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Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.
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Vacunas contra la COVID-19 , COVID-19 , Células B de Memoria , SARS-CoV-2 , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/aislamiento & purificación , Anticuerpos Antivirales/uso terapéutico , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , Modelos Animales de Enfermedad , Humanos , Células B de Memoria/inmunología , Ratones , Pruebas de Neutralización , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.
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Anticuerpos Neutralizantes/inmunología , COVID-19/virología , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Neutralizantes/ultraestructura , Anticuerpos Antivirales/inmunología , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/metabolismo , Epítopos/inmunología , Humanos , Ratones , Ratones Transgénicos , Pruebas de Neutralización , Pandemias , Unión Proteica , Dominios Proteicos , Receptores Virales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Emergence of various circulating SARS-CoV-2 variants of concern (VOCs) promotes the identification of pan-sarbecovirus vaccines and broadly neutralizing antibodies (bNAbs). Here, to characterize monoclonal antibodies cross-reactive against both SARS-CoV-1 and SARS-CoV-2 and to search the criterion for bNAbs against all emerging SARS-CoV-2, we isolated several SARS-CoV-1-cross-reactive monoclonal antibodies (mAbs) from a wildtype SARS-CoV-2 convalescent donor. These antibodies showed broad binding capacity and cross-neutralizing potency against various SARS-CoV-2 VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but failed to efficiently neutralize Omicron variant and its sublineages. Structural analysis revealed how Omicron sublineages, but not other VOCs, efficiently evade an antibody family cross-reactive against SARS-CoV-1 through their escape mutations. Further evaluation of a series of SARS-CoV-1/2-cross-reactive bNAbs showed a negative correlation between the neutralizing activities against SARS-CoV-1 and SARS-CoV-2 Omicron variant. Together, these results suggest the necessity of using cross-neutralization against SARS-CoV-1 and SARS-CoV-2 Omicron as criteria for rational design and development of potent pan-sarbecovirus vaccines and bNAbs.
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COVID-19 , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Vacunas , Humanos , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Monoclonales , Anticuerpos ampliamente neutralizantes , Anticuerpos Antivirales , Glicoproteína de la Espiga del CoronavirusRESUMEN
Colorectal carcinoma (CRC) remains a huge challenge in clinical treatment due to tumor metastasis and recurrence. Stem cell-like colon tumor-repopulating cells (TRCs) are a subpopulation of cancer cells with highly tumorigenic and chemotherapy resistant properties. The core transcription factor c-Myc is essential for maintaining cancer stem-like cell phenotypes, yet its roles and regulatory mechanisms remain unclear in colon TRCs. We report that elevated c-Myc protein supported formation and growth of TRC spheroids. The tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) suppressed c-Myc expression to inhibit TRC expansion and self-renewal. Particularly, DAB2IP disrupted c-Myc stability through glycogen synthase kinase 3ß/protein phosphatase 2A-B56α-mediated phosphorylation and dephosphorylation cascade on c-Myc protein, leading to its eventual degradation through the ubiquitin-proteasome pathway. The expression of DAB2IP was negatively correlated with c-Myc in CRC specimens. Overall, our results improved mechanistic insight into how DAB2IP suppressed TRC growth and self-renewal.
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Proteínas de Unión al Calcio/metabolismo , Neoplasias del Colon/patología , Células Madre Neoplásicas/fisiología , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Animales , Proliferación Celular , Autorrenovación de las Células/fisiología , Neoplasias del Colon/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HCT116 , Células HT29 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/patología , Fenotipo , Fosforilación , Pronóstico , Proteína Fosfatasa 2/metabolismo , Esferoides Celulares/fisiologíaRESUMEN
Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.
