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Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes. Leukotriene synthesis was further enhanced by glucocorticoids and remained elevated at 3–5 months, but had returned to baseline at 12 months post SARS-CoV-2 infection. Stimulation with SARS-CoV-2 spike protein or LPS triggered exaggerated prostanoid-, type I IFN-, and chemokine responses in post COVID-19 MDM. Thus, SARS-CoV-2 infection leaves an inflammatory imprint in the monocyte/ macrophage compartment that drives aberrant macrophage effector functions and eicosanoid metabolism, resulting in long-term immune aberrations in patients recovering from mild COVID-19. [Display omitted]

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 ( Tgfbr2 ) on CD4 + T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells.

The skin prick test (SPT) is the gold standard for diagnosing allergic sensitization to aeroallergies. The Skin Prick Automated Test (SPAT) device has previously demonstrated reduced variability and more consistent test results compared to manual SPT. The current study aims to develop and validate an artificial intelligence (AI) assisted readout method to support physicians in interpreting skin reactions following SPAT. To train the AI algorithm, 7812 wheals (651 patients) are manually labeled. To validate the AI measurement, the longest wheal diameter of 2604 wheals (217 patients) is measured by the treating physician and compared to the AI measurement. In addition, AI-assisted readout is validated on a separate test cohort of 95 patients (1140 wheals). We demonstrate that the AI measurements of the longest wheal diameter exhibit a strong correlation with the physician’s measurements. The AI algorithm shows a specificity of 98·4% and sensitivity of 85·0% in determining positive or negative test results in the validation cohort. In the test cohort, physicians adjust 5·8% of AI measurements, leading to a change in the test interpretation for only 0·5% of cases. AI-assisted readout significantly reduces inter- and intra-observer variability and readout time compared to manual physician measurements. Altogether, the AI-assisted readout method demonstrates high accuracy, with minimal misclassification of test results. Adding AI to SPAT further improves standardization across the SPT process, significantly reducing observer variability and time to readout. Skin prick testing for allergy diagnosis is limited by variability due to differences in test setting and operator expertise. Here, the authors develop and validate an AI-assisted readout method for reading allergy skin test results, and find that integrating AI enhances standardization throughout the skin prick testing process.

Biosensors such as toll-like receptors (TLR) induce the expression of interferons (IFNs) after viral infection that are critical to the first step in cell-intrinsic host defense mechanisms. Their differential influence on epithelial integrity genes, however, remains elusive. A genome-wide gene expression biosensor chip for gene expression sensing was used to examine the effects of type-I, -II, and -III IFN stimulation on the epithelial expression profiles of primary organotypic 3D air-liquid interface airway cultures. All types of IFNs induced similar interferon-stimulated genes (ISGs): OAS1, OAS2, and IFIT2. However, they differentially induced transcription factors, epithelial modulators, and pro-inflammatory genes. Type-I IFN-induced genes were associated with cell–cell adhesion and tight junctions, while type-III IFNs promoted genes important for transepithelial transport. In contrast, type-II IFN stimulated proliferation-triggering genes associated and enhanced pro-inflammatory mediator secretion. In conclusion, with our microarray system, we provide evidence that the three IFN types exceed their antiviral ISG-response by inducing distinct remodeling processes, thereby likely strengthening the epithelial airway barrier by enhancing cross-cell-integrity (I), transepithelial transport (III) and finally reconstruction through proliferation (II).

