ABSTRACT Society faces increasing burden from respiratory immune challenge including respiratory viral infection. Respiratory viral infection, including with influenza A virus, can cause changes in brain function; understanding the link between lung and brain health is critical to anticipating the shifting health needs of our society. The lung and brain engage in bidirectional communication through several signaling mechanisms, allowing these organs to influence each other. It is unknown how lung-brain communication impacts the progression of respiratory viral infection, or how different communication mechanisms are prioritized as inflammatory response progresses. Using a mouse model of infection with influenza A strain PR8, this proposal explores immune signaling in the bidirectional lung-brain axis. The overarching goal of this proposal is to test the hypothesis that the lung and brain exert bidirectional influence during respiratory infection, altering each other’s immune states. My preliminary data shows that during PR8 infection, changes in central nervous system (CNS) occur prior to inflammatory gene upregulation in lung tissue. The signaling mechanisms influencing these rapid CNS changes in neuronal activity, as well as the role of this CNS response on infection progression, remain unknown. Pulmonary neuroendocrine cells (PNECs) are sensory cells which mount an immune response during respiratory inflammatory challenge. These cells are also the only cells in the lung epithelium directly innervated by the vagus nerve. Despite the known immune function of both PNECs and the vagus nerve, the role of PNECs signaling to the CNS during a respiratory infection remains unstudied. In Aim 1, I will explore the role of PNEC signaling in infection by characterizing molecular and vagal signaling from these cells during infection. I will then ablate these cells prior to PR8 infection using a cre-dependent AAV delivery mechanism in calcacre mice to determine whether their signaling contributes to the peripheral or CNS response to infection. Regardless of signaling mechanisms initiating the rapid CNS response to PR8 infection, the ultimate consequence of this response is unknown. Neuronal ensembles can encode immune memory, impacting the immune states of peripheral organs. In Aim 2, I will determine how neuronal activity influences the microglial and peripheral immune response throughout PR8 infection onset. Using high-throughput imaging and a machine learning analysis pipeline, I will map the neuronal and microglial response to PR8 infection in TRAP2::TdTom mice. I will then explore the role of neuronal activity by capturing and later re-activating the neuronal population active during PR8 infection using TRAP2::hM3Dq mice. I will characterize microglial response in CNS tissue and peripheral immune response to determine if activity of the PR8-responsive neuronal population is sufficient to drive immune outcomes. Altogether, this proposal will explore the ...