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Betacoronavirus , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Humanos , Inflamación/prevención & control , Medicina Tradicional China , Pandemias/prevención & control , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , SARS-CoV-2 , Internalización del Virus , Replicación ViralRESUMEN
BACKGROUND: Due to the high morbidity and poor clinical outcomes, early predictive and prognostic biomarker identification is desiderated in colorectal cancer (CRC). As a homologue of the Deleted in Colorectal Cancer (DCC) gene, the role of Neogenin-1 (NEO1) in CRC remained unveiled. This study was designed to probe into the effects and potential function of NEO1 in CRC. METHODS: Online databases, Gene Set Enrichment Analysis (GSEA), quantitative real-time PCR and western blotting were used to evaluate NEO1 expression in colorectal cancer tissues. Survival analysis was performed to predict the prognosis of CRC patients based on NEO1 expression level. Then, cell proliferation was detected by colony formation and Cell Counting Kit 8 (CCK-8) assays. CRC cell migration and invasion were examined by transwell assays. Finally, we utilized the Gene Set Variation Analysis (GSVA) and GSEA to dig the potential mechanisms of NEO1 in CRC. RESULTS: Oncomine database and The Cancer Genome Atlas (TCGA) database showed that NEO1 was down-regulated in CRC. Further results validated that NEO1 mRNA and protein expression were both significantly lower in CRC tumor tissues than in the adjacent tissues in our clinical samples. NEO1 expression was decreased with the progression of CRC. Survival and other clinical characteristic analyses exhibited that low NEO1 expression was related with poor prognosis. A gain-of-function study showed that overexpression of NEO1 restrained proliferation, migration and invasion of CRC cells while a loss-of-function showed the opposite effects. Finally, functional pathway enrichment analysis revealed that NEO1 low expression samples were enriched in inflammation-related signaling pathways, EMT and angiogenesis. CONCLUSION: A tumor suppressor gene NEO1 was identified and verified to be correlated with the prognosis and progression of CRC, which could serve as a prognostic biomarker for CRC patients.
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BACKGROUND: At present, novel coronavirus disease 2019 (COVID-19) has become a serious global public health problem. The current meta-analysis aimed to find risk factors for the COVID-19-related death, helping to enhance the efficacy and reduce the mortality of COVID-19. METHODS: We searched PubMed, Embase, medRxiv, and Cochrane Library for articles published between January 1, 2020, and April 13, 2020. We statistically analyzed the risk factors of the COVID-19 deceased with meta-analysis. RESULTS: A total of 2401 patients in 15 articles were included in this study. Meta-analysis showed that 66.6% of COVID-19 deceased were male, with a median age of 69.9 years. Common symptoms of deceased included fever (70.6-100%), dyspnea (38.89-85.7%), cough (22.4-78%), and fatigue (22-61.9%). The incidence of hypertension, chronic cardiovascular disease, diabetes, and chronic cerebrovascular disease among the COVID-19 deceased were 38.56% (95% confidence interval (CI) 25.84 ~ 52.12%), 17.54% (95% CI 13.38 ~ 21.69%), 22.2% (95% CI 19.30 ~ 25.10%), and 15.58% (95% CI 10.05 ~ 21.12%), respectively. Compared with the surviving COVID-19 patients, the deceased had lower platelet levels (mean difference (MD) = - 39.35, 95% CI - 55.78 ~ - 22.93) and higher C-reactive protein (CRP) (MD = 80.85, 95% CI 62.53 ~ 99.18) and lactate dehydrogenase (LDH) (MD = 246.65, 95% CI 157.43 ~ 335.88) at admission. The most common complications of the deceased were acute respiratory distress syndrome (ARDS) (OR = 100.36, 95% CI 64.44 ~ 156.32) and shock (OR = 96.60, 95% CI 23.80 ~ 392.14). CONCLUSION: Most of the COVID-19 deceased were elderly males. Fever, dyspnea, dry cough, fatigue, hypertension, chronic cardiovascular and cerebrovascular disease, diabetes, and laboratory examinations showed low levels of platelet content, increased CRP and LDH were associated with the risk of dying. ARDS and shock were risk factors for death in COVID-19 patients.
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Enfermedades Cardiovasculares/epidemiología , Infecciones por Coronavirus , Diabetes Mellitus/epidemiología , Pandemias , Neumonía Viral , Anciano , Betacoronavirus , COVID-19 , Causas de Muerte , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/fisiopatología , Femenino , Humanos , Incidencia , Masculino , Mortalidad , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Neumonía Viral/fisiopatología , Factores de Riesgo , SARS-CoV-2 , Factores Sexuales , Evaluación de Síntomas/estadística & datos numéricosRESUMEN
BACKGROUND/AIMS: The apoptosis of activated hepatic stellate cells (HSCs) is the central event in the reversal of liver fibrosis. K63 de-ubiquitinated receptor-interacting protein (RIP)1 promotes apoptosis in tumor necrosis factor (TNF)-α signaling pathway. In the previous study, we have proved that indole-3-carbinol (I3C) could reverse different models of liver fibrosis in rats, but the mechanism is still unclear. Thus, the present research aimed to demonstrate the induction of I3C on apoptosis of HSCs and the underlying molecular mechanism. METHODS: HSC-T6, an immortalized rat liver stellate cell line, was treated for 24 hours with 25, 50 and 100 µM of I3C. The apoptosis of HSC-T6 was analyzed by flow cytometric analysis, acridine orange staining and RT-PCR, respectively. K63 de-ubiquitination of RIP1 and the expression of ubiquitin ligases and deubiquitinases were analyzed by Co-IP assay and western blot. Knockdown of deubiquitinases was undertaken by small interfering RNA (siRNA). RESULTS: The results of flow cytometric analysis indicated that the apoptotic rate of HSC-T6 was induced by I3C in a dose-dependent manner. Observation by acridine orange staining exhibited nuclear condensation and apoptotic bodies in I3C treated cells. Consistently, the expression ratio of Bax/bcl-2 was markedly increased by I3C. These results indicated that I3C could significantly induce apoptosis of HSC-T6 cells. Furthermore, Co-IP assay revealed K63 de-ubiquitination of RIP1 by I3C, associated with the induction of caspase 8. Although I3C had no effect on the expression of ubiquitin ligases cellular inhibitor of apoptosis 1/2 (cIAP1/2), the protein level of deubiquitinase cylindromatosis (CYLD) was significantly induced by I3C. Moreover, CYLD silencing reversed the pro-apoptosis induction effect of I3C and reduced the expression ratio of Bax/bcl-2 in HSC-T6 cells. CONCLUSION: These results demonstrated that I3C could induce apoptosis of HSC through RIP1 K63 de-ubiquitination by upregulating deubiquitinase CYLD.
