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1.
Immunology ; 167(4): 528-543, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36065677

RESUMO

We evaluated the kinetics of antibody responses to Two years into the COVID-19 pandemic and 1 year after the start of vaccination rollout, the world faced a peak of cases associated with the highly contagious Omicron variant of concern (VoC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) and nucleocapsid (N) antigens over five cross-sectional visits (January-November 2021), and the determinants of pre-booster immunoglobulin levels, in a prospective cohort of vaccinated primary health care workers in Catalonia, Spain. Antibodies against S antigens after a full primary vaccination course, mostly with BNT162b2, decreased steadily over time and were higher in pre-exposed (n = 247) than naïve (n = 200) individuals, but seropositivity was maintained at 100% (100% IgG, 95.5% IgA, 30.6% IgM) up to 319 days after the first dose. Antibody binding to variants of concern was highly maintained for IgG compared to wild type but significantly reduced for IgA and IgM, particularly for Beta and Gamma. Factors significantly associated with longer-term antibodies included age, sex, occupation, smoking, adverse reaction to vaccination, levels of pre-vaccination SARS-CoV-2 antibodies, interval between disease onset and vaccination, hospitalization, oxygen supply, post COVID and symptomatology. Earlier morning vaccination hours were associated with higher IgG responses in pre-exposed participants. Symptomatic breakthroughs occurred in 9/447 (2.01%) individuals, all among naïve (9/200, 4.5%) and generally boosted antibody responses. Additionally, an increase in IgA and/or IgM seropositivity to variants, and N seroconversion at later time points (6.54%), indicated asymptomatic breakthrough infections, even among pre-exposed. Seropositivity remained highly stable over almost a year after vaccination. However, gradually waning of anti-S IgGs that correlate with neutralizing activity, coupled to evidence of an increase in breakthrough infections during the Delta and Omicron predominance, provides a rationale for booster immunization.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Vacinas contra COVID-19 , COVID-19/prevenção & controle , Estudos Longitudinais , Estudos Transversais , Vacina BNT162 , Pandemias , Estudos Prospectivos , Vacinação , Anticorpos Antivirais , Atenção Primária à Saúde , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M , Anticorpos Neutralizantes
2.
BMC Med ; 20(1): 379, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36224590

RESUMO

This study evaluated the persistence of IgM, IgA, and IgG to SARS-CoV-2 spike and nucleocapsid antigens up to 616 days since the onset of symptoms in a longitudinal cohort of 247 primary health care workers from Barcelona, Spain, followed up since the start of the pandemic. The study also assesses factors affecting antibody levels, including comorbidities and the responses to variants of concern as well as the frequency of reinfections. Despite a gradual and significant decline in antibody levels with time, seropositivity to five SARS-CoV-2 antigens combined was always higher than 90% over the whole study period. In a subset of 23 participants who had not yet been vaccinated by November 2021, seropositivity remained at 95.65% (47.83% IgM, 95.65% IgA, 95.65% IgG). IgG seropositivity against Alpha and Delta predominant variants was comparable to that against the Wuhan variant, while it was lower for Gamma and Beta (minority) variants and for IgA and IgM. Antibody levels at the time point closest to infection were associated with age, smoking, obesity, hospitalization, fever, anosmia/hypogeusia, chest pain, and hypertension in multivariable regression models. Up to 1 year later, just before the massive roll out of vaccination, antibody levels were associated with age, occupation, hospitalization, duration of symptoms, anosmia/hypogeusia, fever, and headache. In addition, tachycardia and cutaneous symptoms associated with slower antibody decay, and oxygen supply with faster antibody decay. Eight reinfections (3.23%) were detected in low responders, which is consistent with a sustained protective role for anti-spike naturally acquired antibodies. Stable persistence of IgG and IgA responses and cross-recognition of the predominant variants circulating in the 2020-2021 period indicate long-lasting and largely variant-transcending humoral immunity in the initial 20.5 months of the pandemic, in the absence of vaccination.


