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J Neurosci. 2018 Mar 21;38(12):3060-3080. doi: 10.1523/JNEUROSCI.1740-17.2018. Epub 2018 Feb 27.

Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function.

Author information

1
Department of Cellular Neurobiology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany.
2
Helmholtz Centre for Infection Research, Neuroinflammation and Neurodegeneration Group, 38126 Braunschweig, Germany.
3
Helmholtz Centre for Infection Research, Department of Infection Genetics, 38126 Braunschweig, Germany.
4
Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
5
Helmholtz Centre for Infection Research, Genome Analytics Research Group, 38126 Braunschweig, Germany.
6
Department of Infection Genetics, University of Veterinary Medicine Hannover, 30559 Hannover, Germany, and.
7
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163.
8
Department of Cellular Neurobiology, Zoological Institute, TU Braunschweig, 38106 Braunschweig, Germany, m.korte@tu-bs.de.

Abstract

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.

KEYWORDS:

dendritic spines; hippocampus; influenza; microglia; neuroinflammation; structural plasticity

PMID:
29487124
DOI:
10.1523/JNEUROSCI.1740-17.2018
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