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1.
Cell ; 186(1): 112-130.e20, 2023 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-36580912

RESUMEN

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.


Asunto(s)
COVID-19 , Sistema Respiratorio , SARS-CoV-2 , Humanos , Cilios/fisiología , Cilios/virología , COVID-19/virología , Sistema Respiratorio/citología , Sistema Respiratorio/virología , SARS-CoV-2/fisiología , Microvellosidades/fisiología , Microvellosidades/virología , Internalización del Virus , Células Epiteliales/fisiología , Células Epiteliales/virología
2.
Immunity ; 55(6): 1118-1134.e8, 2022 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-35447093

RESUMEN

Understanding the mechanisms of HIV tissue persistence necessitates the ability to visualize tissue microenvironments where infected cells reside; however, technological barriers limit our ability to dissect the cellular components of these HIV reservoirs. Here, we developed protein and nucleic acid in situ imaging (PANINI) to simultaneously quantify DNA, RNA, and protein levels within these tissue compartments. By coupling PANINI with multiplexed ion beam imaging (MIBI), we measured over 30 parameters simultaneously across archival lymphoid tissues from healthy or simian immunodeficiency virus (SIV)-infected nonhuman primates. PANINI enabled the spatial dissection of cellular phenotypes, functional markers, and viral events resulting from infection. SIV infection induced IL-10 expression in lymphoid B cells, which correlated with local macrophage M2 polarization. This highlights a potential viral mechanism for conditioning an immunosuppressive tissue environment for virion production. The spatial multimodal framework here can be extended to decipher tissue responses in other infectious diseases and tumor biology.


Asunto(s)
Infecciones por VIH , Ácidos Nucleicos , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Linfocitos T CD4-Positivos , Virus ADN , Terapia de Inmunosupresión , Macaca mulatta , Macrófagos , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral
3.
Nat Methods ; 20(2): 304-315, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36624212

RESUMEN

The ability to align individual cellular information from multiple experimental sources is fundamental for a systems-level understanding of biological processes. However, currently available tools are mainly designed for single-cell transcriptomics matching and integration, and generally rely on a large number of shared features across datasets for cell matching. This approach underperforms when applied to single-cell proteomic datasets due to the limited number of parameters simultaneously accessed and lack of shared markers across these experiments. Here, we introduce a cell-matching algorithm, matching with partial overlap (MARIO) that accounts for both shared and distinct features, while consisting of vital filtering steps to avoid suboptimal matching. MARIO accurately matches and integrates data from different single-cell proteomic and multimodal methods, including spatial techniques and has cross-species capabilities. MARIO robustly matched tissue macrophages identified from COVID-19 lung autopsies via codetection by indexing imaging to macrophages recovered from COVID-19 bronchoalveolar lavage fluid by cellular indexing of transcriptomes and epitopes by sequencing, revealing unique immune responses within the lung microenvironment of patients with COVID.


Asunto(s)
COVID-19 , Proteómica , Humanos , Proteómica/métodos , Perfilación de la Expresión Génica/métodos , Transcriptoma , Pulmón , Análisis de la Célula Individual/métodos
4.
J Infect Dis ; 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38934845

RESUMEN

BACKGROUND: Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial. METHODS: In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2). RESULTS: In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1). CONCLUSIONS: Data support the continued development of mRNA-1010 as a seasonal influenza vaccine. CLINICALTRIALS.GOV IDENTIFIER: NCT04956575 (https://clinicaltrials.gov/study/NCT04956575).

5.
J Allergy Clin Immunol ; 149(4): 1296-1308.e6, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34863854

RESUMEN

BACKGROUND: Emerging evidence suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with disparate inflammatory characteristics between different racial groups and geographies. Currently, little is known about possible underlying distinguishing factors between these inflammatory differences. OBJECTIVE: Our aim was to interrogate differences in CRSwNP disease between White/non-Asian patients and Japanese patients by using whole transcriptome and single-cell RNA gene expression profiling of nasal polyps (NPs). METHODS: We performed whole transcriptome RNA sequencing with endotype stratification of NPs from 8 White patients (residing in the United States) and 9 Japanese patients (residing in Japan). Reproducibility was confirmed by quantitative PCR in an independent validation set of 46 White and 31 Japanese patients. Single-cell RNA sequencing (scRNAseq) was used to stratify key cell types for contributory transcriptional signatures. RESULTS: Unsupervised clustering analysis identified 2 major endotypes that were present within both cohorts of patients with NPs and had previously been reported at the cytokine level: (1) type 2 endotype and (2) non-type 2 endotype. Importantly, there was a statistically significant difference in the proportion of these endotypes between these geographically distinct subgroups with NPs (P = .03). Droplet-based single-cell RNA sequencing further identified prominent type 2 inflammatory transcript expression: C-C motif chemokine ligand 13 (CCL13) and CCL18 in M2 macrophages, as well as cystatin SN (CST1) and CCL26 in basal, suprabasal, and secretory epithelial cells. CONCLUSION: NPs from both racial groups harbor the same 2 major endotypes, which we have determined to be present in differing ratios between each cohort with CRSwNP disease. Distinct inflammatory and epithelial cells contribute to the type 2 inflammatory profiles observed.


