Abstract

Influenza viruses are a major global cause of morbidity and mortality. Vagal TRPV1 nociceptive sensory neurons, which innervate the airways, are known to mediate defenses against harmful agents. However, their function in lung antiviral defenses remains unclear. Our study reveals that both systemic and vagal-specific ablation of TRPV1 nociceptors reduced survival in mice infected with influenza A virus (IAV), despite no significant changes in viral burden or weight loss. Mice lacking nociceptors showed exacerbated lung pathology and elevated levels of pro-inflammatory cytokines. The increased mortality was not attributable to the loss of the TRPV1 ion channel or neuropeptides CGRP or substance P. Immune profiling through flow cytometry and single-cell RNA sequencing identified significant nociceptor deficiency-mediated changes in 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, anti-GR1-mediated depletion of myeloid cells during IAV infection significantly improved survival, underscoring a role of nociceptors in preventing pathogenic myeloid cell states that contribute to IAV-induced mortality. : TRPV1 neurons facilitate host survival from influenza A virus infection by controlling myeloid cell responses and immunopathology.