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1.
Proc Natl Acad Sci U S A ; 120(52): e2314193120, 2023 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-38109549

RESUMEN

Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Vacunas contra la COVID-19 , Anticuerpos Monoclonales , Epítopos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Glicoproteína de la Espiga del Coronavirus
2.
J Virol ; 83(1): 347-56, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18945787

RESUMEN

C-type lectins play key roles in pathogen recognition, innate immunity, and cell-cell interactions. Here, we report a new C-type lectin (C-type lectin 1) from the shrimp Litopenaeus vannamei (LvCTL1), which has activity against the white spot syndrome virus (WSSV). LvCTL1 is a 156-residue polypeptide containing a C-type carbohydrate recognition domain with an EPN (Glu(99)-Pro(100)-Asn(101)) motif that has a predicted ligand binding specificity for mannose. Reverse transcription-PCR analysis revealed that LvCTL1 mRNA was specifically expressed in the hepatopancreas of L. vannamei. Recombinant LvCTL1 (rLvCTL1) had hemagglutinating activity and ligand binding specificity for mannose and glucose. rLvCTL1 also had a strong affinity for WSSV and interacted with several envelope proteins of WSSV. Furthermore, we showed that the binding of rLvCTL1 to WSSV could protect shrimps from viral infection and prolong the survival of shrimps against WSSV infection. Our results suggest that LvCTL1 is a mannose-binding C-type lectin that binds to envelope proteins of WSSV to exert its antiviral activity. To our knowledge, this is the first report of a shrimp C-type lectin that has direct anti-WSSV activity.


Asunto(s)
Enfermedades de los Animales/prevención & control , Antivirales/farmacología , Lectinas Tipo C/metabolismo , Penaeidae/virología , Virus del Síndrome de la Mancha Blanca 1/efectos de los fármacos , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Perfilación de la Expresión Génica , Glucosa/metabolismo , Hepatopáncreas/metabolismo , Manosa/metabolismo , Datos de Secuencia Molecular , Unión Proteica , Estructura Terciaria de Proteína , Alineación de Secuencia , Análisis de Supervivencia
3.
Fish Shellfish Immunol ; 26(3): 473-82, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19340946

RESUMEN

The NF-kappaB/IkappaBalpha pathway plays an important role in the regulation of immune and inflammatory responses. IkappaBalpha is an inhibitory molecule that sequesters transcription activator NF-kappaB dimer in the cytoplasm of unstimulated cells. Here, we isolated the full-length cDNAs of the mandarin fish (Siniperca chuatsi) alpha inhibitor of NF-kappaB (ScIkappaBalpha) and p65 NF-kappaB (Scp65). Multiple sequence alignments showed that the amino acid sequences of both ScIkappaBalpha and Scp65 contain conserved domains similar to those of mammalian counterparts. Protein pull-down and coimmunoprecipitation assays showed that ScIkappaBalpha directly bound with Scp65. Real-time quantitative PCR analysis showed that ScIkappaBalpha mRNA was constitutive in all mandarin fish tissues detected. After challenge with infectious spleen and kidney necrosis virus (ISKNV), the mRNA level of ScIkappaBalpha was decreased nearly 6 fold in the spleen. This result suggests that the NF-kappaB/IkappaBalpha pathway in mandarin fish may play a role in the immune response against ISKNV.


Asunto(s)
Enfermedades de los Peces/metabolismo , Proteínas I-kappa B/metabolismo , Perciformes/genética , Perciformes/metabolismo , Factor de Transcripción ReIA/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Infecciones por Virus ADN/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Proteínas I-kappa B/química , Iridoviridae/fisiología , Modelos Moleculares , Datos de Secuencia Molecular , Inhibidor NF-kappaB alfa , Unión Proteica , Estructura Terciaria de Proteína , Alineación de Secuencia , Factor de Transcripción ReIA/química
4.
Biochimie ; 165: 210-218, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31401190

RESUMEN

Dysfunction in lipid metabolism may result in a decrease in hepatic autophagy, which contributes to the pathogenesis of non-alcoholic steatohepatitis. ATP-binding cassette transporter A1 transports free cholesterol and phospholipids to apolipoprotein A-I (apoA-I) to form nascent high-density lipoprotein particles. Results from previous studies showed that the overexpression of apoA-I significantly reduced levels of hepatic lipids and endoplasmic reticulum stress by modifying lipid transport. Here, we investigated the effects of apoA-I overexpression on hepatic autophagy in cultured hepatocytes and mice. The overexpression of apoA-I in HepG2 cells resulted in an increase in the levels of autophagy as well as the phosphorylation of AMP-activated protein kinase α (AMPKα) and ULK1 and a decrease in the phosphorylation of mammalian target of rapamycin (mTOR). An AMPK inhibitor and siRNA eliminated this apoA-I effect. Consistently, apoA-I transgenic mice showed increased autophagy and AMPKα phosphorylation. These results suggest that apoA-I overexpression alleviates steatohepatitis by increasing hepatic autophagy through the AMPK-mTOR-ULK1 pathway.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apolipoproteína A-I/fisiología , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Hígado Graso/metabolismo , Hepatocitos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hígado/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Animales , Autofagia , Células Hep G2 , Hepatocitos/citología , Humanos , Metabolismo de los Lípidos , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
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