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1.
Cell ; 186(4): 688-690, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36803601

RESUMEN

Trafficking of live mammals is considered a major risk for emergence of zoonotic viruses. SARS-CoV-2-related coronaviruses have previously been identified in pangolins, the world's most smuggled mammal. A new study identifies a MERS-related coronavirus in trafficked pangolins with broad mammalian tropism and a newly acquired furin cleavage site in Spike.


Asunto(s)
Coronavirus , Pangolines , Animales , Humanos , Quirópteros , COVID-19 , Coronavirus del Síndrome Respiratorio de Oriente Medio , Filogenia , SARS-CoV-2 , Coronavirus/fisiología , Zoonosis
2.
Cell ; 186(4): 850-863.e16, 2023 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-36803605

RESUMEN

It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.


Asunto(s)
Infecciones por Coronavirus , Coronavirus , Dipeptidil Peptidasa 4 , Pangolines , Animales , Humanos , Ratones , Quirópteros , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/virología , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Endopeptidasas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Péptido Hidrolasas/metabolismo , Receptores Virales/metabolismo , Internalización del Virus , Coronavirus/fisiología
3.
Cell ; 185(13): 2279-2291.e17, 2022 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-35700730

RESUMEN

The isolation of CCoV-HuPn-2018 from a child respiratory swab indicates that more coronaviruses are spilling over to humans than previously appreciated. We determined the structures of the CCoV-HuPn-2018 spike glycoprotein trimer in two distinct conformational states and showed that its domain 0 recognizes sialosides. We identified that the CCoV-HuPn-2018 spike binds canine, feline, and porcine aminopeptidase N (APN) orthologs, which serve as entry receptors, and determined the structure of the receptor-binding B domain in complex with canine APN. The introduction of an oligosaccharide at position N739 of human APN renders cells susceptible to CCoV-HuPn-2018 spike-mediated entry, suggesting that single-nucleotide polymorphisms might account for viral detection in some individuals. Human polyclonal plasma antibodies elicited by HCoV-229E infection and a porcine coronavirus monoclonal antibody inhibit CCoV-HuPn-2018 spike-mediated entry, underscoring the cross-neutralizing activity among ɑ-coronaviruses. These data pave the way for vaccine and therapeutic development targeting this zoonotic pathogen representing the eighth human-infecting coronavirus.


Asunto(s)
Coronavirus Humano 229E , Infecciones por Coronavirus , Coronavirus , Animales , Antígenos CD13/química , Antígenos CD13/metabolismo , Gatos , Línea Celular , Coronavirus/metabolismo , Coronavirus Humano 229E/metabolismo , Perros , Humanos , Receptores Virales/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Porcinos
4.
Cell ; 184(17): 4380-4391.e14, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34147139

RESUMEN

Despite the discovery of animal coronaviruses related to SARS-CoV-2, the evolutionary origins of this virus are elusive. We describe a meta-transcriptomic study of 411 bat samples collected from a small geographical region in Yunnan province, China, between May 2019 and November 2020. We identified 24 full-length coronavirus genomes, including four novel SARS-CoV-2-related and three SARS-CoV-related viruses. Rhinolophus pusillus virus RpYN06 was the closest relative of SARS-CoV-2 in most of the genome, although it possessed a more divergent spike gene. The other three SARS-CoV-2-related coronaviruses carried a genetically distinct spike gene that could weakly bind to the hACE2 receptor in vitro. Ecological modeling predicted the co-existence of up to 23 Rhinolophus bat species, with the largest contiguous hotspots extending from South Laos and Vietnam to southern China. Our study highlights the remarkable diversity of bat coronaviruses at the local scale, including close relatives of both SARS-CoV-2 and SARS-CoV.


Asunto(s)
COVID-19/virología , Quirópteros/virología , Coronavirus/genética , Evolución Molecular , SARS-CoV-2/genética , Secuencia de Aminoácidos , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Asia Sudoriental , China , Coronavirus/clasificación , Coronavirus/aislamiento & purificación , Fenómenos Ecológicos y Ambientales , Genoma Viral , Humanos , Modelos Moleculares , Filogenia , SARS-CoV-2/fisiología , Alineación de Secuencia , Análisis de Secuencia de ARN , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Zoonosis Virales
5.
Cell ; 184(1): 184-193.e10, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33232691

RESUMEN

Transcription of SARS-CoV-2 mRNA requires sequential reactions facilitated by the replication and transcription complex (RTC). Here, we present a structural snapshot of SARS-CoV-2 RTC as it transitions toward cap structure synthesis. We determine the atomic cryo-EM structure of an extended RTC assembled by nsp7-nsp82-nsp12-nsp132-RNA and a single RNA-binding protein, nsp9. Nsp9 binds tightly to nsp12 (RdRp) NiRAN, allowing nsp9 N terminus inserting into the catalytic center of nsp12 NiRAN, which then inhibits activity. We also show that nsp12 NiRAN possesses guanylyltransferase activity, catalyzing the formation of cap core structure (GpppA). The orientation of nsp13 that anchors the 5' extension of template RNA shows a remarkable conformational shift, resulting in zinc finger 3 of its ZBD inserting into a minor groove of paired template-primer RNA. These results reason an intermediate state of RTC toward mRNA synthesis, pave a way to understand the RTC architecture, and provide a target for antiviral development.