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Apoptosis/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Indoles/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Ubiquitinación/efectos de los fármacos , Animales , Línea Celular Tumoral , Enzimas Desubicuitinizantes/metabolismo , Relación Dosis-Respuesta a Droga , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Histidine biosynthesis in Corynebacterium glutamicum is regulated not only by feedback inhibition by the first enzyme in the pathway, but also by repression control of the synthesis of the histidine enzymes. C. glutamicum histidine genes are located and transcribed in two unlinked loci, hisEG and hisDCB-orf1-orf2-hisHA-impA-hisFI. We constructed plasmid pK18hisDPtac to replace the native hisD promoter with the tac promoter, and overexpressed phosphoribosyl-ATP-pyrophosphohydrolase, encoded by hisE, and ATP-phosphoribosyltransferase, encoded by hisG. The L-histidine titer at 0.85 g l(-1) was 80 % greater in the transformed bacterium and production of byproducts, L-alanine and L-tryptophan, was significantly decreased. However, accumulation of glutamic acid increased by 58 % (2.8 g l(-1)). This study represents the first attempt to substitute the histidine biosynthesis pathway promoter in the chromosome with a stronger promoter to increase histidine production.
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Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Histidina/biosíntesis , ATP Fosforribosil Transferasa/genética , ATP Fosforribosil Transferasa/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Biotecnología , Corynebacterium glutamicum/enzimología , Fermentación , Histidina/genética , Redes y Vías Metabólicas , Plásmidos/genética , Regiones Promotoras GenéticasRESUMEN
Interleukin-35 (IL-35)-producing B cells (IL-35+B cells) play an important role in diseases, and the expansion of IL-35+ immune cells have been observed in inflammatory bowel disease (IBD). However, how IL-35+B cells function and the manner in which they perform their roles remain unclear. In this study, human samples and animal models were used to confirm the expansion of IL-35+B cells during IBD. In addition, by using il12a-/- and ebi3-/- mice, we demonstrated that the regulatory role of B cells in IBD depends on IL-35. Mechanically, IL-35+B cells can promote its own expansion through endocrine actions and depend on the transcription factor signal transducer and activator of transcription 3. Interestingly, we found that the diversity of intestinal microbes and expression of microbial metabolites decreased during IBD. IL-35+B cells promote the high expression of indoleacetic acid (IAA), and exogenous metabolite supplementation with IAA can further promote the expansion of IL-35+B cells and rescues the disease. This study provides a new concept for the regulatory model of B cells and a new approach for the treatment of IBD.
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Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.
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COVID-19 , SARS-CoV-2 , Animales , Ratones , Anticuerpos , Anticuerpos ampliamente neutralizantes , Mutación/genética , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
The inactivation of tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) by epigenetic and post-transcriptional modification has been reported in multiple human malignancies. DNA methyltransferase 3A (DNMT3A) is involved in de novo establishment of DNA methylation and plays a vital role in tumorigenesis. However, whether DNMT3A can regulate colorectal cancer (CRC) progression via modulation of DAB2IP remains unclear. In this study, we revealed that DNMT3A was significantly increased in CRC, predicting a poor overall survival. Functionally, ectopic expression of DNMT3A in CRC cells enhanced cell proliferation, whereas DNMT3A knockdown had the opposite effect by inducing cell cycle arrest. Mechanistically, methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) proved that the expression of DAB2IP was epigenetically suppressed by DNMT3A-mediated promoter methylation in CRC cells. Using dual-luciferase reporter assay and ChIP-PCR assay, we further confirmed that DNMT3A restrained the transcriptional activity of DAB2IP promoter through directly binging to it. In addition, DNMT3A could activate the MEK/ERK signaling pathway via efficiently downregulating DAB2IP. Inhibition of the MEK/ERK cascade abrogated the oncogenic effects of DNMT3A on CRC cells. In conclusion, our study demonstrates that DNMT3A facilitates CRC progression by regulating DAB2IP mediated MEK/ERK activation, providing promising targets for CRC treatment.
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Neoplasias Colorrectales/patología , ADN Metiltransferasa 3A/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Metilación de ADN , ADN Metiltransferasa 3A/antagonistas & inhibidores , ADN Metiltransferasa 3A/genética , Humanos , Pronóstico , Piridonas/farmacología , Pirimidinonas/farmacología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Proteínas Activadoras de ras GTPasa/antagonistas & inhibidores , Proteínas Activadoras de ras GTPasa/genéticaRESUMEN
Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.
RESUMEN
New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes ß-coronavirus lineage B (ß-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional "down" conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD "up". Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-ß-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against ß-CoV-B and newly emerging SARS-CoV-2 variants of concern.
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COVID-19 , SARS-CoV-2 , Enzima Convertidora de Angiotensina 2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Epítopos , Humanos , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism. However, the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored. In this article, we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody-FcγR complexes. We further explain how its spike (S) protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin, TMPRSS2, and cathepsins. We then review the ongoing experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds with anti-SARS-CoV-2 activity, and discuss how these antiviral therapies targeting host-pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle (6-HB) fusion core. Finally, the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.
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COVID-19/metabolismo , COVID-19/terapia , Interacciones Huésped-Patógeno , SARS-CoV-2/fisiología , Acoplamiento Viral , Internalización del Virus , COVID-19/epidemiología , COVID-19/patología , HumanosRESUMEN
BACKGROUND: Ischemic colitis (IC) was investigated to be associated with dyslipidemia and subcutaneous adipose tissue. Nonalcoholic fatty liver disease (NAFLD) is associated with ischemic diseases such as coronary heart disease, ischemic stroke. But there is a paucity of data regarding the association between NAFLD and IC. NAFLD may be associated with the treatment and prognosis of IC. We investigated risk factors and characteristics associated with NAFLD in patients with IC. METHODS: Patients with IC (NAFLD: 34 and controls: 81) from Zhongnan Hospital were investigated retrospectively from January 2012 to December 2018. Clinical data were compared by chi-square tests or independent samples T-tests. Binary logistic regressions and Kaplan-Meier analysis were performed to evaluate risk factors and prognosis, respectively. RESULTS: NAFLD was diagnosed in 28.19% patients with IC. In the logistic regression analysis, hypertension [odds ratio (OR) 3.523; P = 0.019], elevated alanine aminotransferase (ALT) (OR 6.278; P = 0.048), elevated triglyceride (OR 4.667; P = 0.003) and increased weight (OR 1.055; P = 0.039) were risk factors of NAFLD in patients with IC. Patients with NAFLD were more likely to require the vasodilators (P = 0.011) and get a relapse of IC (P = 0.011). CONCLUSION: NAFLD was found in 28.19% of patients with IC. Hypertension, increased weight, elevated ALT and triglyceride are independent predictors of NAFLD in patients with IC. NAFLD in patients with IC is associated with a greater probability of requiring for the vasodilators. NAFLD in IC and period of bowel rest are risk factors for the recurrence of IC.
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Colitis Isquémica , Hipertensión , Enfermedad del Hígado Graso no Alcohólico , Alanina Transaminasa , Colitis Isquémica/diagnóstico , Colitis Isquémica/epidemiología , Colitis Isquémica/etiología , Humanos , Hipertensión/epidemiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Triglicéridos , VasodilatadoresRESUMEN
The main symptoms of coronavirus disease 2019 (COVID-19) are respiratory manifestations, while some confirmed patients developed gastrointestinal symptoms or even initially presented digestive symptoms. The link between pneumonia and gastrointestinal symptoms caused by severe acute respiratory symptoms coronavirus 2 focused our attention on the concept of 'gut-lung axis'. In this review, we discuss the inevitability and possible mechanisms of the occurrence of intestinal symptoms or intestinal dysfunction in COVID-19 from the perspective of the gut-lung axis, as well as the influence of the imbalance of intestinal homeostasis on the respiratory symptoms of COVID-19. The interaction between lung and intestine might lead to a vicious cycle of pulmonary and intestinal inflammation which may be a potential factor leading to the death of patients with COVID-19.
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Dolor Abdominal/fisiopatología , COVID-19/fisiopatología , Diarrea/fisiopatología , Intestinos/fisiopatología , Pulmón/fisiopatología , Vómitos/fisiopatología , Heces/virología , Microbioma Gastrointestinal/inmunología , Humanos , Mucosa Intestinal/inmunología , Intestinos/inmunología , Pulmón/inmunología , Mucosa Respiratoria/inmunología , SARS-CoV-2RESUMEN
Several potent neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus have been identified. However, antibody-dependent enhancement (ADE) has not been comprehensively studied for SARS-CoV-2, and the relationship between enhancing versus neutralizing activities and antibody epitopes remains unknown. Here, we select a convalescent individual with potent IgG neutralizing activity and characterize his antibody response. Monoclonal antibodies isolated from memory B cells target four groups of five non-overlapping receptor-binding domain (RBD) epitopes. Antibodies to one group of these RBD epitopes mediate ADE of entry in Raji cells via an Fcγ receptor-dependent mechanism. In contrast, antibodies targeting two other distinct epitope groups neutralize SARS-CoV-2 without ADE, while antibodies against the fourth epitope group are poorly neutralizing. One antibody, XG014, potently cross-neutralizes SARS-CoV-2 variants, as well as SARS-CoV-1, with respective IC50 (50% inhibitory concentration) values as low as 5.1 and 23.7 ng/mL, while not exhibiting ADE. Therefore, neutralization and ADE of human SARS-CoV-2 antibodies correlate with non-overlapping RBD epitopes.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Acrecentamiento Dependiente de Anticuerpo , Epítopos/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/uso terapéutico , Reacciones Antígeno-Anticuerpo , COVID-19/inmunología , COVID-19/virología , Línea Celular , Niño , Análisis por Conglomerados , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Persona de Mediana Edad , Dominios Proteicos/inmunología , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto Joven , Tratamiento Farmacológico de COVID-19RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.
Asunto(s)
COVID-19/prevención & control , Especificidad de Órganos/genética , Feniltiohidantoína/análogos & derivados , SARS-CoV-2/efectos de los fármacos , Serina Endopeptidasas/genética , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Benzamidas , COVID-19/epidemiología , COVID-19/virología , Línea Celular Tumoral , Células Cultivadas , Expresión Génica/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Masculino , Ratones Noqueados , Nitrilos , Pandemias , Feniltiohidantoína/farmacología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/virología , Unión Proteica/efectos de los fármacos , SARS-CoV-2/fisiología , Serina Endopeptidasas/metabolismoRESUMEN
OBJECTIVES: An outbreak of novel coronavirus in 2019 threatens the health of people, and there is no proven pharmacological treatment. Although corticosteroids were widely used during outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, their efficacy remainedhighly controversial. We aimed to further evaluate the influence of corticosteroids on patients with coronavirus infection. METHODS: We conducted a comprehensive search of literature published in PubMed, Embase, Cochrane library, and China National Knowledge Infrastructure (CNKI) from January 1, 2002 to March 15, 2020. All statistical analyses in this study were performed on stata14.0. RESULTS: A total of 5270 patients from 15 studies were included in this meta-analysis. The result indicated that critical patients were more likely to require corticosteroids therapy (risk ratio [RR]â¯=â¯1.56, 95% confidence interval [CI]â¯=â¯1.28-1.90, P<0.001). However, corticosteroid treatment was associated with higher mortality (RRâ¯=â¯2.11, 95%CIâ¯=â¯1.13-3.94, Pâ¯=â¯0.019), longer length of stay (weighted mean difference [WMD]â¯=â¯6.31, 95%CIâ¯=â¯5.26-7.37, P<0.001), a higher rate of bacterial infection (RRâ¯=â¯2.08, 95%CIâ¯=â¯1.54-2.81, P<0.001), and hypokalemia (RRâ¯=â¯2.21, 95%CIâ¯=â¯1.07-4.55, Pâ¯=â¯0.032) but not hyperglycemia (RRâ¯=â¯1.37, 95%CI=0.68-2.76, P = 0.376) or hypocalcemia (RRâ¯=â¯1.35, 95%CIâ¯=â¯0.77-2.37, Pâ¯=â¯0.302). CONCLUSIONS: Patients with severe conditions are more likely to require corticosteroids. Corticosteroid use is associated with increased mortality in patients with coronavirus pneumonia.