Asunto(s)
Pólipos Nasales , Rinitis , Sinusitis , Enfermedad Crónica , Humanos , Japón , Pólipos Nasales/genética , Reproducibilidad de los Resultados , Rinitis/genética , Sinusitis/genética
6.
Pediatr Allergy Immunol ; 28(7): 619-627, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28782296

RESUMEN

Food allergy is a significant medical problem that affects up to 8% of children in developed countries. At present, there are no curative therapies available in routine practice and management of food allergy involves strict allergen avoidance, education, and prompt treatment upon accidental exposure. Oral immunotherapy (OIT) is an efficacious experimental approach to food allergy and has been shown to provide a substantial benefit in terms of allergen desensitization. However, OIT is associated with high rates of allergic reactions, and the period of protection offered by OIT appears to be limited and highly variable. Recurrence of allergen sensitivity after a period of treatment discontinuation is commonly observed. With the aim of overcoming these limitations of OIT, several trials have studied omalizumab (anti-IgE monoclonal antibody) as an adjuvant treatment for patients undergoing OIT. Results from these trials have shown that the addition of omalizumab to OIT leads to a significant decrease in the frequency and severity of reactions, which allows for an increase in the threshold of tolerance to food allergens. This review provides a summary of the current literature and addresses some of the key questions that remain regarding the use of omalizumab in conjunction with OIT.


Asunto(s)
Antialérgicos/uso terapéutico , Anticuerpos Antiidiotipos/inmunología , Hipersensibilidad a los Alimentos/tratamiento farmacológico , Inmunoterapia/efectos adversos , Omalizumab/uso terapéutico , Administración Oral , Adolescente , Niño , Desensibilización Inmunológica/métodos , Quimioterapia Combinada , Hipersensibilidad a los Alimentos/inmunología , Humanos , Tolerancia Inmunológica , Inmunoterapia/métodos , Adulto Joven
8.
Nat Commun ; 14(1): 3631, 2023 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-37336877

RESUMEN

Despite vaccine availability, influenza remains a substantial global public health concern. Here, we report interim findings on the primary and secondary objectives of the safety, reactogenicity, and humoral immunogenicity of a quadrivalent messenger RNA (mRNA) vaccine against seasonal influenza, mRNA-1010, from the first 2 parts of a 3-part, first-in-human, phase 1/2 clinical trial in healthy adults aged ≥18 years (NCT04956575). In the placebo-controlled Part 1, a single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) elicited hemagglutination inhibition (HAI) titers against vaccine-matched strains. In the active-comparator-controlled Part 2, mRNA-1010 (25 µg, 50 µg, or 100 µg) elicited higher HAI titers than a standard dose, inactivated seasonal influenza vaccine for influenza A strains and comparable HAI titers for influenza B strains. No safety concerns were identified; solicited adverse reactions were dose-dependent and more frequent after receipt of mRNA-1010 than the active comparator. These interim data support continued development of mRNA-1010.


Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Humanos , Adulto , Adolescente , Gripe Humana/prevención & control , Estaciones del Año , Vacunas de Productos Inactivados/efectos adversos , Anticuerpos Antivirales , Pruebas de Inhibición de Hemaglutinación , Vacunas Combinadas , Método Doble Ciego
9.
Clin Transl Sci ; 16(6): 1049-1062, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36929625