Assuntos
Ageusia , COVID-19 , Anosmia , Anticorpos Antivirais , COVID-19/epidemiologia , Humanos , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M , Oxigênio , Reinfecção , SARS-CoV-2
3.
BMC Med ; 20(1): 347, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36109713

RESUMO

BACKGROUND: Heterogeneity of the population in relation to infection, COVID-19 vaccination, and host characteristics is likely reflected in the underlying SARS-CoV-2 antibody responses. METHODS: We measured IgM, IgA, and IgG levels against SARS-CoV-2 spike and nucleocapsid antigens in 1076 adults of a cohort study in Catalonia between June and November 2020 and a second time between May and July 2021. Questionnaire data and electronic health records on vaccination and COVID-19 testing were available in both periods. Data on several lifestyle, health-related, and sociodemographic characteristics were also available. RESULTS: Antibody seroreversion occurred in 35.8% of the 64 participants non-vaccinated and infected almost a year ago and was related to asymptomatic infection, age above 60 years, and smoking. Moreover, the analysis on kinetics revealed that among all responses, IgG RBD, IgA RBD, and IgG S2 decreased less within 1 year after infection. Among vaccinated, 2.1% did not present antibodies at the time of testing and approximately 1% had breakthrough infections post-vaccination. In the post-vaccination era, IgM responses and those against nucleoprotein were much less prevalent. In previously infected individuals, vaccination boosted the immune response and there was a slight but statistically significant increase in responses after a 2nd compared to the 1st dose. Infected vaccinated participants had superior antibody levels across time compared to naïve-vaccinated people. mRNA vaccines and, particularly the Spikevax, induced higher antibodies after 1st and 2nd doses compared to Vaxzevria or Janssen COVID-19 vaccines. In multivariable regression analyses, antibody responses after vaccination were predicted by the type of vaccine, infection age, sex, smoking, and mental and cardiovascular diseases. CONCLUSIONS: Our data support that infected people would benefit from vaccination. Results also indicate that hybrid immunity results in superior antibody responses and infection-naïve people would need a booster dose earlier than previously infected people. Mental diseases are associated with less efficient responses to vaccination.


Assuntos
COVID-19 , Vacinas Virais , Formação de Anticorpos , COVID-19/prevenção & controle , Teste para COVID-19 , Vacinas contra COVID-19 , Estudos de Coortes , Humanos , Imunoglobulina A , Imunoglobulina G , Imunoglobulina M , Pessoa de Meia-Idade , Nucleoproteínas , SARS-CoV-2 , Espanha/epidemiologia , Vacinação , Vacinas Virais/farmacologia
4.
J Infect Dis ; 223(1): 62-71, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33175145

RESUMO

BACKGROUND: At the COVID-19 spring 2020 pandemic peak in Spain, prevalence of SARS-CoV-2 infection in a cohort of 578 randomly selected health care workers (HCWs) from Hospital Clínic de Barcelona was 11.2%. METHODS: A follow-up survey 1 month later (April-May 2020) measured infection by rRT-PCR and IgM, IgA, and IgG to the receptor-binding domain of the spike protein by Luminex. Antibody kinetics, including IgG subclasses, was assessed until month 3. RESULTS: At month 1, the prevalence of infection measured by rRT-PCR and serology was 14.9% (84/565) and seroprevalence 14.5% (82/565). We found 25 (5%) new infections in 501 participants without previous evidence of infection. IgM, IgG, and IgA levels declined in 3 months (antibody decay rates 0.15 [95% CI, .11-.19], 0.66 [95% CI, .54-.82], and 0.12 [95% CI, .09-.16], respectively), and 68.33% of HCWs had seroreverted for IgM, 3.08% for IgG, and 24.29% for IgA. The most frequent subclass responses were IgG1 (highest levels) and IgG2, followed by IgG3, and only IgA1 but no IgA2 was detected. CONCLUSIONS: Continuous and improved surveillance of SARS-CoV-2 infections in HCWs remains critical, particularly in high-risk groups. The observed fast decay of IgA and IgM levels has implications for seroprevalence studies using these isotypes.


