Project Summary: Regulation of immune responses in the lung is a critical determinant of health. While the immune system must respond to viral and bacterial pathogens, these responses must be finely tuned so as not to reduce organ function. Aberrant immune responses to viral pathogens in the lung can result in significant morbidity and mortality. Control of maladaptive host immune responses occurs through a number of mechanisms including input from the nervous system. Reciprocal communication between these two systems throughout the body has emerged as a mechanism to detect pathogens and coordinate host-protective immune responses and control inflammation. Although neuro-immune circuits in the lung are known to exist, the contribution of these to the regulation of inflammation caused by virus-derived pathogen-associated molecular patterns is unknown. Building on our preliminary data showing the regulation of lung inflammation by a unique neuro-immune circuit, the overall goals of this project are to precisely determine the role of vagal afferent neurons, the neuro-immune circuitry, signaling used, and how immune cell function is regulated. By using complementary and unique tools, the role of vagal afferent neurons and the processes these neurons evoke to suppress lung inflammation will be determined. To achieve this, we will use selective activation of vagal afferent neurons, perform identification of lung-specific vagal afferents, and confirm the role of β2AR and the source of catecholamines that regulate acute lung inflammation induced by a TLR agonist. Finally, we will assess if this novel anti-inflammatory pathway can be evoked to control inflammation during influenza infection (SA1). Understanding of the endogenous reflex triggered by lung inflammation will be performed using a combination of optogenetic silencing of the vagal afferents, pharmacological antagonists, and novel mice with conditional TLR7 deficiency in vagal afferents, to deduce if neurons sense viral components, and the mechanisms of immune regulation elicited. Finally, the role of sympathetic lung innervation will be assessed, and the requirement for specific neurotransmitter receptors tested (SA2). Together, these proposed studies will decipher the contribution and components of a novel lung anti-inflammatory pathway that limits acute lung inflammation.