Differential regulation of viral entry-associated genes modulated by inflammatory cytokines in the nasal epithelium.

This study aimed to investigate the impact of different types of nasal inflammation on the regulation of entry-associated genes of respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus 229E (HCoV-229E), and influenza virus, in the nasal epithelium. Subjects were classified into three groups: control, eosinophilic chronic rhinosinusitis (ECRS), and noneosinophilic CRS (NECRS) groups. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), alanyl aminopeptidase (ANPEP), dipeptidyl peptidase 4 (DPP4), and beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1), and beta-galactoside alpha-2,3-sialyltransferase 4 (ST3GAL4) were selected as key entry-associated genes for SARS-CoV-2, HCoV-229E, MERS-CoV, and influenza, respectively, and were evaluated. Brushing samples obtained from each group and human nasal epithelial cells cultured using an air-liquid interface system were treated for 7 days with typical inflammatory cytokines and analyzed using real-time polymerase chain reaction. Western blot analysis and confocal microscopy were performed. The entry-associated genes showed distinct regulation patterns in response to each interleukin-4 (IL-4), interleukin-13 (IL-13), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Specifically, ACE2 significantly decreased in type 2 cytokines (IL-4 and IL-13), while TMPRSS2 significantly decreased in type 1 cytokines (TNF-α and IFN-γ). ANPEP significantly decreased in both types of cytokines. Remarkably, DPP4 significantly increased in type 2 cytokines and decreased in type 1 cytokines. Moreover, ST6GAL1 and ST3GAL4 significantly increased in type 2 cytokines and decreased in type 1 cytokines, particularly IFN-γ. These findings were supported by western blot analysis and confocal imaging results, especially for ACE2 and DPP4. The findings regarding differential regulation suggest that patients with ECRS, primarily mediated by type 2 inflammation, may have lower susceptibility to SARS-CoV-2 and HCoV-229E infections but higher susceptibility to MERS-CoV and influenza infections.

Mucosal Immunity against SARS-CoV-2 in the Respiratory Tract.

The respiratory tract, the first-line defense, is constantly exposed to inhaled allergens, pollutants, and pathogens such as respiratory viruses. Emerging evidence has demonstrated that the coordination of innate and adaptive immune responses in the respiratory tract plays a crucial role in the protection against invading respiratory pathogens. Therefore, a better understanding of mucosal immunity in the airways is critical for the development of novel therapeutics and next-generation vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory viruses. Since the coronavirus disease 2019 pandemic, our knowledge of mucosal immune responses in the airways has expanded. In this review, we describe the latest knowledge regarding the key components of the mucosal immune system in the respiratory tract. In addition, we summarize the host immune responses in the upper and lower airways following SARS-CoV-2 infection and vaccination, and discuss the impact of allergic airway inflammation on mucosal immune responses against SARS-CoV-2.

SARS-CoV-2 spike-specific nasal-resident CD49a+CD8+ memory T cells exert immediate effector functions with enhanced IFN-γ production.

Virus-specific nasal resident T cells are important for protection against subsequent infection with a similar virus. Here we examine the phenotypes and functions of SARS-CoV-2-specific T cells in the nasal mucosa of vaccinated individuals with breakthrough infection (BTI) or without infection. Nasal tissues are obtained from participants during sinus surgery. Analysis of activation-induced markers implicates that a considerable proportion of spike (S)-reactive nasal CD8+ T cells express CD103, a tissue-resident marker. MHC-I multimer staining is performed to analyze the ex vivo phenotype and function of SARS-CoV-2 S-specific CD8+ T cells. We detect multimer+CD8+ T cells with tissue-resident phenotypes in nasal tissue samples from vaccinees without infection as well as vaccinees with BTI. Multimer+CD8+ T cells remain present in nasal tissues over one year after the last exposure to S antigen, although the frequency decreases. Upon direct ex vivo stimulation with epitope peptides, nasal multimer+CD8+ T cells-particularly the CD49a+ subset-exhibit immediate effector functions, including IFN-γ production. CITE-seq analysis of S-reactive AIM+CD8+ T cells confirms the enhanced effector function of the CD49a+ subset. These findings indicate that among individuals previously exposed to S antigen by vaccination or BTI, S-specific nasal-resident CD49a+CD8+ memory T cells can rapidly respond to SARS-CoV-2 during infection or reinfection.

Differential Correlations among Allergy Tests According to Indoor Allergens in Allergic Rhinitis.

