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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
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“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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Löscher, W., & Howe, C. L. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.870868 · Cited by 35
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Ohm, M., Hosseini, S., Lonnemann, N., He, W., More, T. H., Goldmann, O., Medina, E., Hiller, K., & Körte, M. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03188-3 · Cited by 36
“Neuroinflam-mation can eventually impair cognitive functions such as learning and memory processes well beyond the initial phase of sepsis or viral infection [6, 29].”
BackgroundMethodSelf-citationНиколаевна, Б. А., Pershin, V. I., Zaborskaya, O. G., Tkachenko, N., Mironov, A. A., Guryev, E. L., Kurbatov, L. K., Gainullin, M., & Mukhina, I. V. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01033 · Cited by 32
“This finding correlates with the previously made by Hosseini et al. (2018) where the overexpression of inflammatory factors didn’t affect the activity of animals in open field test, although the chronic inflammation can lead to a memory loss (Zhou et al., 2016).”
ResultCOVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences
Baazaoui, N., & Iqbal, K. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220105 · Cited by 35
“deterioration in the hippocampus-dependent learning 533 and a reduction in the long-term potentiation asso534 ciated impairment in spatial memory were reported 535 [110].”
BackgroundCamp, B., Stegemann‐Koniszewski, S., & Schreiber, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115699 · Cited by 31
“Furthermore, persisting neuro-inflammation has been observed following infection with neurotropic as well as non-neurotropic IAV strains in mice [110].”
BackgroundSerafini, R. A., Frere, J. J., Zimering, J. H., Giosan, I. M., Pryce, K. D., Golynker, I., Panis, M., Ruiz, A., tenOever, B. R., & Zachariou, V. (2023) · Science Signaling · doi:10.1126/scisignal.ade4984 · Cited by 29
“In these studies, the source of coronavirus-induced neurological dysfunction was linked to two major causes: direct virus-induced damage and collateral damage to host cells by antiviral immune responses (48, 49).”
BackgroundPiacentini, R., & Grassi, C. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01690 · Cited by 30
“Noteworthy, other than pulmonary diseases, infection by influenza viruses induces had been reported to induce cognitive deficit and synaptic remodeling associated with increased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α) (Jurgens et al., 2012; Hosseini et al., 2018).”
BackgroundCiticoline and COVID-19-Related Cognitive and Other Neurologic Complications
Turana, Y., Nathaniel, M., Shen, R., Ali, S., & Aparasu, R. R. (2021) · Brain Sciences · doi:10.3390/brainsci12010059 · Cited by 33
Zhang‐James, Y., Clay, J. W. S., Aber, R. B., Gamble, H. M., & Faraone, S. V. (2024) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2024.03.023 · Cited by 32
Lonnemann, N., Hosseini, S., Ohm, M., Geffers, R., Hiller, K., Dinarello, C. A., & Körte, M. (2021) · eLife · doi:10.7554/elife.75889 · Cited by 29
Self-citationPlasmalogens inhibit neuroinflammation and promote cognitive function
Hossain, M. S., Mawatari, S., & Fujino, T. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.11.005 · Cited by 31
Neurotrophin Signaling Impairment by Viral Infections in the Central Nervous System
Böhmwald, K., Andrade, C. A., Mora, V. P., Muñóz, J. T., Ramírez, R. A., Rojas, M. F., & Kalergis, A. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105817 · Cited by 27
“Interestingly, in vivo studies have demonstrated that the levels of BDNF decrease in the hippocampus of influenza virus-infected mice, regardless of whether they are neurotropic (H3N2 and H7N7) or non-neurotropic (H1N1) [142,143].”
BackgroundGrant, R. A., Poor, T. A., Sichizya, L., Diaz, E., Bailey, J. I., Soni, S., Senkow, K. J., Pérez-Leonor, X. G., Abdala‐Valencia, H., Lu, Z., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.178859 · Cited by 27
“Nevertheless, prolonged cognitive dysfunction in survivors of pneumonia or sepsis was recognized before the pandemic (4, 7–9 , 23– 26).”