RESUMEN

Observational studies have identified the potential prognostic value for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral load and anti-SARS-CoV-2 antibodies in coronavirus disease 2019 (COVID-19). However, viral load in nasopharyngeal (NP) swabs produced inconsistent results in prognostic analyses, and the prognostic value of viral load or antibodies has not been confirmed in large clinical trials. COVACTA and REMDACTA were double-blind, randomized, controlled trials with a combined enrollment of 1078 patients hospitalized with COVID-19 treated with tocilizumab or placebo in COVACTA or tocilizumab plus remdesivir or placebo plus remdesivir in REMDACTA. We assessed the potential prognostic value of NP and serum SARS-CoV-2 viral load and serum anti-SARS-CoV-2 antibodies at baseline as biomarkers for clinical outcomes in patients enrolled in these trials. In adjusted Cox proportional hazard models, serum viral load was a more reliable predictor of clinical outcomes than NP viral load; high serum viral load was associated with higher risk for death and mechanical ventilation/death and lower likelihood of hospital discharge (high vs. negative viral load hazard ratios [95% confidence interval {CI}] were 2.87 [1.57-5.25], 3.86 [2.23-6.68], and 0.23 [0.14-0.36], respectively, in COVACTA and 8.11 [2.95-22.26], 10.29 [4.5-23.55], and 0.21 [0.15-0.29], respectively, in REMDACTA) and high serum viral load correlated with levels of inflammatory cytokines and lung damage biomarkers. High anti-SARS-CoV-2 spike protein antibody (ACOV2S) levels were associated with higher likelihood of hospital discharge (high vs. below the limit of quantification hazard ratios [95% CI] were 2.55 [1.59-4.08] for COVACTA and 1.54 [1.13-2.09] for REMDACTA). These results support the role of baseline SARS-CoV-2 serum viral load and ACOV2S antibody titers in predicting clinical outcomes for patients hospitalized with COVID-19.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Pronóstico , Carga Viral , Pulmón , Anticuerpos Antivirales
10.
Nat Microbiol ; 8(1): 121-134, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36604514

RESUMEN

The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.


Asunto(s)
COVID-19 , SARS-CoV-2 , Chlorocebus aethiops , Ratones , Humanos , Animales , SARS-CoV-2/metabolismo , Células Vero , Enzima Convertidora de Angiotensina 2 , Peptidil-Dipeptidasa A/metabolismo , Antivirales/farmacología
11.
Lancet Infect Dis ; 23(9): 1007-1019, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37348519

RESUMEN

BACKGROUND: The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial. METHODS: In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 µg omicron BA.1 monovalent or bivalent vaccines or 50 µg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing. FINDINGS: Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6-4·7]) and mRNA-1273 (4·1 [3·5-4·7]), and for the omicron BA.1 bivalent (5·5 [4·8-6·2]) and mRNA-1273 (5·4 [4·8-6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45-1·95) and 1·53 (1·41-1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9-3169·9]) versus mRNA-1273 (2911·3 [2750·9-3081·0]) and lower for the monovalent (2699·7 [2431·3-2997·7] vs 3020·6 [2776·5-3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96-1·15) and 0·82 (95% CI 0·74-0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events. INTERPRETATION: Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge. FUNDING: Moderna.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Vacuna nCoV-2019 mRNA-1273 , COVID-19/prevención & control , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Reino Unido , Inmunogenicidad Vacunal , Anticuerpos Antivirales
12.
Laryngoscope ; 132(11): 2089-2095, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-34724213

RESUMEN

OBJECTIVES/HYPOTHESIS: To determine the effect of povidone-iodine (PVP-I) nasal sprays on nasopharyngeal (NP) viral load as assessed by cycle threshold (Ct) on quantitative polymerase chain reaction (qPCR) of SARS-CoV-2 in outpatients. STUDY DESIGN: Three arm, triple blinded, randomized, placebo-controlled clinical trial. METHODS: Participants were randomized within 5 days of testing positive for COVID-19 to receive nasal sprays containing placebo (0.9% saline), 0.5% PVP-I, or 2.0% PVP-I. NP swabs for qPCR analysis were taken at baseline, 1-hour post-PVP-I spray (two sprays/nostril), and 3 days post-PVP-I spray (20 sprays/nostril). Symptom and adverse event questionnaires were completed at baseline, day 3, and day 5. University of Pennsylvania Smell Identification Tests (UPSIT) were completed at baseline and day 30. RESULTS: Mean Ct values increased over time in all groups, indicating declining viral loads, with no statistically significant difference noted in the rate of change between placebo and PVP-I groups. The 2.0% PVP-I group showed statistically significant improvement in all symptom categories; however, it also reported a high rate of nasal burning. Olfaction via UPSIT showed improvement by at least one category in all groups. There were no hospitalizations or mortalities within 30 days of study enrollment. CONCLUSIONS: Saline and low concentration PVP-I nasal sprays are well tolerated. Similar reductions in SARS-CoV-2 NP viral load were seen over time in all groups. All treatment groups showed improvement in olfaction over 30 days. These data suggest that dilute versions of PVP-I nasal spray are safe for topical use in the nasal cavity, but that PVP-I does not demonstrate virucidal activity in COVID-19 positive outpatients. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:2089-2095, 2022.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Rociadores Nasales , Povidona Yodada/uso terapéutico , Solución Salina , Carga Viral
13.
EClinicalMedicine ; 47: 101409, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35475258

