Molecular Consequences of Peripheral Influenza A Infection on Cell Populations in the Murine Hypothalamus
Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we showed that most neuronal cell populations are downregulating their transcriptional landscape including genes contributing to the energy homeostasis in the mitochondria and protein translation in the cytosol. Our data suggest that a preventive mechanism might exist in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. This is complemented by increased activity of microglia monitoring their surroundings. Overall design: single-nucleus RNA sequencing of the murine hypothalmus of female mice. Sampled at 3, 7 and 23 days post infection. Intranasally infected with h