BackgroundOrchestration of antiviral responses within the infected central nervous system
Pavlou, A., Mulenge, F., Gern, O. L., Busker, L. M., Greimel, E., Waltl, I., & Kalinke, U. (2024) · Cellular and Molecular Immunology · doi:10.1038/s41423-024-01181-7 · Cited by 24
Cornelius, A., Hosseini, S., Schreier, S., Fritzsch, D., Weichert, L., Michaelsen‐Preusse, K., Fendt, M., & Kröger, A. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01951-w · Cited by 25
“Other studies show that this effect was not limited to acute infection and lasts longer [20].”
BackgroundMethodInfluentialSelf-citationBöhmwald, K., Andrade, C. A., & Kalergis, A. M. (2021) · Pharmaceuticals · doi:10.3390/ph14040340 · Cited by 28
Petrisko, T. J., Gómez-Arboledas, Á., & Tenner, A. J. (2021) · Advances in immunology · doi:10.1016/bs.ai.2021.09.003 · Cited by 23
Biological agents and the aging brain: glial inflammation and neurotoxic signaling
Latham, A. S., Moreno, J. A., & Geer, C. E. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1244149 · Cited by 27
“Interestingly, these long-term CNS alterations occurred in non-neurotropic strains of the virus as well (Hosseini et al., 2018).”
BackgroundThe Impact of Non-Neurotropic Influenza Strains on the Brain: A Role for Microglial Priming?
Barbosa‐Silva, M. C., Santos, L. E., & Rangel, B. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1368-18.2018 · Cited by 23
“Despite the eventual recovery, the central effects observed by Hosseini et al. (2018) might have long-term consequences, due to innate immune plasticity.”
BackgroundMethodResultInfluentialKarthik, S., Saraswathi, I., Alarifi, A., Al-Atram, A. A., Mickeymaray, S., Paramasivam, A., Shaikh, S., Jeraud, M., & Alothaim, A. S. (2022) · PeerJ · doi:10.7717/peerj.14227 · Cited by 23
Mayer, M. G., & Fischer, T. (2025) · American Journal Of Pathology · doi:10.1016/j.ajpath.2025.03.011 · Cited by 22
Neuroinflammation in Post COVID‐19 Sequelae: Neuroinvasion and Neuroimmune Crosstalk
Reis, R. S. D., Selvam, S., & Ayyavoo, V. (2024) · Reviews in Medical Virology · doi:10.1002/rmv.70009 · Cited by 22
Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization
Hoore, M., Khailaie, S., Montaseri, G., Mitra, T., & Meyer‐Hermann, M. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.07.011 · Cited by 22
Radzišauskienė, D., Vitkauskaitė, M., Žvinytė, K., & Mameniškienė, R. (2020) · Brain and Behavior · doi:10.1002/brb3.1916 · Cited by 20
Rizzo, M. D., Crawford, R. B., Bach, A. P., Sermet, S., Amalfitano, A., & Kaminski, N. E. (2019) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2019.576969 · Cited by 20
Froggatt, H. M., & Heaton, N. S. (2022) · FEBS Journal · doi:10.1111/febs.16363 · Cited by 20
Long-term Consequences of COVID-19: Chemosensory Disorders
Liao, B., Deng, Y., Zeng, M., & Liu, Z. (2022) · Current Allergy and Asthma Reports · doi:10.1007/s11882-022-01062-x · Cited by 18
Influenza vaccine is able to prevent neuroinflammation triggered by H7N7 IAV infection
Demuth, L., Ohm, M., Michaelsen‐Preusse, K., Schulze, K., Riese, P., Guzmán, C. A., Körte, M., & Hosseini, S. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1142639 · Cited by 17
“Experiments in animal models have previously shown that IAV infections trigger neuroinflammation in the acute phase of the disease, including activation of microglia and release of proinflammatory cytokines (Jang et al., 2012; Jurgens et al., 2012; Sadasivan et al., 2015; Hosseini et al., 2018).”
BackgroundMethodInfluentialSelf-citationClark, J. J., Penrice-Randal, R., Sharma, P., Kipar, A., Dong, X., Pennington, S. H., Marriott, A. E., Colombo, S., DAVIDSON, A., Williamson, M. K., et al. (2024) · Viruses · doi:10.3390/v16060863 · Cited by 28
“While brain infection has been well documented in cases of influenza [53–55], this is predominantly limited to neurotropic and highly pathogenic strains and occurs via the breakdown of the BBB following high levels of viremia [54,56].”