Protein biomarkers in nasal secretions can be used as a measure to differentiate between allergies, airway diseases and infections for non-invasive diagnostics. The point-of-care quantification of biomarker levels using flow-based microarray facilitates precise and rapid diagnosis and displays the potential for targeted and effective treatment. For the first time, we developed a flow-based chemiluminescence sandwich microarray immunoassay (CL-SMIA) for the quantification of nasal interferon-beta (IFN-β) on the Microarray Chip Reader-Research (MCR-R). Polycarbonate foils are used as a cost-effective surface for immobilizing capture antibodies. By using a commercially available set of anti-human IFN-β antibodies, the CL-SMIA can be compared directly to an enzyme-linked immunosorbent assay (ELISA) performed in microtiter plates concerning the bioanalytical performance and economic issues. Pre-incubation of the sample with detection antibodies facilitates the lower consumption of detection antibodies, as this allows for a longer interaction time between the antibody and the biomarker. The direct injection of pre-incubated samples into the microarray chips eliminates the adsorption of proteins in the tubing as well as the contamination of the tubing and valves of the MCR-R with clinical samples. The small flow cell allows for a low sample volume of 50 μL. The limit of detection of 4.53 pg mL−1 was slightly increased compared to a sandwich ELISA performed on microtiter plates which were 1.60 pg mL−1. The possibility to perform the CL-SMIA in a multiplexed mode makes it a promising assay for the rapid and cost-effective non-invasive detection of biomarkers in nasal secretions.

SARS-CoV-2 has evolved to enter the host via the ACE2 receptor which is part of the kinin-kallikrein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV-2-infection and epithelial mechanisms of the kinin-kallikrein-system at the kinin B2 receptor level in SARS-CoV-2-infection that is of direct translational relevance. From acute SARS-CoV-2-positive study participants and -negative controls, transcriptomes of nasal curettages were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R-antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays, and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo. Here, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive study participants. A B2R-antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero-E6 cells. B2R-antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2, G protein–coupled receptor signaling, and ion transport in vitro and in a murine airway inflammation in vivo model. In summary, this study provides evidence that treatment with B2R-antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R-antagonists, like icatibant, in the treatment of early-stage COVID-19.Key messagesInduction of kinin B2 receptor in the nose of SARS-CoV-2-positive patients.Treatment with B2R-antagonist protects airway epithelial cells from SARS-CoV-2.B2R-antagonist reduces ACE2 levels in vivo and ex vivo.Protection by B2R-antagonist is mediated by inhibiting viral replication and spread.

BackgroundThe combination of cervical spondylodiscitis and esophageal fistula is rare but life-threatening. Due to both the rarity of these conditions’ coincidence and the complexity and heterogeneity of individual cases, there is no optimal treatment or management approach. The aims of this study are to obtain an overview of patients’ outcomes and to discuss treatment options.MethodThis study is a retrospective analysis of patients who presented with cervical spondylodiscitis and associated esophageal fistula between January 2010 and November 2018. We examined reports of 59 patients who suffered from cervical spondylodiscitis and included nine patients (15.25%) who had an esophageal fistula as the underlying cause. We assessed clinical findings, treatment, and outcome.ResultsThree of the nine patients were female, and the mean age of the sample was 64.56 years. Six of the patients had a history of esophagopharyngeal cancer and had undergone tumor resection followed by radiotherapy. Two of the remaining patients’ fistulas were caused by an iatrogenic injury during cervical spine surgery and a swallowed toothpick; in the final case, the origin remained unclear. Five patients presented with tetraparesis or tetraplegia, and the other four patients were neurologically intact. In seven cases, dorsal instrumentation was initially performed. Three patients secondarily received a ventral approach for debridement, and one received explantation of the ventral implants. Two patients died during the hospital stay, and three were transferred to a palliative care unit. Thus, the spondylodiscitis and esophageal fistula were cured in only four patients. At discharge, two patients were neurologically intact, two others remained in tetraparesis.ConclusionsCervical spondylodiscitis in association with an esophageal fistula carries high morbidity and high mortality. Because patients whose infections are not cured have high morbidity, we recommend using interdisciplinary and individual management, including definite surgical treatment of the discitis and fistula, in every case.

TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs. Competing Interest Statement Dr. Chaker reports grants for clinical studies and research and other from Allergopharma , ALK Abello, AstraZeneca, Bencard / Allergen Therapeutics, ASIT Biotech, Immunotek, Lofarma, GSK, Novartis, LETI, Roche, Sanofi Genzyme and Zeller. Prof. Schmidt-Weber reports speaker fees from Bencard, personal fees from Allergopharma, during the conduct of the study.