RESUMEN

Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference -0·5% [95% CI -9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase-quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti-SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

14.
Cell Metab ; 33(8): 1565-1576.e5, 2021 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-34081912

RESUMEN

Emerging evidence points toward an intricate relationship between the pandemic of coronavirus disease 2019 (COVID-19) and diabetes. While preexisting diabetes is associated with severe COVID-19, it is unclear whether COVID-19 severity is a cause or consequence of diabetes. To mechanistically link COVID-19 to diabetes, we tested whether insulin-producing pancreatic ß cells can be infected by SARS-CoV-2 and cause ß cell depletion. We found that the SARS-CoV-2 receptor, ACE2, and related entry factors (TMPRSS2, NRP1, and TRFC) are expressed in ß cells, with selectively high expression of NRP1. We discovered that SARS-CoV-2 infects human pancreatic ß cells in patients who succumbed to COVID-19 and selectively infects human islet ß cells in vitro. We demonstrated that SARS-CoV-2 infection attenuates pancreatic insulin levels and secretion and induces ß cell apoptosis, each rescued by NRP1 inhibition. Phosphoproteomic pathway analysis of infected islets indicates apoptotic ß cell signaling, similar to that observed in type 1 diabetes (T1D). In summary, our study shows SARS-CoV-2 can directly induce ß cell killing.


Asunto(s)
COVID-19/virología , Diabetes Mellitus/virología , Células Secretoras de Insulina/virología , Neuropilina-1/metabolismo , Receptores Virales/metabolismo , SARS-CoV-2/patogenicidad , Internalización del Virus , Células A549 , Adulto , Anciano , Anciano de 80 o más Años , Enzima Convertidora de Angiotensina 2/metabolismo , Antígenos CD/metabolismo , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , COVID-19/complicaciones , COVID-19/diagnóstico , Estudios de Casos y Controles , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/metabolismo , Femenino , Interacciones Huésped-Patógeno , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Receptores de Transferrina/metabolismo , SARS-CoV-2/metabolismo , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo
15.
Cell Rep Med ; 2(10): 100421, 2021 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-34604819

RESUMEN

Understanding viral tropism is an essential step toward reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, decreasing mortality from coronavirus disease 2019 (COVID-19) and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head and neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head and neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in interferon (IFN)-ß1 levels between smokers and non-smokers.


Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/transmisión , Mucosa Respiratoria/metabolismo , Serina Endopeptidasas/genética , Fumadores , Tropismo Viral , Anciano , Anciano de 80 o más Años , COVID-19/genética , COVID-19/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Cavidad Nasal/metabolismo , SARS-CoV-2/fisiología , Tráquea/metabolismo
16.
In Vivo ; 34(5): 2571-2576, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32871786

RESUMEN

BACKGROUND/AIM: Functional endoscopic sinus surgery (FESS) is frequently conducted for restoring sinus ventilation and function. Postoperative care is critical for success. However, loss to follow-up is disturbing. The specific aim of this study was to identify critical factors contributing to loss of patients to follow-up and how to improve it. PATIENTS AND METHODS: A total of 221 patients with chronic rhinosinusitis undergoing FESS were enrolled. Patients were divided into three groups according to their follow-up after surgery: Less than 1 month (short-term), 1-3 months (medium-term) and more than 3 months (long-term). The gender, age, smoking status, comorbidities, laterality, Lund-Mackay score, 22-question Sinonasal Outcome Test, nasal obstruction Visual Analogue Scale and mucociliary clearance were evaluated for their contribution to better compliance in follow-up. RESULTS: The results revealed that older patients had better compliance in follow-up compared with younger ones (p=0.0093). Other factors were not contributory (p>0.05). CONCLUSION: In contrast to the US, older patients in Taiwan have better compliance in postoperative follow-up, while younger ones require more education on the importance of follow-up.


