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

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. 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.

Neuroprotective effect of menaquinone-4 (MK-4) on transient global cerebral ischemia/reperfusion injury in rat

“…In the reversal phase of the Morris water maze test, the platform was moved to the opposite quadrant (SW) and the rats were trained for another 3 consecutive days. This test needs cognitive flexibility [65]. The results indicated that escape latency was significantly higher in I/R and I/ R + DMSO tested groups compared to control, in addition here injection of MK-4 reversed the phenotype in I/R animals (two-way RM ANOVA: F Escape latency (3, 20) = 22,58, p < 0.001, Fig 3G).…”

Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?

“…Several studies have shown that influenza A can be associated with encephalitis, Reye's syndrome, febrile seizure, Guillain-Barré syndrome, acute necrotizing encephalopathy and possibly acute disseminated encephalomyelitis (ADEM) [153][154][155][156][157][158]. 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]. The influenza A virus has also been associated with the risk of developing Parkinson's disease (PD) [151] and has recently been shown to exacerbate experimental autoimmune encephalomyelitis (EAE), which is reminiscent of the observation that multiple sclerosis (MS) relapses have been associated with viral infections (including influenza A) of the upper respiratory tract [163][164][165].…”

Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain

“…Herpes simplex viruses can spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system in the colon [52]. Influenza A virus may have access to the CNS and alter the hippocampus function via the vagus nerve, affecting cognition and behavior [53,54]. Although there is no direct evidence to show that SARS-CoV-2 can enter the CNS retrogradely via the intestinal branch of the vagus nerve, the disrupted gastrointestinal environment may influence the integrity of the BBB through immune, neural, and humoral pathways, thus facilitating the movement of the peripheral virus into the CNS.…”