ACE2 downregulation in olfactory mucosa: Eosinophilic rhinosinusitis as COVID-19 protective factor?
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ABSTRACT:
SUBMITTER: Marin C
PROVIDER: S-EPMC8222895 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
| S-SCDT-EMM-2022-15904 | biostudies-other
Project description: Not available
| S-EPMC7675498 | biostudies-literature
Project description:BackgroundRecent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes.MethodsA meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression.ResultsApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18-1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50-2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1-7.ConclusionsApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin-angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.
| S-EPMC9910247 | biostudies-literature
Project description:Describe the transcriptomic profile of Golden Hamster olfactory bulb in response to SARS-CoV-2 infection, separating by sexes.
2021-06-19 | E-MTAB-10442 | biostudies-arrayexpress
Project description:BackgroundOlfactory dysfunction (OD) is associated with both post-viral and inflammatory etiologies such as COVID-19 and chronic rhinosinusitis/rhinitis (CRS/R) respectively, to result in reduced quality of life (QoL). However, the former typically induces a sudden-onset OD while the latter has a gradual presentation. This study aims to establish and compare health utility values (HUVs) and olfactory-specific QoL measurements between patients with COVID-19 and CRS/R related OD.MethodsThis prospective study surveyed COVID-19 and CRS/R patients with self-reported OD using HUV assessments (EuroQol-visual analog scale [EQ-VAS], EuroQol-5 dimension [EQ-5D], time trade-off [TTO]) and olfactory and sinonasal QoL measures (questionnaire of olfactory disorders -negative and positive statements [QOD-NS + PS] and sino-nasal outcome test [SNOT-22]). A subgroup of subjects completed objective olfactory testing. Intergroup mean scores were compared using Mann-Whitney U tests.ResultsOne hundred eleven subjects were enrolled: mean age ± SD (43.0 ± 15.4 years), 55.9% female. CRS/R was associated with lower HUVs as measured by EQ-VAS (CRS/R: 0.67 ± 0.18 vs. COVID-19: 0.74 ± 0.19, p = .03) and worse SNOT-22 scores in both overall (CRS/R: 49.03 ± 21.04 vs. COVID-19: 27.58 ± 18.45, p < .001) and subgroup analysis of objectively confirmed OD subjects (CRS/R: 52.40 ± 22.78 vs. COVID-19: 29.84 ± 21.10, p = .01). On the other hand, COVID-19 has greater burden on olfactory-specific QoL (QOD-NS + PS, COVID-19: 23.19 ± 13.73 vs. CRS/R: 17.25 ± 11.38, p = .04). Both groups demonstrated a similar decrease in health using the EQ-5D assessment.ConclusionCRS/R associated OD has a more severe impact on general health and sinonasal specific QoL outcomes, while COVID-19 associated OD has a greater burden on olfactory-specific QoL.Level of evidenceLevel 2c.
| S-EPMC9538416 | biostudies-literature
Project description:A subset of COVID-19 patients exhibit altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium and olfactory bulb that express cell entry molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find that samples from whole olfactory mucosa in species including mouse and human express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, neither olfactory sensory neurons nor olfactory bulb neurons express these genes, which are instead expressed in support cells, stem cells, and perivascular cells. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.
2020-07-30 | GSE151346 | GEO
Project description:The outbreak of coronavirus disease 2019 (COVID-19) has posed a severe threat to global health management system since it has been detected in the human body. This pandemic was prompted by severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2) and rapidly developed into a public emergency with an alarming increase in cases and deaths. The increasing explorations to SARS-CoV-2 infection guide us to consider whether bone lesion is followed by this pathologic process. We especially focus on the underlying pathobiology that SARS-CoV-2 possibly mediated in bone remodeling and analyze the association of bone destruction with ACE2 in COVID-19 incidence, for preferable understanding the pathogenesis and providing necessary clinical management in orthopedics.
