Long-term neuroinflammation induced by influenza A virus infection and the impact on hippocampal neuron morphology and function

Influenza A viruses (IAV) as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target of these viruses in mammals is the lung, an influenza infection can be associated with neurological complications. However, the long-term consequences of an IAV infection for the central nervous system remain largely elusive. In the first part of this study, two months old female mice were infected intranasally with non-neurotropic (H1N1 and H3N2) as well as neurotropic (H7N7) IAV subtypes in order to investigate possible long-term effects on hippocampal structure and function. Dendritic spine loss detected at 30 days post infection was associated with an impairment in spatial learning, reduced Schaffer collateral long-term potentiation and an increase in the population of activated microglia and astrocyte density along with elevated levels of proinflammatory cytokines. While neuroinflammation induced by neurotropic H7N7 IAV showed the strongest effect, systemic infection with the non-neurotropic H3N2 subtype resulted as well in long-term impairments in synapse number and hippocampal function. Taken together, these findings clearly show that even an IAV infection restricted to the periphery can lead to long-term neuroinflammation and synapse loss with severe impact on hippocampal function in young adult animals in a virus subtype-specific manner. As the findings of the first part of this study show, neuroinflammation induced by viral infection leads to high levels of proinflammatory cytokines such as interferons (IFNs) which can affect hippocampal function well beyond the acute disease phase. Little is known, however, about IFN signaling under physiological conditions in the healthy brain. Therefore, the second part of this study focused on the role of type I IFN signaling for synaptic plasticity and cognitive function. Experiments with healthy conventional type I interferon receptor (IFNAR) KO mice showed reduced hippocampal spine density together with deficits in synaptic plasticity and spatial learning. Analysis of different cell type specific conditional IFNAR KO animals indicated that IFN signaling in astrocytes is responsible for this phenotype. Further experiments are needed to identify the detailed signaling pathways and cellular mechanisms involved in the IFN mediated crosstalk between neurons and astrocytes discovered here, and the role for synaptic plasticity and cognitive function.