Asunto(s)
Rinitis , Sinusitis , Anciano , Enfermedad Crónica , Endoscopía , Estudios de Seguimiento , Humanos , Rinitis/epidemiología , Rinitis/cirugía , Sinusitis/epidemiología , Sinusitis/cirugía , Taiwán/epidemiología , Resultado del Tratamiento
17.
Sci Rep ; 10(1): 18635, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-33122743

RESUMEN

Evidence shows that chronic rhinosinusitis (CRS) is associated with prior presence of autoimmune diseases; however, large-scale population-based studies in the literature are limited. We conducted a population-based case-control study investigating the association between CRS and premorbid autoimmune diseases by using the National Health Insurance Research Database in Taiwan. The CRS group included adult patients newly diagnosed with CRS between 2001 and 2013. The date of diagnosis was defined as the index date. The comparison group included individuals without CRS, with 1:4 frequency matching for gender, age, and index year. Premorbid diseases were forward traced to 1996. Univariate and multivariate logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals. The CRS group consisted of 30,611 patients, and the comparison group consisted of 122,444 individuals. Patients with CRS had a higher significant association with premorbid autoimmune diseases (adjusted OR 1.39 [1.28-1.50]). Specifically, patients with CRS had a higher significant association with ankylosing spondylitis, polymyositis, psoriasis, rheumatoid arthritis, sicca syndrome, and systemic lupus erythematosus (adjusted OR 1.49 [1.34-1.67], 3.47 [1.12-10.8], 1.22 [1.04-1.43], 1.60 [1.31-1.96], 2.10 [1.63-2.72], and 1.69 [1.26-2.25]). In subgroup analysis, CRS with and without nasal polyps demonstrated a significant association with premorbid autoimmune diseases (adjusted OR 1.34 [1.14-1.58] and 1.50 [1.38-1.62]). In addition, CRS with fungal and non-fungal infections also demonstrated a significant association with premorbid autoimmune diseases (adjusted OR 2.02 [1.72-2.49] and 1.39 [1.28-1.51]). In conclusion, a significant association between CRS and premorbid autoimmune diseases has been identified. These underlying mechanisms need further investigation.


Asunto(s)
Enfermedades Autoinmunes/complicaciones , Vigilancia de la Población , Sinusitis/complicaciones , Adulto , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven
18.
Nat Commun ; 11(1): 5453, 2020 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-33116139

RESUMEN

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Infecciones por Coronavirus/patología , Expresión Génica/efectos de los fármacos , Peptidil-Dipeptidasa A/genética , Neumonía Viral/patología , Sistema Respiratorio/patología , Factores de Edad , Enzima Convertidora de Angiotensina 2 , COVID-19 , Cilios/metabolismo , Infecciones por Coronavirus/virología , Células Endoteliales , Células Caliciformes/metabolismo , Humanos , Pulmón/patología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Sistema Respiratorio/metabolismo , Sistema Respiratorio/virología , Factores Sexuales , Sinusitis/metabolismo , Fumar
19.
medRxiv ; 2020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32511516

RESUMEN

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.

20.
Eur J Pharmacol ; 578(2-3): 123-36, 2008 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-17961544

RESUMEN

The ability of the sigma(1) receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma(1) receptor ligands vary more than 50-fold. The potential of the sigma(1) receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma(1) receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D(4) receptor selective compounds bind sigma(1) receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma(1) receptor were confirmed with our screening assay.


Asunto(s)
Butirofenonas/metabolismo , Fármacos del Sistema Nervioso Central/farmacología , Clonación Molecular , Dopaminérgicos/metabolismo , Ensayo de Unión Radioligante , Receptores de Dopamina D4/metabolismo , Receptores sigma/metabolismo , Unión Competitiva , Butirofenonas/química , Butirofenonas/farmacología , Línea Celular Tumoral , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/metabolismo , Dopaminérgicos/química , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Fluvoxamina/metabolismo , Haloperidol/análogos & derivados , Haloperidol/metabolismo , Humanos , Ligandos , Metanfetamina/metabolismo , Estructura Molecular , Pentazocina/metabolismo , Progesterona/metabolismo , Unión Proteica , Receptores de Dopamina D4/efectos de los fármacos , Receptores sigma/efectos de los fármacos , Receptores sigma/genética , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Transfección , Tritio , Receptor Sigma-1
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