Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences for the CNS of an infection with neurotropic but also with non-neurotropic influenza A virus (IAV) variants remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) as well as non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. While spine number was significantly reduced 30 days post infection (pi) with H7N7 or H3N2, full recovery could only be observed much later at 120 days pi. Notably, infection with H1N1 virus which was shown previously to acutely affect spine number and hippocampus-dependent learning 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 an 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 as well as 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 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 as well as cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by IAV infection can induce longer lasting virus-specific alterations in neuronal connectivity detectable still one month after infection which 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 also trigger neuroinflammation and associated chronic alterations in the CNS.