OBJECTIVES: Several allergy tests are used for the diagnosis of allergic rhinitis; however, few studies have reported a direct comparison of the skin prick test (SPT), multiple allergen simultaneous test (MAST), and ImmunoCAP according to specific allergens. This study aimed to evaluate the correlations between each test and allergic rhinitis symptoms and to evaluate the correlations of the MAST and ImmunoCAP with the SPT for representative indoor allergens in Korea. METHODS: Electronic medical charts were retrospectively reviewed, and 698 patients with allergic rhinitis who had performed SPT, MAST, and ImmunoCAP were enrolled. Correlations between each allergy test for 4 representative indoor allergens and the symptoms of allergic rhinitis were analyzed. Agreements of the MAST and ImmunoCAP with the SPT were compared according to each allergen. RESULTS: The SPT showed higher correlations with allergic rhinitis symptoms for 4 indoor allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat, and dog allergens) than the MAST or ImmunoCAP. In comparison between the MAST and SPT, the least correlation was observed for the dog allergen, whereas between the ImmunoCAP and SPT, the least correlation was observed for the cat allergen. The correlation between the ImmunoCAP and SPT was higher than that between the MAST and SPT for the dog allergen, whereas no significant differences were noted for other allergens. CONCLUSIONS: Overall, the SPT showed a higher correlation with allergic rhinitis symptoms than the MAST or ImmunoCAP for 4 indoor allergens. ImmunoCAP showed similar reactivity to MAST; however, it showed better positivity with dog allergen in patients who were reactive to the allergen in the SPT. Care should be taken while evaluating dog allergen sensitization using the MAST.

Association between obesity and chronic rhinosinusitis with nasal polyps: a national population-based study.

OBJECTIVES: We performed a cross-sectional analysis of data from the nationwide Korea National Health and Nutrition Examination Survey to evaluate the association between obesity and chronic rhinosinusitis with nasal polyps (CRSwNP) or without nasal polyp (CRSsNP). DESIGN: Retrospective cross-sectional analysis of health survey data. SETTING: Voluntary survey of representative South Korean populations. PARTICIPANTS: In total, 32 384 individuals aged 19 years or older with available data on CRS and obesity were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Diagnosis of CRSwNP or CRSsNP was performed by trained otolaryngologists through sinus endoscopy and surveys of medical history. General and central obesity was diagnosed using body mass index (BMI) and waist circumference (WC), respectively. METHODS: A multivariate logistic regression analysis was used to clarify the association between CRSwNP or CRSsNP and obesity according to BMI and WC. Non-obese individuals were recruited as controls. RESULTS: The prevalence of CRSwNP was higher in the general (OR, 1.438; 95% CI, 1.170 to 1.768; p<0.001) and central (OR, 1.251; 95% CI, 1.031 to 1.520; p=0.033) obesity groups than in the control group. Prevalence of CRSsNP was not correlated with obesity. In a logistic regression analysis, olfactory dysfunction (OR, 1.329; 95% CI, 1.137 to 1.553; p<0.001) and purulent discharge (OR, 1.383; 95% CI, 1.193 to 1.603; p<0.001) showed a higher incidence in the central obesity group than in the control group. CONCLUSIONS: We demonstrated an association between CRSwNP and general and central obesity. Further investigations on the mechanism underlying this correlation are necessary for an improved understanding of the pathogenesis of CRSwNP.

Heterogeneity of MYO15A variants significantly determine the feasibility of acoustic stimulation with hearing aid and cochlear implant.

Autosomal recessive nonsyndromic hearing loss 3 (DFNB3) mainly leads to congenital and severe-to-profound hearing impairment, which is caused by variants in MYO15A. However, audiological heterogeneity in patients with DFNB3 hinders precision medicine in hearing rehabilitation. Here, we aimed to elucidate the heterogeneity of the auditory phenotypes of MYO15A variants according to the affected domain and the feasibilities for acoustic stimulation. We conducted whole-exome sequencing for 10 unrelated individuals from seven multiplex families with DFNB3; 11 MYO15A variants, including the novel frameshift c.900delT (p.Pro301Argfs*143) and nonsense c.4879G > T (p.Glu1627*) variants, were identified. In seven probands, residual hearing at low frequencies was significantly higher in the groups with one or two N-terminal frameshift variants in trans conformation compared to that in the group without these variants. This is consistent with the 56 individuals from the previously published reports that carried a varying number of N-terminal truncating variants in MYO15A. In addition, patients with missense variants in the second FERM domain had better hearing at low frequencies than patients without these variants. Subsequently, acoustic stimulation provided by devices such as hearing aids or cochlear implants was feasible in patients with one or two N-terminal truncating variants or a second FERM missense variant. In conclusion, N-terminal or second FERM variants in MYO15A allow the practical use of acoustic stimulation through hearing aids or electroacoustic stimulation for aural rehabilitation.