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The nose is a complex organ that filters and warms breathing airflow. The nasal epithelium is the first barrier between the host and the external environment and is covered by a mucus gel that is poorly documented. Mucins are large, heavily O-glycosylated polymeric molecules secreted in the nose lumen by specialized cells, and they are responsible for the biochemical properties of the mucus gel. The mucus traps particles and clears them, and it also bathes microbiota, host molecules, and receptors that are all essential for odor perception in the olfactory epithelium. We used histology and immunohistochemistry to study the expression of the two main airway polymeric mucins, Muc5ac and Muc5b, in wild-type, green fluorescent protein-reporter Muc5b, and in genetically Muc5b-deficient mice. We report that Muc5ac is produced by goblet cells at the cell surface in the respiratory epithelium but is not expressed in the olfactory epithelium, whereas Muc5b is secreted by Bowman’s glands situated in the lamina propria beneath the olfactory epithelium and also by goblet cells in the distal part of the respiratory epithelium. We also observed that Muc5b-deficient mice exhibited depletion of Bowman’s glands. Using lectins, we found that terminally O-glycosylated chains of Muc5b were sialylated but not fucosylated, whereas Muc5ac was fucosylated but not sialylated. Specific localization and specific terminal glycosylation of the two mucins suggest different functions of the mucins.

A small fraction of patients with cystic fibrosis have a genetic defect that introduces a premature stop codon into the CFTR gene; this results in a truncated protein that does not fulfill its normal biologic function. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that lead to dysfunction of the CFTR protein, which is an apical membrane protein regulating the transport of chloride and sodium in secretory epithelial cells. 1 Since the discovery of the CFTR gene, more than 1000 mutations have been identified, including missense, deletion or insertion, frame shift, splice site, and nonsense mutations. 2 Nonsense or stop mutations contain signals that cause a truncated or unstable protein, should result in a deficiency or absence of CFTR chloride channels, and are associated with a severe cystic fibrosis . . .

Innate lymphoid cells (ILCs) are crucial for the immune surveillance at mucosal sites. ILCs coordinate early eradication of pathogens and contribute to tissue healing and remodeling, features that are dysfunctional in patients with cystic fibrosis (CF). The mechanisms by which ILCs contribute to CF-immunopathology are ill-defined. Here, we show that group 2 ILCs (ILC2s) transdifferentiated into IL-17-secreting cells in the presence of the epithelial-derived cytokines IL-1β, IL-23 and TGF-β. This conversion is abrogated by IL-4 or vitamin D3. IL-17 producing ILC2s induce IL-8 secretion by epithelial cells and their presence in nasal polyps of CF patients is associated with neutrophilia. Our data suggest that ILC2s undergo transdifferentiation in CF nasal polyps in response to local cytokines, which are induced by infectious agents. Innate lymphoid cells (ILCs) play critical immunological roles including immune surveillance at mucosal sites. Here the authors show that during nasal inflammation pathogen-induced cytokine production guides the differentiation of ILCs.

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy. The innate immune response in epithelial cells after SARS-CoV-2 infection is not fully understood. Here the authors use human air-liquid interface culture and show single cell transcription changes and delayed type I Interferon responses after SARS-CoV-2 infection compared with other respiratory viruses.

Organoid is an ideal in vitro model with cellular heterogeneity and genetic stability when passaging. Currently, organoids are exploited as new tools in a variety of preclinical researches and applications for disease modeling, drug screening, host-microbial interactions, and regenerative therapy. Advances have been made in the establishment of nasal and olfactory epithelium organoids that are used to investigate the pathogenesis of smell-related diseases and cellular/molecular mechanism underlying the regeneration of olfactory epithelium. A set of critical genes are identified to function in cell proliferation and neuronal differentiation in olfactory epithelium organoids. Besides, nasal epithelium organoids derived from chronic rhinosinusitis patients have been established to reveal the pathogenesis of this disease, potentially applied in drug responses in individual patient. The present article reviews recent research progresses of nasal and olfactory epithelium organoids in fundamental and preclinical researches, and proposes current advances and potential future direction in the field of organoid research and application.

Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory airway disease involving non-eosinophilic and eosinophilic phenotypes, which translate to various endotypes. Activated eosinophils and neutrophils are known to generate extracellular traps consisting of DNA and cytotoxic granule proteins. We sought to investigate the presence of eosinophil and neutrophil extracellular traps (EETs and NETs, respectively) in human CRS tissues and to clarify the associations with their clinical features. Nasal polyp (NP) or ethmoid tissue slides of 43 subjects from endoscopic sinus surgery for CRS were analysed. Quantitative analysis of EETs and NETs was performed by confocal microscopy using immunofluorescent staining. For correlation study, the presence of NPs, number of infiltrating tissue eosinophils, preoperative Lund–Mackay scores, and other comorbidities were analysed. EET formation was observed to varying degrees in all CRS groups and was correlated with the number of tissue eosinophils (r  =  0.83, p  < 0.001) regardless of the presence of NPs. Patients with more EETs demonstrated higher Lund–Mackay scores (r  =  0.51, p  = 0.009), blood eosinophilia (r  =  0.80, p  < 0.001), and decreased olfactory function (r  = −0.65, p  < 0.001). No correlation between the extent of EET formation and the presence of atopy or asthma was apparent. However, none of the CRS groups containing neutrophils formed NETs in this study. Eosinophilic CRS indicates the presence of EETs. Formation of EETs could have a role in clinical decision-making and prediction of treatment outcome of CRS, regardless of NP status.

Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens 1 , yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear 2 . Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs) 3 . Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA + B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses. Nasal vaccination induces B cell expansion in the nasal-associated lymphoid tissues, followed by homing to the nasal turbinates and glandular acinar structures.

Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50–100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application. Targeting different aspects of mutant CFTR structural defects with combination therapy leads to more potent rescue of function than that following single therapy.

Detailed profile of the immune cells in the upper airway could help to improve nasal vaccines. Detailed profile of the immune cells in the upper airway could help to improve nasal vaccines. Close-up of a mother wiping a toddler's nose with tissue

Several studies suggest that nasal nitric oxide (nNO) measurement could be a test for primary ciliary dyskinesia (PCD), but the procedure and interpretation have not been standardized. To use a standard protocol for measuring nNO to establish a disease-specific cutoff value at one site, and then validate at six other sites. At the lead site, nNO was prospectively measured in individuals later confirmed to have PCD by ciliary ultrastructural defects (n = 143) or DNAH11 mutations (n = 6); and in 78 healthy and 146 disease control subjects, including individuals with asthma (n = 37), cystic fibrosis (n = 77), and chronic obstructive pulmonary disease (n = 32). A disease-specific cutoff value was determined, using generalized estimating equations (GEEs). Six other sites prospectively measured nNO in 155 consecutive individuals enrolled for evaluation for possible PCD. At the lead site, nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min), asthma (267.8 ± 103.2; 125.0-589.7 nl/min), or chronic obstructive pulmonary disease (223.7 ± 87.1; 109.7-449.1 nl/min); however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min). The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999). At six other sites, this cutoff identified 70 of the 71 (98.6%) participants with confirmed PCD. Using a standardized protocol in multicenter studies, nNO measurement accurately identifies individuals with PCD, and supports its usefulness as a test to support the clinical diagnosis of PCD.