| S-EPMC7416709 | biostudies-literature
Project description:BACKGROUND:Olfactory-specific quality of life (QOL) can be measured using the Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS), which examines various aspects of olfactory dysfunction. It is unknown if certain factors of the QOD-NS differentially impact QOL. METHODS:Patients with chronic rhinosinusitis (CRS) completed the QOD-NS, 22-item Sino-Nasal Outcome Test (SNOT-22), Medical Outcomes Study Short Form 6-D (SF-6D) health utility measure, and Patient Health Questionnaire-2 (PHQ-2) depression screen. Exploratory factor analysis of the QOD-NS was performed. Associations between QOD-NS factors and other QOL metrics were analyzed before and after endoscopic sinus surgery (ESS). RESULTS:Outcomes were examined on 132 patients. The QOD-NS contains 4 distinct factors. There was no difference in associations between the different factors and baseline clinical characteristics. ESS had greatest effect size (d) on factors 2 and 4 (d = 0.29 and 0.27, respectively, p < 0.05). Postsurgical changes in the SF-6D and SNOT-22 had the strongest correlation with factor 2 scores (r = 0.29 and 0.34, respectively, p < 0.05), and changes in the PHQ-2 had the strongest correlation to factor 3 (r = 0.24, p < 0.05). Abnormal QOD-NS scores at baseline were associated with effect size increases of 50% to 100% (p < 0.05). CONCLUSION:The QOD-NS measures 4 distinct factors. Eating-related questions had the greatest improvement after ESS. Health utility and CRS-specific QOL improvement most strongly associated with factor 2, while PHQ-2 changes are most highly associated with factor 3, suggesting a differential impact of the factors of the QOD-NS on varying aspects of QOL.
| S-EPMC6035764 | biostudies-literature
Project description:Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2-skewed inflammation and increased colonization by Staphylococcus aureus. CRSwNP can be distinguished as eosinophilic (ECRSwNP) and non-eosinophilic (NECRSwNP) by the infiltration of eosinophils. The local microbiota plays an important role in the persistent inflammation of CRSwNP. To evaluate the bacterial community composition on the distinct types of CRSwNP patients, we collected nasal swabs from 16 ECRSwNP patients, 18 NECRSwNP patients, and 39 healthy control subjects. The microbiome structure for all the samples were analyzed by high-throughput 16S rRNA gene sequencing. Concentration of S. aureus was determined using TaqMan quantitative polymerase chain reaction (qPCR) targeting the nuclease (nuc) gene. The result showed significant differences in the sinus microbiome among healthy control subjects and CRSwNP patients. Microbiota community diversity was significantly lower in NECRSwNP samples compared to that of healthy control subjects. Interestingly, the abundance of several pathogenic bacteria was diverse between ECRSwNP and NECRSwNP patients. Although Staphylococcus prevailed in all groups, the abundance of Staphylococcus was significantly higher in the healthy control group than the ECRSwNP group. More importantly, the abundance of S. aureus was much higher in NECRSwNP patients. This study highlights that microbiota composition may contribute to the different clinical types of CRSwNP, inspiring new therapeutic strategies to resolve this chronic inflammation process.
| S-EPMC8346020 | biostudies-literature
Project description:Requests from researchers for olfactory mucosal biopsies are increasing as a result of advances in the fields of neuroscience and stem cell biology. Published studies report variable rates of success in obtaining true olfactory tissue, often below 50%. In cases where biopsies are not obtained carefully and confirmed through histological techniques, erroneous conclusions are made. Attention to the epithelium alone without submucosal analysis may add to the confusion. A consistent biopsy technique can help rhinologists obtain higher yields of olfactory mucosa. Confirmatory tissue staining analysis assures olfactory mucosa has been obtained, thereby strengthening clinical correlations and scientific conclusions.Biopsies of the septum within the anterior olfactory cleft were obtained under endoscopic guidance in an office procedure room using topical local anesthetic (lidocaine). After mucosal incision, a small, cupped, biopsy forceps was used to obtain specimens approximately 2 to 3 mm in size. Specimens were sectioned and analyzed with immunohistochemistry for presence of olfactory epithelium and/or olfactory fascicles.A total of 14 subjects were biopsied in this analysis. Four subjects had biopsies in the operating room (OR). The remaining 10 underwent biopsies in the clinic. All biopsies obtained in the OR revealed evidence of olfactory mucosa. Of the 10 clinic biopsies, 8 (80%) revealed evidence of olfactory mucosa. No complications were encountered.High yields of olfactory mucosa can be obtained safely in an office-based setting. Technique, including attention to the area of biopsy, and confirmatory analysis are important in assuring presence of olfactory tissue.
| S-EPMC4921276 | biostudies-literature