”
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“It was indeed shown previously that the progressive nature of neurotropic virus-induced damage in the dentate gyrus (DG), such as during Borna virus infection, is associated with impaired performance in the Morris water maze (Rubin et al., 1999).”
BackgroundRBFOX3/NeuN is Required for Hippocampal Circuit Balance and Function
Wang, H., Hsieh, P.-F., Huang, D.-F., Chin, P.-S., Chou, C., Tung, C.-C., Chen, S.-Y., Lee, L., Gau, S. S., & Huang, H. (2015) · Scientific Reports · doi:10.1038/srep17383 · Cited by 82 · cited 1×
“In addition, Rbfox3 knock-out mice show deficits in synaptic transmission and plasticity in the DG (Wang et al., 2015).”
BackgroundNuttall, J. R., & Oteiza, P. I. (2013) · Genes & Nutrition · doi:10.1007/s12263-013-0379-x · Cited by 75
Lynch, M. A. (2002) · Vitamins and hormones · doi:10.1016/s0083-6729(02)64006-3 · Cited by 71
Inflammatory monocytes damage the hippocampus during acute picornavirus infection of the brain
Howe, C. L., LaFrance-Corey, R. G., Sundsbak, R. S., & LaFrance, S. J. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-50 · Cited by 62 · cited 1×
“, IL-1 , IL-6, TNF- , and IFN- ) can be observed across multiple brain regions, including the hippocampus (Howe et al., 2012; Elmore et al., 2014; Heneka et al., 2014; Klein et al., 2017).”
BackgroundMajde, J. A., Bohnet, S. G., Ellis, G., Churchill, L., Leyva-Grado, V. H., Wu, M., Szentirmai, É., Rehman, A., & Krueger, J. M. (2007) · Journal of NeuroVirology · doi:10.1080/13550280701427069 · Cited by 62 · cited 2×
“First, we used the well characterized PR8 (A/PuertoRico/8/34) nonneurotropic virus (Majde et al., 2007; Hodgson et al., 2012).”
BackgroundMethodCooper, D. S., Saxena, N., Yang, H. S., Lee, H., Moring, A. G., Lee, A., & Choi, I. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408646200 · Cited by 61
Virus-induced neurobehavioral disorders: mechanisms and implications
Tomonaga, K. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2003.12.001 · Cited by 60 · cited 1×
“Neurotropic IAV strains are indeed able to enter the CNS through the blood– brain barrier (BBB) or microvascular endothelial cells (Tomonaga, 2004).”
BackgroundCell Adhesion Molecules: An Overview
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The Neuropsychiatric Disease-Associated Genecacna1cMediates Survival of Young Hippocampal Neurons
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“, 1979) in our studies, for which we established a well characterized mouse model (Leist et al., 2016).”
BackgroundSelf-citationSex differences in murine susceptibility to systemic viral infections
Geurs, T. L., Hill, E. B., Lippold, D., & French, A. R. (2011) · Journal of Autoimmunity · doi:10.1016/j.jaut.2011.12.003 · Cited by 53 · cited 1×
“Earlier studies demonstrated that female mice are more susceptible and produce more neutralizing antibodies and higher levels of chemokines and cytokines than males during infection with influenza viruses (Geurs et al., 2012), so only female mice were used in this study.”
MethodPolicing the Police: Astrocytes Modulate Microglial Activation: Figure 1.
Shih, A. Y., Fernandes, H. B., Choi, F., Kozoriz, M. G., Liu, Y., Li, P., Cowan, C. M., & Klegeris, A. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0936-06.2006 · Cited by 49
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“The second non-neurotropic virus belonged to the H3N2 subtype, maHK68 (mouse-adapted A/Hong-Kong/1/68) (Haller et al., 1979).”
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“It is interesting that the interferon-responsive gene Ifit3, which is reported to be involved in cognitive decline in aged mice (Bordner et al., 2011), was specifically upregulated in the hippocampus of H7N7-infected mice and is mainly expressed in granule cells (Cho et al.”
BackgroundElmore, M. R. P., Burton, M. D., Conrad, M. S., Rytych, J. L., Alstine, W. G. V., & Johnson, R. W. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2180-13.2014 · Cited by 41 · cited 1×
“, IL-1 , IL-6, TNF- , and IFN- ) can be observed across multiple brain regions, including the hippocampus (Howe et al., 2012; Elmore et al., 2014; Heneka et al., 2014; Klein et al., 2017).”