Assuntos
Anticorpos Antivirais/sangue , COVID-19/imunologia , Pessoal de Saúde , Adulto , Estudos Transversais , Feminino , Seguimentos , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Cinética , Masculino , Pessoa de Meia-Idade , Soroconversão , Estudos Soroepidemiológicos , Espanha/epidemiologia
5.
BMC Med ; 19(1): 155, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183003

RESUMO

We assessed the duration and baseline determinants of antibody responses to SARS-CoV-2 spike antigens and the occurrence of reinfections in a prospective cohort of 173 Spanish primary health care worker patients followed initially for 9 months and subsequently up to 12.5 months after COVID-19 symptoms onset. Seropositivity to SARS-CoV-2 spike and receptor-binding domain antigens up to 149-270 days was 92.49% (90.17% IgG, 76.3% IgA, 60.69% IgM). In a subset of 64 health care workers who had not yet been vaccinated by April 2021, seropositivity was 96.88% (95.31% IgG, 82.81% IgA) up to 322-379 days post symptoms onset. Four suspected reinfections were detected by passive case detection, two among seronegative individuals (5 and 7 months after the first episode), and one low antibody responder. Antibody levels significantly correlated with fever, hospitalization, anosmia/hypogeusia, allergies, smoking, and occupation. Stable sustainment of IgG responses raises hope for long-lasting COVID-19 vaccine immunity.


Assuntos
COVID-19/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Adulto , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Reinfecção/sangue , Reinfecção/epidemiologia , Reinfecção/virologia , SARS-CoV-2/isolamento & purificação , Estudos Soroepidemiológicos , Espanha/epidemiologia
6.
BMC Med ; 19(1): 309, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34809617

RESUMO

BACKGROUND: Surveillance tools to estimate viral transmission dynamics in young populations are essential to guide recommendations for school opening and management during viral epidemics. Ideally, sensitive techniques are required to detect low viral load exposures among asymptomatic children. We aimed to estimate SARS-CoV-2 infection rates in children and adult populations in a school-like environment during the initial COVID-19 pandemic waves using an antibody-based field-deployable and non-invasive approach. METHODS: Saliva antibody conversion defined as ≥ 4-fold increase in IgM, IgA, and/or IgG levels to five SARS-CoV-2 antigens including spike and nucleocapsid constructs was evaluated in 1509 children and 396 adults by high-throughput Luminex assays in samples collected weekly in 22 summer schools and 2 pre-schools in 27 venues in Barcelona, Spain, from June 29th to July 31st, 2020. RESULTS: Saliva antibody conversion between two visits over a 5-week period was 3.22% (49/1518) or 2.36% if accounting for potentially cross-reactive antibodies, six times higher than the cumulative infection rate (0.53%) assessed by weekly saliva RT-PCR screening. IgG conversion was higher in adults (2.94%, 11/374) than children (1.31%, 15/1144) (p=0.035), IgG and IgA levels moderately increased with age, and antibodies were higher in females. Most antibody converters increased both IgG and IgA antibodies but some augmented either IgG or IgA, with a faster decay over time for IgA than IgG. Nucleocapsid rather than spike was the main antigen target. Anti-spike antibodies were significantly higher in individuals not reporting symptoms than symptomatic individuals, suggesting a protective role against COVID-19. CONCLUSION: Saliva antibody profiling including three isotypes and multiplexing antigens is a useful and user-friendlier tool for screening pediatric populations to detect low viral load exposures among children, particularly while they are not vaccinated and vulnerable to highly contagious variants, and to recommend public health policies during pandemics.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Antivirais , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G , Pandemias , Saliva , Instituições Acadêmicas , Espanha/epidemiologia , Glicoproteína da Espícula de Coronavírus
7.
J Clin Microbiol ; 59(2)2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33127841

