Crosstalk between immune cells and the microbiota in mucosal tissues can set an individual on a trajectory toward health or disease. Little is known about these early-life events in the human respiratory tract. We examined bacterial colonization and immune system maturation in the lower airways over the first year of life. The lower respiratory tract microbiota forms within the first 2 postnatal months. Within the first weeks, three microbial profiles are evident, broadly distinguished as dysbiotic or diverse, and representing different microbial virulence potentials, including proteolysis of immunoglobulin A (IgA) that is critical for mucosal defense. Delivery mode determines microbiota constituents in preterm, but not term, births. Gestational age is a key determinant of immune maturation, with airway cells progressively increasing expression of proallergic cytokine interleukin-33 and genes linked with IgA. These data reveal microbial and immunological development in human airways, and may inform early-life interventions to prevent respiratory diseases.

Highlights d Staphylococcus aureus skin infection leads to specific and functional IgE antibodies d Skin-initiated immunity protects against secondary lung and skin infections d Mast cells and IgE antibodies play key roles in acquired resistance to S. aureus d IgE-activated mast cells interfere with S. aureus growth and toxicity

Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.

Background: In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgErelated type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC-mediated BV detoxification. Methods: We applied in vitro and in vivo fluorescence microscopyimaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. Results: Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. Conclusions: Our results both reveal that IgE sensitization enhances the MC's ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived * * * * * *** ***

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Lipocalin 2 (LCN2) is a secreted glycoprotein with roles in multiple biological processes. It contributes to host defense by interference with bacterial iron uptake and exerts immunomodulatory functions in various diseases. Here, we aimed to characterize the function of LCN2 in lung macrophages and dendritic cells (DCs) using Lcn2-/- mice. Transcriptome analysis revealed strong LCN2-related effects in CD103+ DCs during homeostasis, with differential regulation of antigen processing and presentation and antiviral immunity pathways. We next validated the relevance of LCN2 in a mouse model of influenza infection, wherein LCN2 protected from excessive weight loss and improved survival. LCN2-deficiency was associated with enlarged mediastinal lymph nodes and increased lung T cell numbers, indicating a dysregulated immune response to influenza infection. Depletion of CD8+ T cells equalized weight loss between WT and Lcn2-/- mice, proving that LCN2 protects from excessive disease morbidity by dampening CD8+ T cell responses. In vivo T cell chimerism and in vitro T cell proliferation assays indicated that improved antigen processing by CD103+ DCs, rather than T cell intrinsic effects of LCN2, contribute to the exacerbated T cell response. Considering the antibacterial potential of LCN2 and that commensal microbes can modulate antiviral immune responses, we speculated that LCN2 might cause the observed influenza phenotype via the microbiome. Comparing the lung and gut microbiome of WT and Lcn2-/- mice by 16S rRNA gene sequencing, we observed profound effects of LCN2 on gut microbial composition. Interestingly, antibiotic treatment or co-housing of WT and Lcn2-/- mice prior to influenza infection equalized lung CD8+ T cell counts, suggesting that the LCN2-related effects are mediated by the microbiome. In summary, our results highlight a novel regulatory function of LCN2 in the modulation of antiviral immunity.

Purpose To investigate the reproducibility of radiomics features extracted from two-dimensional regions of interest (2D ROIs) versus whole lung (3D) ROIs in repeated in-vivo fetal magnetic resonance imaging (MRI) acquisitions. Methods Thirty fetal MRI scans including two axial T2-weighted acquisitions of the lungs were analysed. 2D (lung at the level of the carina) and 3D (whole lung) ROIs were manually segmented using ITK-Snap. Ninety-five radiomics features were extracted from 2 and 3D ROIs in initial and repeat acquisitions using Pyradiomics. Radiomics feature intra-class correlation coefficients (ICC) were calculated between 2 and 3D ROIs in the initial acquisition, and between 2 and 3D ROIs in repeated acquisitions, respectively. Results MRI data of 11 (36.7%) female and 19 (63.3%) male fetuses acquired at a median 25 + 0 gestational weeks plus days (GW) (interquartile range [IQR] 23 + 4 − 27 + 0 GW) were assessed. Median radiomics feature ICC between 2 and 3D ROIs in the initial MRI acquisition was 0.733 (IQR 0.313–0.814, range 0.018–0.970). ICCs between radiomics features extracted using 3D ROIs in initial and repeat acquisitions (median 0.908 [IQR 0.824–0.929, range 0.335–0.996]) were significantly higher compared to 2D ROIs (0.771 [0.699–0.835, 0.048–0.965]) (p < 0.001). Conclusion Fetal MRI radiomics features extracted from 3D whole lung segmentation masks showed significantly higher reproducibility across repeat acquisitions compared to 2D ROIs. Therefore, fetal MRI whole lung radiomics features are robust diagnostic and potentially prognostic tools in the image-based in-vivo quantitative assessment of lung development.