Biology subjects

Doherty, T. A.

Publications and source records attributed to Doherty, T. A..

4 recordsLinked to original sources

bioRxiv2024

Comprehensive sequencing of the lung neuroimmune landscape in response to asthmatic induction

Evidence demonstrates that sensory neurons respond to pathogenic/allergic infiltration and mediate immune responses, forming an integral part of host defense that become hypersensitized during allergy. Our objective was to investigate how asthmatic induction alters the pulmonary neuroimmune transcriptome. We hypothesized that asthmatic induction would upregulate genes in the vagal ganglia (nodose/jugular ganglia), which would be associated with asthmatic immunity, and that these would be clustered, primarily in nodose neurons. Furthermore, lungs would increase transcripts associated with nerve activation, and these would be centered in neural and neuroendocrine-like cells. Bulk RNA-seq revealed that genes related to allergen sensing were increased in asthmatic ganglia nodose/jugular ganglia compared to control ganglia. These genes were associated with nodose clusters as shown by single-nucleus RNA sequencing, and a distinct caudal-to-rostral spatial arrangement was presented as delineated by spatial transcriptomics. The distinct clusters closely match previous identification of nodose neuron clusters. Correspondingly, the lung transcriptome was altered with asthmatic induction such that transcripts associated with neural excitation were upregulated. The spatial distribution of these transcripts was revealed by spatial transcriptomics to illustrate that these were expressed in neuroendocrine-like cells/club cells, and neurons. These results show that the neuroimmune transcriptome is altered in response to asthmatic induction in a cell cluster and spatially distinct manner. Significance statementThis study provides a comprehensive transcriptomic map of the neuroimmune alterations in response to asthmatic induction.

immunology↗

bioRxiv2024

PIP-Seq identifies novel heterogeneous lung innate lymphocyte population activation after combustion product exposure

Innate lymphoid cells (ILCs) are a heterogeneous population that play diverse roles in airway inflammation after exposure to allergens and infections. However, how ILCs respond after exposure to environmental toxins is not well understood. Here we show a novel method for studying the heterogeneity of rare lung ILC populations by magnetic enrichment for lung ILCs followed by particle-templated instant partition sequencing (PIP-seq). Using this method, we were able to identify novel group 1 and group 2 ILC subsets that exist after exposure to both fungal allergen and burn pit-related constituents (BPC) that include dioxin, aromatic hydrocarbon, and particulate matter. Toxin exposure in combination with fungal allergen induced activation of specific ILC1/NK and ILC2 populations as well as promoted neutrophilic lung inflammation. Oxidative stress pathways and downregulation of specific ribosomal protein genes (Rpl41 and Rps19) implicated in anti-inflammatory responses were present after BPC exposure. Increased IFN{gamma} expression and other pro-neutrophilic mediator transcripts were increased in BPC-stimulated lung innate lymphoid cells. Further, the addition of BPC induced Hspa8 (encodes HSC70) and aryl hydrocarbon transcription factor activity across multiple lung ILC subsets. Overall, using an airway disease model that develops after occupational and environmental exposures, we demonstrate an effective method to better understand heterogenous ILC subset activation.

immunology↗

bioRxiv2024

Sensory neurons regulate stimulus-dependent humoral immunity

Sensory neurons sense pathogenic infiltration, informing immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release, and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE, and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides that specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/574231v3_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1a96e0org.highwire.dtl.DTLVardef@1a75c97org.highwire.dtl.DTLVardef@afd6f8org.highwire.dtl.DTLVardef@4a6666_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed both lung proliferating CD127+ST2+ ILC2s and Alternaria- and IL-33-induced lung inflammation. Further, transcriptomic analysis of CD127-ST2- Thy1.2+ ILCs, which were expanded and activated by CDG, revealed an ILC1 signature. CDG administration led to accumulation of IFN{gamma}+ and T-bet+ ILC1s, as well as neutrophilia, independent of IL-18R, IL-12, and STAT6 but dependent on stimulator of interferon genes (STING) and partially dependent on type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.

immunology↗