RESUMO

Reliable serological tests are required to determine the prevalence of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to characterize immunity to the disease in order to address key knowledge gaps in the coronavirus disease 2019 (COVID-19) pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and enzyme-linked immunosorbent assays (ELISAs) with their higher precision, dynamic range, throughput, miniaturization, cost-efficiency, and multiplexing capacity. We developed three qSAT assays for IgM, IgA, and IgG against a panel of eight SARS-CoV-2 antigens, including spike protein (S), nucleocapsid protein (N), and membrane protein (M) constructs. The assays were optimized to minimize the processing time and maximize the signal-to-noise ratio. We evaluated their performances using 128 prepandemic plasma samples (negative controls) and 104 plasma samples from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 5 were asymptomatic, 51 had mild symptoms, and 48 were hospitalized. Preexisting IgG antibodies recognizing N, M, and S proteins were detected in negative controls, which is suggestive of cross-reactivity to common-cold coronaviruses. The best-performing antibody/antigen signatures had specificities of 100% and sensitivities of 95.78% at ≥14 days and 95.65% at ≥21 days since the onset of symptoms, with areas under the curve (AUCs) of 0.977 and 0.999, respectively. Combining multiple markers as assessed by qSAT assays has the highest efficiency, breadth, and versatility to accurately detect low-level antibody responses for obtaining reliable data on the prevalence of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody correlates of immunity and their kinetics, required for vaccine development to combat the COVID-19 pandemic.


Assuntos
Antígenos Virais/imunologia , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Isotipos de Imunoglobulinas/sangue , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , COVID-19/sangue , Reações Cruzadas , Feminino , Humanos , Imunoensaio , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Estruturais Virais/imunologia
8.
Eur Biophys J ; 50(3-4): 411-427, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33881594

RESUMO

Microscale thermophoresis (MST), and the closely related Temperature Related Intensity Change (TRIC), are synonyms for a recently developed measurement technique in the field of biophysics to quantify biomolecular interactions, using the (capillary-based) NanoTemper Monolith and (multiwell plate-based) Dianthus instruments. Although this technique has been extensively used within the scientific community due to its low sample consumption, ease of use, and ubiquitous applicability, MST/TRIC has not enjoyed the unambiguous acceptance from biophysicists afforded to other biophysical techniques like isothermal titration calorimetry (ITC) or surface plasmon resonance (SPR). This might be attributed to several facts, e.g., that various (not fully understood) effects are contributing to the signal, that the technique is licensed to only a single instrument developer, NanoTemper Technology, and that its reliability and reproducibility have never been tested independently and systematically. Thus, a working group of ARBRE-MOBIEU has set up a benchmark study on MST/TRIC to assess this technique as a method to characterize biomolecular interactions. Here we present the results of this study involving 32 scientific groups within Europe and two groups from the US, carrying out experiments on 40 Monolith instruments, employing a standard operation procedure and centrally prepared samples. A protein-small molecule interaction, a newly developed protein-protein interaction system and a pure dye were used as test systems. We characterized the instrument properties and evaluated instrument performance, reproducibility, the effect of different analysis tools, the influence of the experimenter during data analysis, and thus the overall reliability of this method.


Assuntos
Benchmarking , Laboratórios , Calorimetria , Reprodutibilidade dos Testes , Temperatura
9.
Blood ; 123(26): 4111-9, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24786774

RESUMO

Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma/metabolismo , Mutação de Sentido Incorreto , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/metabolismo , Substituição de Aminoácidos , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína X Associada a bcl-2/genética
11.
Microsc Microanal ; 21(5): 1264-70, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26235380

RESUMO

The inflammatory resorption of dental root apex (i.e., the process of removal of cementum and/or dentine through the activity of resorbing cells) may show different configurations and damage the apical root structure. As knowing the morphology of resorption areas of human teeth is essential for the success of endodontic treatments, we investigated the apical resorption by scanning electron microscopy, focusing on roots with granulomas. A total of 30 teeth (with penetrating carious lesions and chronic periapical lesions) were examined, the apical third of the roots were removed and analyzed to estimate periforaminal and foraminal resorption, shape and morphology of foramen resorption, centering of the periforaminal resorption area, and diameters of each apical foramen. Periforaminal resorption was present in all samples, whereas foraminal resorption was present in 92% of cases (mainly funnel shaped). Lacunae were observed in the foraminal resorption area with an average diameter of 35±14 µm. The major and minor diameters of the foramina in teeth with resorption were 443 and 313 µm, respectively (higher than in healthy teeth). This result indicates an expansion of the apical diameters caused by the pathology, which could encourage a different clinical instrumentation for these teeth.


Assuntos
Granuloma/complicações , Microscopia Eletrônica de Varredura , Reabsorção da Raiz/patologia , Raiz Dentária/ultraestrutura , Humanos
12.
Med Oral Patol Oral Cir Bucal ; 20(2): e205-10, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25662544

RESUMO

With easy chemical synthesis from its precursor, methamphetamine (MA) is now widespread in many countries. The abuse of methamphetamine is associated with several negative effects on health, because MA is a neurotoxin and a dangerous central nervous system stimulant. It changes levels of neurotransmitters in the brain, releasing dopamine and inhibiting nor epinephrine uptake which increases sympathetic nervous system activity and can lead to cardiac arrhythmia, hypertension and tachypnea. The consequences of MA abuse are clearly manifested in oral diseases (like "meth mouth") which is characterised by extensive caries, teeth grinding with ensuing dental wear and trismus. The present review was designed to fill the gap in knowledge about methamphetamine abuse in the European Union (EU) and to illustrate the main clinical effects of prolonged use. After describing the pharmacology and systemic effects of methamphetamine and concentrating on its effects on the mouth, the present review compares the epidemiology and incidence of abuse in the world, particularly the USA and the EU.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/complicações , Doenças da Boca/induzido quimicamente , Doenças Dentárias/induzido quimicamente , Europa (Continente) , Humanos
13.
J Hist Dent ; 62(3): 116-21, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25951672

RESUMO

Johann Baptist Ritter von Spix (1781-1826), a German zoologist, was famous in his time and highly honored after making one of the first exploration voyages in the wildest part of Brazil. He was almost forgotten in the annals of history for nearly two centuries after his birth, at which time some enlightened biographers brought him back into prominence in both the biological and zoological fields. On the contrary though, he had never been forgotten in the science of odontostomatology thanks to his discovery of the "Lingula Mandibularis" also known as "Spine of Spix". Johannes Baptist Spix was born in Hoechstadt, Germany in 1781. He was the Conservator of the Museum of Natural History in Munich and was a distinguished Comparative Anatomist. He died Munich inl 1826. The purposes of this work are to present some biographical notes on J.B. Ritter von Spix, to explain whythe "Lingula Mandibularis" has been called by the name of Spix and why this eponym has been used as such.


Assuntos
Epônimos , Mandíbula/anatomia & histologia , Anatomia Comparada/história , Alemanha , História do Século XVIII , História do Século XIX , Humanos , Zoologia/história
14.
Microbes Infect ; : 105423, 2024 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-39299570

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) studies usually rely on cross-sectional data of large cohorts but limited repeated samples, overlooking significant inter-individual antibody kinetic differences. By combining Luminex, activation-induced marker (AIM) and IFN-γ/IL-2 Fluorospot assays, we characterized the IgM, IgA, and IgG antibody kinetics using 610 samples from 31 healthy adults over two years after COVID-19 vaccination, and the T-cell responses six months post-booster. Antibody trajectories varied among isotypes: IgG decayed slowly, IgA exhibited an initial sharp decline, which gradually slowed down and stabilized above the seropositivity threshold. Contrarily, IgM rapidly dropped to undetectable levels after primary vaccination. Importantly, three vaccine doses induced higher and more durable anti-spike IgG and IgA levels compared to two doses, whereas infection led to the highest antibody peak and slowest antibody decay rate compared to vaccination. Comparing with ancestral virus, antibody levels recognizing Omicron subvariants had a faster antibody decay. Finally, polyfunctional T cells were positively associated with subsequent IgA responses. These results revealed distinctive antibody patterns by isotype and highlight the benefits of booster doses in enhancing and sustaining antibody responses.

15.
Nat Biotechnol ; 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195987

RESUMO

Microorganisms can be equipped with synthetic genetic programs for the production of targeted therapeutic molecules. Cutibacterium acnes is the most abundant commensal of the human skin, making it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin, in vivo, for the modulation of cutaneous sebum production.

16.
Nat Commun ; 15(1): 3302, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658535

RESUMO

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.


Assuntos
Cicatriz , Colágeno , Fibroblastos , Cicatrização , Peixe-Zebra , Humanos , Animais , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Colágeno/metabolismo , Cicatrização/efeitos dos fármacos , Cicatriz/metabolismo , Cicatriz/patologia , Cicatriz/tratamento farmacológico , Pele/metabolismo , Pele/patologia , Pele/efeitos dos fármacos , Fibrose , Peptídeos/farmacologia , Peptídeos/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos
17.
Nat Commun ; 15(1): 1051, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316751

RESUMO

Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from a COVID-19 convalescent individual infected during the first pandemic wave. 17T2 is a class 1 VH1-58/κ3-20 antibody, derived from a receptor binding domain (RBD)-specific IgA+ memory B cell, with a broad neutralizing activity against former and new SARS-CoV-2 variants, including XBB.1.16 and BA.2.86 Omicron subvariants. Consistently, 17T2 demonstrates in vivo prophylactic and therapeutic activity against Omicron BA.1.1 infection in K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that 17T2 binds the BA.1 spike with the RBD in "up" position and blocks the receptor binding motif, as other structurally similar antibodies do, including S2E12. Yet, unlike S2E12, 17T2 retains its neutralizing activity against all variants tested, probably due to a larger RBD contact area. These results highlight the impact of small structural antibody changes on neutralizing performance and identify 17T2 as a potential candidate for future clinical interventions.


Assuntos
Anticorpos Monoclonais , COVID-19 , Humanos , Animais , Camundongos , SARS-CoV-2 , Microscopia Crioeletrônica , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes , Anticorpos Antivirais , Glicoproteína da Espícula de Coronavírus/genética
18.
J Hist Dent ; 61(1): 37-45, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23691776

RESUMO

Teeth and their pathologies are frequent themes in classical music. The teeth have inspired popular songwriters such as Thomas Crecquillon, Carl Loewe, Amilcare Ponchielli & Christian Sinding; as well as composers whose works are still played all over the world, such as Robert Schumann and Jacques Offenbach. This paper examines several selections in which the inspiring theme is the teeth and the pain they can cause, from the suffering of toothache, to the happier occasion of a baby's first tooth.


Assuntos
Música/história , Dente , Odontalgia/história , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , Humanos
19.
Sci Rep ; 13(1): 3862, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36890175

RESUMO

The characterization of the antibody response to SARS-CoV-2 and its determinants are key for the understanding of COVID-19. The identification of vulnerable populations to the infection and to its socioeconomic impact is indispensable for inclusive policies. We conducted an age-stratified cross-sectional community-based seroprevalence survey between June 12th and 19th 2020-during the easing of lockdown-in Cizur, Spain. We quantified IgG, IgM and IgA levels against SARS-CoV-2 spike and its receptor-binding domain in a sample of 728 randomly selected, voluntarily registered inhabitants. We estimated a 7.9% seroprevalence in the general population, with the lowest seroprevalence among children under ten (n = 3/142, 2.1%) and the highest among adolescents (11-20 years old, n = 18/159, 11.3%). We found a heterogeneous immune-response profile across participants regarding isotype/antigen-specific seropositivity, although levels generally correlated. Those with technical education level were the most financially affected. Fifty-five percent had visited a supermarket and 43% a sanitary centre since mid-February 2020. When comparing by gender, men had left the household more frequently. In conclusion, few days after strict lockdown, the burden of SARS-CoV-2 infection was the lowest in children under 10. The findings also suggest that a wider isotype-antigen panel confers higher sensitivity. Finally, the economic impact biases should be considered when designing public health measures.


Assuntos
COVID-19 , Adolescente , Criança , Masculino , Humanos , Adulto Jovem , Adulto , COVID-19/epidemiologia , SARS-CoV-2 , Espanha/epidemiologia , Estudos Transversais , Estudos Soroepidemiológicos , Controle de Doenças Transmissíveis , Escolaridade , Isotipos de Imunoglobulinas , Anticorpos Antivirais
20.
Microbiol Spectr ; 11(1): e0316522, 2023 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-36622140

RESUMO

The ability of antibodies to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important correlate of protection. For routine evaluation of protection, however, a simple and cost-efficient anti-SARS-CoV-2 serological assay predictive of serum neutralizing activity is needed. We analyzed clinical epidemiological data and blood samples from two cohorts of health care workers in Barcelona and Munich to compare several immunological readouts for evaluating antibody levels that could be surrogates of neutralizing activity. We measured IgG levels against SARS-CoV-2 spike protein (S), its S2 subunit, the S1 receptor binding domain (RBD), and the full length and C terminus of nucleocapsid (N) protein by Luminex, and against RBD by enzyme-linked immunosorbent assay (ELISA), and assessed those as predictors of plasma surrogate-neutralizing activity measured by a flow cytometry assay. In addition, we determined the clinical and demographic factors affecting plasma surrogate-neutralizing capacity. Both cohorts showed a high positive correlation between IgG levels to S antigen, especially to RBD, and the levels of plasma surrogate-neutralizing activity, suggesting RBD IgG as a good correlate of plasma neutralizing activity. Symptomatic infection, with symptoms such as loss of taste, dyspnea, rigors, fever and fatigue, was positively associated with anti-RBD IgG positivity by ELISA and Luminex, and with plasma surrogate-neutralizing activity. Our serological assays allow for the prediction of serum neutralization activity without the cost, hazards, time, and expertise needed for surrogate or conventional neutralization assays. Once a cutoff is established, these relatively simple high-throughput antibody assays will provide a fast and cost-effective method of assessing levels of protection from SARS-CoV-2 infection. IMPORTANCE Neutralizing antibody titers are the best correlate of protection against SARS-CoV-2. However, current tests to measure plasma or serum neutralizing activity do not allow high-throughput screening at the population level. Serological tests could be an alternative if they are proved to be good predictors of plasma neutralizing activity. In this study, we analyzed the SARS-CoV-2 serological profiles of two cohorts of health care workers by applying Luminex and ELISA in-house serological assays. Correlations of both serological tests were assessed between them and with a flow cytometry assay to determine plasma surrogate-neutralizing activity. Both assays showed a high positive correlation between IgG levels to S antigens, especially RBD, and the levels of plasma surrogate-neutralizing activity. This result suggests IgG to RBD as a good correlate of plasma surrogate-neutralizing activity and indicates that serology of IgG to RBD could be used to assess levels of protection from SARS-CoV-2 infection.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Ensaio de Imunoadsorção Enzimática , Anticorpos Neutralizantes , Pessoal de Saúde , Imunoglobulina G , Anticorpos Antivirais
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