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1.
J Clin Invest ; 131(17)2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34623327

RESUMEN

Defining the correlates of protection necessary to manage the COVID-19 pandemic requires the analysis of both antibody and T cell parameters, but the complexity of traditional tests limits virus-specific T cell measurements. We tested the sensitivity and performance of a simple and rapid SARS-CoV-2 spike protein-specific T cell test based on the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by cytokine (IFN-γ, IL-2) measurement in different cohorts including BNT162b2-vaccinated individuals (n = 112), convalescent asymptomatic and symptomatic COVID-19 patients (n = 130), and SARS-CoV-1-convalescent individuals (n = 12). The sensitivity of this rapid test is comparable to that of traditional methods of T cell analysis (ELISPOT, activation-induced marker). Using this test, we observed a similar mean magnitude of T cell responses between the vaccinees and SARS-CoV-2 convalescents 3 months after vaccination or virus priming. However, a wide heterogeneity of the magnitude of spike-specific T cell responses characterized the individual responses, irrespective of the time of analysis. The magnitude of these spike-specific T cell responses cannot be predicted from the neutralizing antibody levels. Hence, both humoral and cellular spike-specific immunity should be tested after vaccination to define the correlates of protection necessary to evaluate current vaccine strategies.


Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19 , Inmunidad Celular/efectos de los fármacos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Linfocitos T , Adulto , COVID-19/sangre , COVID-19/inmunología , COVID-19/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/sangre , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo
2.
PLoS One ; 16(10): e0258255, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34624024

RESUMEN

This study aimed to assess the prevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) total antibodies in the north, middle, and south regions of West Bank and the prevalence of SARS-CoV-2 specific antibodies (IgA, IgM, and IgG) in the Palestinian population. This was a cross-sectional study. The serological and epidemiological data of 1269 persons were assessed. Participants were selected randomly among primary health care center attendees in Palestine between November 1, 2020 and December 31, 2020. All serum samples were tested for total antibodies using an enzyme-linked immunosorbent assay (ELISA) test. IgM, IgG, and IgA-specific antibody titers were measured using ELISA. The overall prevalence (with 95% confidence intervals [CIs]) of SARS-CoV-2 total antibodies and specific antibodies were estimated. A multivariate regression model was used to assess the predictive factors for SARS-CoV-2-specific antibodies. The overall seroprevalence of SARS-CoV-2 antibodies was 24·0% (95% CI, 21·7%-26·5%). Seroprevalence was significantly higher among people living in south West Bank (adjusted Odds ratio [aOR], 2·22; 95% CI: 1·58-3·11), people who had COVID-19 symptoms (aOR, 3·92; 95% CI, 2·83-5·43), people with a COVID-19 contact history (aOR, 1·44; 95% CI, 1·03-2·03), patients with hypertension (aOR, 1·57; 95% CI, 1·06-2·33), and non-smokers (aOR, 0·47; 95% CI, 0·31-0·72). A total of 171 blood samples from SARS-CoV-2-positive patients were chosen at random for additional serological testing. Specific IgM, IgG, and IgA antibodies were positive in 14·0% (95% CI, 9·2%-20·2%), 88·3% (82·5%-92·7%), and 42·1% (34·6%-59·9%) of the samples, respectively. SARS-CoV-2 antibodies were common among PHC center attendees and were significantly associated to sex, smoking, and COVID-19 contact history. However, considering that almost three-quarters of this population remains susceptible, maintaining public health measures and encouraging access to immunization is critical in protecting this population.


