Abstract

Influenza viruses are a major global cause of morbidity and mortality. Although vagal TRPV1 nociceptive sensory neurons are known to mediate defenses against harmful agents, including pathogens, their function in lung antiviral defenses remains unclear. Our study demonstrates that both systemic and vagal-specific ablation of TRPV1 nociceptors reduce survival in mice infected with influenza A virus (IAV). Despite no difference in viral load, mice lacking TRPV1 neurons exhibited increased viral spread, exacerbated lung pathology, and elevated levels of proinflammatory cytokines. Loss of TRPV1 neurons altered the lung immune landscape, including an expansion of neutrophils and monocyte-derived macrophages. Transcriptional analysis revealed impaired interferon signaling in myeloid cells and an imbalance in distinct neutrophil subpopulations in the absence of nociceptors. Furthermore, antibody-mediated depletion of myeloid cells during IAV infection substantially improved survival after nociceptor ablation, underscoring the role of TRPV1 neurons in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality.