Umans, B. D. | Search bioRxiv

bioRxiv2024

Oxygen-induced stress reveals context-specific gene regulatory effects in human brain organoids

The interaction between genetic variants and environmental stressors is key to understanding the mechanisms underlying neurological diseases. In this study, we used human brain organoids to explore how varying oxygen levels expose context-dependent gene regulatory effects. By subjecting a genetically diverse panel of 21 brain organoids to hypoxic and hyperoxic conditions, we identified thousands of gene regulatory changes that are undetectable under baseline conditions, with 1,745 trait-associated genes showing regulatory effects only in response to oxygen stress. To capture more nuanced transcriptional patterns, we employed topic modeling, which revealed context-specific gene regulation linked to dynamic cellular processes and environmental responses, offering a deeper understanding of how gene regulation is modulated in the brain. These findings underscore the importance of genotype-environment interactions in genetic studies of neurological disorders and provide new insights into the hidden regulatory mechanisms influenced by environmental factors in the brain.

genomics↗

bioRxiv2024

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. 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. One Sentence Summary: TRPV1+ neurons facilitate host survival from influenza A virus infection by controlling myeloid cell responses and immunopathology.

immunology↗