Asunto(s)
Anticuerpos Antivirales/sangre , Árabes , Prueba Serológica para COVID-19 , COVID-19 , SARS-CoV-2/metabolismo , Adulto , Anciano , COVID-19/sangre , COVID-19/diagnóstico , COVID-19/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia
3.
Oxid Med Cell Longev ; 2021: 5513868, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34646423

RESUMEN

COVID-19 is a widespread global pandemic with nearly 185 million confirmed cases and about four million deaths. It is caused by an infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily affects the alveolar type II pneumocytes. The infection induces pathological responses including increased inflammation, oxidative stress, and apoptosis. This situation results in impaired gas exchange, hypoxia, and other sequelae that lead to multisystem organ failure and death. As summarized in this article, many interventions and therapeutics have been proposed and investigated to combat the viral infection-induced inflammation and oxidative stress that contributes to the etiology and pathogenesis of COVID-19. However, these methods have not significantly improved treatment outcomes. This may partly be attributable to their inability at restoring redox and inflammatory homeostasis, for which molecular hydrogen (H2), an emerging novel medical gas, may complement. Herein, we systematically review the antioxidative, anti-inflammatory, and antiapoptotic mechanisms of H2. Its small molecular size and nonpolarity allow H2 to rapidly diffuse through cell membranes and penetrate cellular organelles. H2 has been demonstrated to suppress NF-κB inflammatory signaling and induce the Nrf2/Keap1 antioxidant pathway, as well as to improve mitochondrial function and enhance cellular bioenergetics. Many preclinical and clinical studies have demonstrated the beneficial effects of H2 in varying diseases, including COVID-19. However, the exact mechanisms, primary modes of action, and its true clinical effects remain to be delineated and verified. Accordingly, additional mechanistic and clinical research into this novel medical gas to combat COVID-19 complications is warranted.


Asunto(s)
COVID-19 , Hidrógeno/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , SARS-CoV-2/metabolismo , Transducción de Señal/efectos de los fármacos , COVID-19/tratamiento farmacológico , COVID-19/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo
4.
Pak J Pharm Sci ; 34(3(Supplementary)): 1119-1126, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-34602441

RESUMEN

The pandemic Coronavirus (Covid-19) is continuously growing and spreading at the highest rate in all over the world. So, it is necessary to produce the new medicinal agents against this virus. The aim of the present study is to design a potent compound against COVID-19. Based on 3C-like main protease and recently developed solved structure (PDB ID: 6Y2F), a series of remdesivir analogs are designed and analyzed by employing molecular modeling against the SARS-CoV-2 by insilico approach. The molecular dynamics (MD) simulation for 500ps was performed to check the stability and orientation to inside the binding pocket for analogs R3, R9, R14 and R15. The study results exhibit that compsound R9 has strong interaction or least binding energy (-10.04kcal/mol) as compare to the other analogues due to the presences of methyl bromide and it may be useful to further investigation in vitro testing against Covid-19.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Adenosina Monofosfato/uso terapéutico , Alanina/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Pandemias/prevención & control , SARS-CoV-2/metabolismo , Proteínas no Estructurales Virales/metabolismo
5.
Sci Rep ; 11(1): 19675, 2021 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-34608231

RESUMEN

Kidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney's critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.


Asunto(s)
Lesión Renal Aguda/patología , Biomarcadores/orina , COVID-19/inmunología , Insuficiencia Renal Crónica/patología , Lesión Renal Aguda/complicaciones , Adulto , Anciano , Antígenos CD/orina , Biomarcadores/sangre , Antígeno Ca-125/orina , COVID-19/mortalidad , COVID-19/patología , COVID-19/virología , Quimiocinas CC/sangre , Estudios Transversales , Femenino , Humanos , Interleucina-12/orina , Interleucina-6/sangre , Masculino , Proteínas de la Membrana/orina , Persona de Mediana Edad , Polipéptido alfa Relacionado con Calcitonina/sangre , Insuficiencia Renal Crónica/complicaciones , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/sangre
6.
Eur Phys J E Soft Matter ; 44(10): 123, 2021 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-34613523

RESUMEN

We present a novel technique to predict binding affinity trends between two molecules from atomistic molecular dynamics simulations. The technique uses a neural network algorithm applied to a series of images encoding the distance between two molecules in time. We demonstrate that our algorithm is capable of separating with high accuracy non-hydrophobic mutations with low binding affinity from those with high binding affinity. Moreover, we show high accuracy in prediction using a small subset of the simulation, therefore requiring a much shorter simulation time. We apply our algorithm to the binding between several variants of the SARS-CoV-2 spike protein and the human receptor ACE2.


Asunto(s)
Inteligencia Artificial , Modelos Moleculares , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , Humanos , Conformación Proteica
7.
Dis Markers ; 2021: 6803510, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34603560

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.


Asunto(s)
COVID-19/metabolismo , Quimiotaxis , Monocitos/patología , Neutrófilos/patología , Sistemas de Lectura Abierta/fisiología , Neumonía/patología , Proteínas Virales/metabolismo , Células A549 , Quimiocina CCL2/metabolismo , Humanos , Técnicas In Vitro , Monocitos/inmunología , Monocitos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neumonía/inmunología , Neumonía/metabolismo , SARS-CoV-2/metabolismo , Proteínas Virales/genética
8.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34484128

RESUMEN

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Asunto(s)
COVID-19/metabolismo , Cardiomiopatías/metabolismo , Grasa Intraabdominal/metabolismo , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/complicaciones , COVID-19/inmunología , Cardiomiopatías/inmunología , Cardiomiopatías/patología , Cardiopatías/inmunología , Cardiopatías/metabolismo , Cardiopatías/patología , Humanos , Inflamación , Grasa Intraabdominal/patología , Obesidad/complicaciones , Obesidad/inmunología , Obesidad/patología , Pericardio , Pronóstico , SARS-CoV-2/metabolismo , Serina Endopeptidasas/metabolismo
9.
Sci Rep ; 11(1): 17534, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34475438

RESUMEN

The COVID-19 pandemic threatens indigenous peoples living in suburban areas of large Brazilian cities and has thus far intensified their pre-existing socio-economic inequalities. We evaluated the epidemiological situation of SARS-CoV-2 infection among residents of the biggest urban multiethnic indigenous community of the Amazonas state, Brazil. Blood samples of 280 indigenous people living in the surrounding area of Manaus were tested for the presence of anti-SARS-CoV-2 IgA or IgG antibodies. The risk factors and sociodemographic information were assessed through an epidemiological questionnaire. We found a total positivity rate of 64.64% (95% CI 59.01-70.28) for SARS-CoV-2 infection. IgA and IgG were detected in 55.71% (95% CI 49.89-61.54) and 60.71% (95% CI 54.98-66.45) of the individuals, respectively. Over 80% of positive individuals were positive for both IgA and IgG.No significant difference in positivity rates between genders or age groups was observed. Moreover, the age group ≥ 60 years old showed the highest antibody ratios (IgA mean ratio = 3.080 ± 1.623; IgG mean ratio = 4.221 ± 1.832), while the age groups 13-19 and 20-29 showed the lowest IgA (mean ratio = 2.268 ± 0.919) and IgG ratios (mean ratio = 2.207 ± 1.246), respectively. Individuals leaving the home more frequently were at higher risk of infection (Odds ratio (OD) 2.61; 95% CI 1.00-1.49; p = 0.048). Five or more individuals per household increased fivefold the risk of virus transmission (OR 2.56; 95% CI 1.09-6.01; p = 0.019). The disproportionate dissemination of SARS-CoV-2 infection observed among the study population might be driven by typical cultural behavior and socioeconomic inequalities. Despite the pandemic threat, this population is not being targeted by public policies and appears to be chronically invisible to the Brazilian authorities.


Asunto(s)
Prueba Serológica para COVID-19 , COVID-19 , Pueblos Indígenas , Pandemias , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Brasil/epidemiología , Brasil/etnología , COVID-19/sangre , COVID-19/epidemiología , COVID-19/etnología , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad
10.
Sci Rep ; 11(1): 17594, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34475485

RESUMEN

Supplemental vitamin D can reduce the risk and mortality of viral pneumonia. The relationship between 25 hydroxyvitamin D [25(OH)D] levels and the severity and mortality of Coronavirus disease 2019 (COVID-19) was evaluated. In this cross-sectional study, the admitted patients with COVID-19 were categorized as mild, moderate, severe, and critical based on clinical and radiologic characteristics. Calcium, phosphorus, albumin, creatinine, and serum 25(OH)D were measured and their correlation with the severity of disease and mortality were analyzed. During 2 months, 508 patients (442 patients in general wards and 66 patients in the intensive care unit (ICU)) were included. The participants were 56 ± 17 years old (52% male, 37% with comorbidity). Concerning severity, 13%, 42%, 36%, and 9% had mild, moderate, severe, and critical diseases, respectively. The mortality rate was 10.8%. Admission to ICU, severity of disease and mortality decreased significantly across quartiles of 25(OH)D. According to multivariate logistic regression analysis, disease mortality had a positive correlation with age and had a negative correlation with the serum level of 25(OH)D, calcium, and albumin. In hospitalized patients with COVID-19, low 25(OH)D was associated with severe disease and increased ICU admission and mortality rate.


Asunto(s)
COVID-19/sangre , COVID-19/mortalidad , SARS-CoV-2/metabolismo , Índice de Severidad de la Enfermedad , Vitamina D/análogos & derivados , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina D/sangre
11.
Sci Rep ; 11(1): 17642, 2021 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-34480056

RESUMEN

SARS-CoV-2 is considered a global emergency, resulting in an exacerbated crisis in the health public in the world. Although there are advances in vaccine development, it is still limited for many countries. On the other hand, an immunological response that mediates protective immunity or indicates that predict disease outcome in SARS-CoV-2 infection remains undefined. This work aimed to assess the antibody levels, avidity, and subclasses of IgG to RBD protein, in symptomatic patients with severe and mild forms of COVID-19 in Brazil using an adapted in-house RBD-IgG ELISA. The RBD IgG-ELISA showed 100% of specificity and 94.3% of sensibility on detecting antibodies in the sera of hospitalized patients. Patients who presented severe COVID-19 had higher anti-RBD IgG levels compared to patients with mild disease. Additionally, most patients analyzed displayed low antibody avidity, with 64.4% of the samples of patients who recovered from the disease and 84.6% of those who died in this avidity range. Our data also reveals an increase of IgG1 and IgG3 levels since the 8th day after symptoms onset, while IgG4 levels maintained less detectable during the study period. Surprisingly, patients who died during 8-14 and 15-21 days also showed higher anti-RBD IgG4 levels in comparison with the recovered (P < 0.05), suggesting that some life-threatening patients can elicit IgG4 to RBD antibody response in the first weeks of symptoms onset. Our findings constitute the effort to clarify IgG antibodies' kinetics, avidity, and subclasses against SARS-CoV-2 RBD in symptomatic patients with COVID-19 in Brazil, highlighting the importance of IgG antibody avidity in association with IgG4 detection as tool laboratory in the follow-up of hospitalized patients with more significant potential for life-threatening.


Asunto(s)
Anticuerpos Antivirales , Afinidad de Anticuerpos , COVID-19 , Inmunoglobulina G , SARS-CoV-2 , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Brasil/epidemiología , COVID-19/sangre , COVID-19/epidemiología , COVID-19/inmunología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo
12.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-34470866

RESUMEN

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development.


Asunto(s)
Vacunas contra la COVID-19/administración & dosificación , COVID-19/virología , Macaca mulatta/inmunología , Nanopartículas/química , Receptores Virales/metabolismo , SARS-CoV-2/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/biosíntesis , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Ferritinas/química , SARS-CoV-2/metabolismo , Linfocitos T/inmunología
13.
Oxid Med Cell Longev ; 2021: 7866992, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34497683

RESUMEN

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is posing a great threat to the global economy and public health security. Together with the acknowledged angiotensin-converting enzyme 2, glucose-regulated protein 78, transferrin receptor, AXL, kidney injury molecule-1, and neuropilin 1 are also identified as potential receptors to mediate SARS-CoV-2 infection. Therefore, how to inhibit or delay the binding of SARS-CoV-2 with the abovementioned receptors is a key step for the prevention and treatment of COVID-19. As the third gasotransmitter, hydrogen sulfide (H2S) plays an important role in many physiological and pathophysiological processes. Recently, survivors were reported to have significantly higher H2S levels in COVID-19 patients, and mortality was significantly greater among patients with decreased H2S levels. Considering that the beneficial role of H2S against COVID-19 and COVID-19-induced comorbidities and multiorgan damage has been well-examined and reported in some excellent reviews, this review will discuss the recent findings on the potential receptors of SARS-CoV-2 and how H2S modulates the above receptors, in turn blocking SARS-CoV-2 entry into host cells.


Asunto(s)
Antivirales/farmacología , Sulfuro de Hidrógeno/farmacología , Receptores de Superficie Celular/metabolismo , SARS-CoV-2/metabolismo , Animales , Humanos , Especificidad de Órganos/efectos de los fármacos , Sustancias Protectoras/farmacología , SARS-CoV-2/efectos de los fármacos
14.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-34502086

RESUMEN

In recent years, enzymes have risen as promising therapeutic tools for different pathologies, from metabolic deficiencies, such as fibrosis conditions, ocular pathologies or joint problems, to cancer or cardiovascular diseases. Treatments based on the catalytic activity of enzymes are able to convert a wide range of target molecules to restore the correct physiological metabolism. These treatments present several advantages compared to established therapeutic approaches thanks to their affinity and specificity properties. However, enzymes present some challenges, such as short in vivo half-life, lack of targeted action and, in particular, patient immune system reaction against the enzyme. For this reason, it is important to monitor serum immune response during treatment. This can be achieved by conventional techniques (ELISA) but also by new promising tools such as microarrays. These assays have gained popularity due to their high-throughput analysis capacity, their simplicity, and their potential to monitor the immune response of patients during enzyme therapies. In this growing field, research is still ongoing to solve current health problems such as COVID-19. Currently, promising therapeutic alternatives using the angiotensin-converting enzyme 2 (ACE2) are being studied to treat COVID-19.


Asunto(s)
Enzima Convertidora de Angiotensina 2/uso terapéutico , COVID-19/tratamiento farmacológico , Terapia Enzimática/métodos , Proteínas Recombinantes/uso terapéutico , Enzima Convertidora de Angiotensina 2/farmacología , Ensayos Clínicos Fase II como Asunto , Composición de Medicamentos/métodos , Estabilidad de Enzimas , Terapia Enzimática/historia , Terapia Enzimática/tendencias , Semivida , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Proteínas Recombinantes/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , Resultado del Tratamiento , Internalización del Virus/efectos de los fármacos
15.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-34502139

RESUMEN

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of the COVID19 pandemic. The SARS-CoV-2 genome encodes for a small accessory protein termed Orf9b, which targets the mitochondrial outer membrane protein TOM70 in infected cells. TOM70 is involved in a signaling cascade that ultimately leads to the induction of type I interferons (IFN-I). This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70. Binding of Orf9b to TOM70 decreases the expression of IFN-I; however, the underlying mechanism remains elusive. We show that the binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. We characterized the binding site of Orf9b within the C-terminal domain of TOM70 and found that a serine in position 53 of Orf9b and a glutamate in position 477 of TOM70 are crucial for the association of both proteins. A phosphomimetic variant Orf9bS53E showed drastically reduced binding to TOM70 and did not inhibit Hsp90 recruitment, suggesting that Orf9b-TOM70 complex formation is regulated by phosphorylation. Eventually, we identified the N-terminal TPR domain of TOM70 as a second binding site for Orf9b, which indicates a so far unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.


Asunto(s)
COVID-19/transmisión , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , SARS-CoV-2/patogenicidad , Animales , Sitios de Unión/genética , COVID-19/inmunología , COVID-19/virología , Chlorocebus aethiops , Proteínas de la Nucleocápside de Coronavirus/genética , Proteínas de la Nucleocápside de Coronavirus/inmunología , Proteínas de la Nucleocápside de Coronavirus/aislamiento & purificación , Humanos , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/aislamiento & purificación , Mutación , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Fosfoproteínas/aislamiento & purificación , Fosfoproteínas/metabolismo , Fosforilación , Unión Proteica/genética , Unión Proteica/inmunología , Dominios Proteicos/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Células Vero
16.
Int J Biol Macromol ; 190: 636-648, 2021 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-34517025

RESUMEN

SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/química , COVID-19/tratamiento farmacológico , Proteínas de la Nucleocápside de Coronavirus/química , ADN Helicasas/química , Decitabina/química , Mesilato de Imatinib/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteínas de Unión a Poli-ADP-Ribosa/química , ARN Helicasas/química , Proteínas con Motivos de Reconocimiento de ARN/química , Proteínas de Unión al ARN/química , SARS-CoV-2/química , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , COVID-19/metabolismo , Proteínas de la Nucleocápside de Coronavirus/metabolismo , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/metabolismo , Decitabina/farmacología , Sistemas de Liberación de Medicamentos , Genómica , Mesilato de Imatinib/farmacología , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/antagonistas & inhibidores , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Proteínas de Unión al ARN/antagonistas & inhibidores , Proteínas de Unión al ARN/metabolismo , SARS-CoV-2/metabolismo
17.
Biochemistry ; 60(40): 2978-2986, 2021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34570469

RESUMEN

The SARS-CoV-2 spike protein is the primary antigenic determinant of the virus and has been studied extensively, yet the process of membrane fusion remains poorly understood. The fusion domain (FD) of viral glycoproteins is well established as facilitating the initiation of membrane fusion. An improved understanding of the structural plasticity associated with these highly conserved regions aids in our knowledge of the molecular mechanisms that drive viral fusion. Within the spike protein, the FD of SARS-CoV-2 exists immediately following S2' cleavage at the N-terminus of the S2 domain. Here we have shown that following the introduction of a membrane at pH 7.4, the FD undergoes a transition from a random coil to a more structurally well-defined postfusion state. Furthermore, we have classified the domain into two distinct regions, a fusion peptide (FP, S816-G838) and a fusion loop (FL, D839-F855). The FP forms a helix-turn-helix motif upon association with a membrane, and the favorable entropy gained during this transition from a random coil is likely the driving force behind membrane insertion. Membrane depth experiments then revealed the FP is found inserted within the membrane below the lipid headgroups, while the interaction of the FL with the membrane is shallower in nature. Thus, we propose a structural model relevant to fusion at the plasma membrane in which the FP inserts itself just below the phospholipid headgroups and the FL lays upon the lipid membrane surface.


Asunto(s)
Membrana Celular/metabolismo , Fusión de Membrana/fisiología , Modelos Biológicos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , COVID-19/genética , COVID-19/metabolismo , Membrana Celular/genética , Humanos , Unión Proteica/fisiología , SARS-CoV-2/química , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética
18.
Front Immunol ; 12: 636966, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34557180

RESUMEN

Since 2003, the world has been confronted with three new betacoronaviruses that cause human respiratory infections: SARS-CoV, which causes severe acute respiratory syndrome (SARS), MERS-CoV, which causes Middle East respiratory syndrome (MERS), and SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19). The mechanisms of coronavirus transmission and dissemination in the human body determine the diagnostic and therapeutic strategies. An important problem is the possibility that viral particles overcome tissue barriers such as the intestine, respiratory tract, blood-brain barrier, and placenta. In this work, we will 1) consider the issue of endocytosis and the possibility of transcytosis and paracellular trafficking of coronaviruses across tissue barriers with an emphasis on the intestinal epithelium; 2) discuss the possibility of antibody-mediated transcytosis of opsonized viruses due to complexes of immunoglobulins with their receptors; 3) assess the possibility of the virus transfer into extracellular vesicles during intracellular transport; and 4) describe the clinical significance of these processes. Models of the intestinal epithelium and other barrier tissues for in vitro transcytosis studies will also be briefly characterized.


Asunto(s)
Endocitosis , Mucosa Intestinal/virología , SARS-CoV-2/metabolismo , Anticuerpos Antivirales/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , COVID-19/transmisión , COVID-19/virología , Ensayos Clínicos como Asunto , Endocitosis/efectos de los fármacos , Humanos , Mucosa Intestinal/metabolismo , Modelos Biológicos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Uniones Estrechas/metabolismo , Uniones Estrechas/virología , Transcitosis/efectos de los fármacos , Acoplamiento Viral
19.
Sci Rep ; 11(1): 19140, 2021 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-34580409

RESUMEN

Despite the reported low expression of the primary SARS-CoV-2 receptor ACE2 in distinct ocular tissues, some clinical evidence suggests that SARS-CoV-2 can infect the eye. In this study, we explored potential entry sites for SARS-CoV-2 by viral S protein histochemistry on various ocular tissues and compared the staining patterns with RNA and protein expression of TMPRSS2 and ACE2. Potential viral entry sites were investigated by histochemistry using tagged recombinant viral S protein on 52 ocular tissue samples including specimens of the cornea, conjunctiva, lid margin, lacrimal gland tissue, retina, choroid, and RPE. In addition, ACE2 and TMPRSS2 immunohistochemistry were performed on the same ocular tissue, each with distinct antibodies binding to different epitopes. Lung tissue samples were used as positive controls. Finally, bulk RNA sequencing (RNA-Seq) was used to determine the expression of ACE2 and its auxiliary factors in the tissues mentioned above. S protein histochemistry revealed a positive staining in lung tissue but absent staining in the cornea, the conjunctiva, eye lid samples, the lacrimal glands, the retina and the optic nerve which was supported by hardly any immunoreactivity for ACE2 and TMPRSS2 and scarce ACE2 and TMPRSS2 RNA expression. Negligible staining with antibodies targeting ACE2 or TMPRSS2 was seen in the main and accessory lacrimal glands. In contrast, ocular staining (S protein, ACE2, TMPRSS2) was distinctly present in pigmented cells of the RPE and choroid, as well as in the ciliary body and the iris stroma. S protein histochemistry revealed hardly any SARS-CoV-2 entry sites in all ocular tissues examined. Similarly, no significant ACE2 or TMPRSS2 expression was found in extra- and intraocular tissue. While this study suggest a rather low risk of ocular infection with SARS-CoV-2, it should be noted, that potential viral entry sites may increase in response to inflammation or in certain disease states.


Asunto(s)
COVID-19/prevención & control , Conjuntiva/metabolismo , Córnea/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/virología , Conjuntiva/virología , Córnea/virología , Perfilación de la Expresión Génica/métodos , Humanos , Inmunohistoquímica/métodos , RNA-Seq/métodos , SARS-CoV-2/fisiología , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Internalización del Virus
20.
Cell Res ; 31(10): 1047-1060, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34465913

RESUMEN

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike's S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike's receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~103 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 106 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.


Asunto(s)
COVID-19/diagnóstico , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Resistencia a la Tracción , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , COVID-19/terapia , COVID-19/virología , Humanos , Concentración de Iones de Hidrógeno , Inmunización Pasiva , Simulación de Dinámica Molecular , Unión Proteica , Dominios Proteicos/inmunología , Subunidades de Proteína/química , Subunidades de Proteína/inmunología , Subunidades de Proteína/metabolismo , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Internalización del Virus
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