Vagal TRPV1+ sensory neurons regulate myeloid cell dynamics and protect against influenza virus infection

Influenza viruses are a major global cause of morbidity and mortality. While vagal TRPV1+ nociceptive sensory neurons are known to mediate defenses against harmful agents, their function in lung antiviral defenses remains unclear. Our study reveals 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 pro-inflammatory 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 these myeloid cells and an imbalance in distinct neutrophil sub-populations in the absence of nociceptors. Furthermore, antibody-mediated depletion of myeloid cells during IAV infection significantly improved survival, underscoring a role of TRPV1+ nociceptors in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality. To define the role of TRPV1+ neurons in regulating the immune compartment of the lung during IAV infection, we performed single-cell RNA sequencing of lung immune cells isolated from vehicle and RTX-treated naïve animals or IAV PR8-infected animals at 7 days post-infection