BackgroundUnaltered T cell responses to common antigens in individuals with Parkinson's disease
Williams, G. P., Muskat, K., Frazier, A., Xu, Y., Mateus, J., Grifoni, A., Antunes, R. D. S., Weiskopf, D., Amara, A. W., Standaert, D. G., et al. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120510 · Cited by 17
Al-Shalan, H. A. M., Lü, Z., Dong, Z., Wang, P., Nicholls, P. K., Boughton, B. A., Stumbles, P. A., Greene, W. K., & Ma, B. (2023) · Virology Journal · doi:10.1186/s12985-023-02239-0 · Cited by 17
“…which IAV causes acute and long-term primary/ secondary neuroinflammatory/neurological disorders/ complications (e.g., seizures, encephalopathy, brain fog, encephalitis, stroke, focal neurologic deficits, Guillain-Barré syndrome, acute disseminated encephalomyelitis, and transverse myelitis) [44].”
BackgroundLiang, L., Mao, S., Wang, J., Ding, X., & Zen, J. (2019) · ExRNA · doi:10.1186/s41544-019-0031-z · Cited by 16
“Infection by neurotropic viruses as well as the consequent immune response can lead to irreversible disruption of functional structure in CNS, which frequently cause significant clinical phenotype [21, 22, 60].”
BackgroundRole of Necroptosis in Central Nervous System Diseases
Shao, H., Wu, W., Wang, P., Han, T., & Zhuang, C. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00405 · Cited by 16
Clark, J. J., Penrice-Randal, R., Sharma, P., Kipar, A., Dong, X., Pennington, S. H., Marriott, A. E., Colombo, S. A. P., Davidson, A. D., Williamson, M. K., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.13.334532 · Cited by 17
How viral infections cause neuronal dysfunction: a focus on the role of microglia and astrocytes
Hosseini, S., & Korte, M. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220771 · Cited by 17
Self-citationSaucier, J., Comeau, D., Robichaud, G. A., & Chamard-Witkowski, L. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1221266 · Cited by 16
“These processes alter BBB permeability, structural hippocampal plasticity, and may underlie cognitive dysfunction (86, 87).”
BackgroundViral infection and host immune response in diabetes
Joshi, G., Das, A., Verma, G., & Guchhait, P. (2023) · IUBMB Life · doi:10.1002/iub.2794 · Cited by 21
Chen, H., Lan, S., Tseng, Y., Chang, Y., Lu, Y., & Lan, M. (2024) · BMC Infectious Diseases · doi:10.1186/s12879-024-09844-6 · Cited by 15
“This mechanism has been shown to contribute to the neurological complications associated with nonneurotropic influenza strains, such as H1N1 [51] and H3N2 [52].”
BackgroundWang, B., Su, Q., Luo, J., Li, M., Wu, Q., Chang, H., Du, J., Huang, C., Ma, J., Han, S., et al. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.593202 · Cited by 15
Cassidy, B. R., Sonntag, W. E., Leenen, P. J. M., & Drevets, D. A. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00281-0 · Cited by 14
The microbiome in post-acute infection syndrome (PAIS)
Guo, C., Yi, B., Wu, J., & Lu, J. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.08.002 · Cited by 14
“glia in mice up to a month after the initial infection [57].”
BackgroundSieracka, J., Sieracki, P., Kozera, G., Szurowska, E., Gulczyński, J., Sobolewski, P. K., Kloc, W., & Iżycka‐Świeszewska, E. (2021) · Folia Neuropathologica · doi:10.5114/fn.2021.105128 · Cited by 14
“Common non-neurotrophic strains of influenza can cause injury to the hippocampus, interfering with normal behaviour after the acute infection [43].”
BackgroundA Cytokine-based model for the pathophysiology of Long COVID symptomsPreprint
Low, R. N., Low, R. J., & Akrami, A. (2020) · doi:10.31219/osf.io/7gcnv · Cited by 14
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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