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Avian influenza and the brain—Comments on the occasion of resurrection of the Spanish flu virus
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“For instance, the highly pathogenic avian influenza virus (H5N1) can infect the CNS and subsequently lead to neuronal cell death in the substantia nigra pars compacta (Kristensson, 2006; Jang et al., 2012) induced by neuroinflammation through the activation of glial cells and altered proinflammatory/inflammatory cytok…”
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“In addition, immunohistochemistry for the virus was analyzed using a semiquantitative scoring system from 0 no, 1 few, 2 multiple, to 3 numerous infected cells (Gerhauser et al., 2007).”
MethodSelf-citationDiOrio, M., de Fijter, S., Schwartz, M., Page, S. L., Jhung, M. A., Finelli, L., Peacock, G., Yeung, L. F., Honein, M. A., Moore, C. A., et al. (2012) · Cited by 27
The Mouse as Model System to Study Host‐Pathogen Interactions in Influenza A Infections
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Self-citationNeurologic Complications of Influenza
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“However, evidence accumulates that an infection with IAV may also be associated with neurological complications in humans (Surana et al., 2011; Ekstrand, 2012; Shah et al., 2014).”
BackgroundHodgson, N. R., Bohnet, S. G., Majde, J. A., & Krueger, J. M. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.07.238 · Cited by 18 · cited 2×
“First, we used the well characterized PR8 (A/PuertoRico/8/34) nonneurotropic virus (Majde et al., 2007; Hodgson et al., 2012).”
BackgroundMethodShinya, K., Suto, A., Kawakami, M., Sakamoto, H., Umemura, T., Kawaoka, Y., Kasai, N., & Ito, T. (2005) · Archives of Virology · doi:10.1007/s00705-005-0539-4 · Cited by 18 · cited 1×
“Avian H7N7 viruses are able to infect humans and represent a potential future pandemic threat (Lang et al., 1981; Banks et al., 1998; Fouchier et al., 2004; Shinya et al., 2005).”
BackgroundWhishaw, I. Q. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.04.011 · Cited by 17
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“Interestingly, the dopamine neurotransmitter transporter gene Slc6a3, which has been associated with depression and other neuropsychiatric disorders (Sinanan and Hillary, 1981; Uddin et al., 2011), was among the most strongly upregulated genes especially after H7N7 infection.”
BackgroundWhishaw, I. Q. (2004) · Behavioural Brain Research · doi:10.1016/j.bbr.2004.04.013 · Cited by 13
Cellular Antiviral Factors that Target Particle Infectivity of HIV-1
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Dynamic gene expression analysis in a H1N1 influenza virus mouse pneumonia model
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Research works printed but not linked: 1
- 10.2307/1165312 · DOI · Paper page
Cited by
Sorted by citations
Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dubé, M., & Talbot, P. J. (2019) · Viruses · doi:10.3390/v12010014 · Cited by 1,048
“Animal models have shown that, using either the olfactory route or vagus nerve, influenza A virus may have access to the CNS and alter the hippocampus and the regulation of neurotransmission, while affecting cognition and behavior as long-term sequelae [8, 69, [159] [160] [161] [162] .”
BackgroundNeurologic alterations due to respiratory virus infections
Bohmwald, K., Gálvez, N. M. S., Ríos, M., & Kalergis, A. M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00386 · Cited by 636
“According to these findings, specifically the detection of the viral RNA in the hippocampus, Hosseini et al. (2018) recently evaluated three different mouse-adapted IAVs: two non-neurotropic virus H1N1 (PR8) and H3N2 (maHK68); one neurotropic virus H7N7 (rSC35M).”
BackgroundInfluentialDysregulation of brain and choroid plexus cell types in severe COVID-19
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03710-0 · Cited by 620
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
Fernández-Castañeda, A., Lu, P., Geraghty, A. C., Song, E., Lee, M.-H., Wood, J., O’Dea, M. R., Dutton, S., Shamardani, K., Nwangwu, K., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.008 · Cited by 521
The neurobiology of long COVID
Monje, M., & Iwasaki, A. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.006 · Cited by 415
“The similarities and differences evident between influenza—a disease also associated with neurological and neuropsychiatric sequalae (Honigsbaum 2013; Hosseini et al., 2018; Jurgens et al., 2012; Menninger, 1919)—and SARS-CoV-2 infections underscore the principle that the immune response to a…”
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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