Asunto(s)
ARN Polimerasa Dependiente de ARN de Coronavirus/química , Microscopía por Crioelectrón , ARN Mensajero/química , ARN Viral/química , SARS-CoV-2/química , Proteinas del Complejo de Replicasa Viral/química , Secuencia de Aminoácidos , Coronavirus/química , Coronavirus/clasificación , Coronavirus/enzimología , ARN Polimerasa Dependiente de ARN de Coronavirus/metabolismo , Metiltransferasas/metabolismo , Modelos Moleculares , ARN Helicasas/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , SARS-CoV-2/enzimología , Alineación de Secuencia , Transcripción Genética , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Replicación Viral
6.
Cell ; 184(1): 106-119.e14, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33333024

RESUMEN

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.


Asunto(s)
COVID-19/genética , Infecciones por Coronavirus/genética , Coronavirus/fisiología , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno , SARS-CoV-2/fisiología , Células A549 , Animales , Vías Biosintéticas/efectos de los fármacos , COVID-19/virología , Línea Celular , Chlorocebus aethiops , Colesterol/biosíntesis , Colesterol/metabolismo , Análisis por Conglomerados , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Resfriado Común/genética , Resfriado Común/virología , Coronavirus/clasificación , Infecciones por Coronavirus/virología , Técnicas de Inactivación de Genes , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Ratones , Fosfatidilinositoles/biosíntesis , Células Vero , Internalización del Virus/efectos de los fármacos , Replicación Viral
7.
Cell ; 184(2): 476-488.e11, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33412089

RESUMEN

Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival. In addition to neutralization of wild-type SARS-CoV-2, patient sera were also able to neutralize the recently emerged SARS-CoV-2 mutant D614G, suggesting cross-protection from reinfection by either strain. However, SARS-CoV-2 sera generally lacked cross-neutralization to a highly homologous pre-emergent bat coronavirus, WIV1-CoV, which has not yet crossed the species barrier. These results highlight the importance of neutralizing humoral immunity on disease progression and the need to develop broadly protective interventions to prevent future coronavirus pandemics.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Biomarcadores/análisis , COVID-19/inmunología , COVID-19/fisiopatología , Adulto , Anticuerpos Neutralizantes/análisis , Anticuerpos Antivirales/análisis , Anticuerpos Antivirales/sangre , Biomarcadores/sangre , COVID-19/sangre , COVID-19/epidemiología , Comorbilidad , Coronavirus/clasificación , Coronavirus/fisiología , Reacciones Cruzadas , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina A/análisis , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , Dominios Proteicos , SARS-CoV-2/química , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Glicoproteína de la Espiga del Coronavirus/química , Análisis de Supervivencia , Resultado del Tratamiento
8.
Cell ; 184(1): 76-91.e13, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-33147444

RESUMEN

Identification of host genes essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may reveal novel therapeutic targets and inform our understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here we performed genome-wide CRISPR screens in Vero-E6 cells with SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), bat CoV HKU5 expressing the SARS-CoV-1 spike, and vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike. We identified known SARS-CoV-2 host factors, including the receptor ACE2 and protease Cathepsin L. We additionally discovered pro-viral genes and pathways, including HMGB1 and the SWI/SNF chromatin remodeling complex, that are SARS lineage and pan-coronavirus specific, respectively. We show that HMGB1 regulates ACE2 expression and is critical for entry of SARS-CoV-2, SARS-CoV-1, and NL63. We also show that small-molecule antagonists of identified gene products inhibited SARS-CoV-2 infection in monkey and human cells, demonstrating the conserved role of these genetic hits across species. This identifies potential therapeutic targets for SARS-CoV-2 and reveals SARS lineage-specific and pan-CoV host factors that regulate susceptibility to highly pathogenic CoVs.


Asunto(s)
Infecciones por Coronavirus/genética , Estudio de Asociación del Genoma Completo , Interacciones Huésped-Patógeno , SARS-CoV-2/fisiología , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/inmunología , COVID-19/virología , Línea Celular , Chlorocebus aethiops , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Coronavirus/clasificación , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Técnicas de Inactivación de Genes , Redes Reguladoras de Genes , Células HEK293 , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Células Vero , Internalización del Virus
9.
Cell ; 182(6): 1401-1418.e18, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32810439

RESUMEN

Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.


Asunto(s)
Infecciones por Coronavirus , Coronavirus , Pandemias , Neumonía Viral , Betacoronavirus , COVID-19 , Citometría de Flujo , Humanos , Complejo de Antígeno L1 de Leucocito , Monocitos , Células Mieloides , Estudios Prospectivos , SARS-CoV-2
10.
Cell ; 181(2): 271-280.e8, 2020 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-32142651

RESUMEN

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos , Cloruro de Amonio/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/química , Betacoronavirus/genética , COVID-19 , Línea Celular , Coronavirus/química , Coronavirus/genética , Coronavirus/fisiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Desarrollo de Medicamentos , Ésteres , Gabexato/análogos & derivados , Gabexato/farmacología , Guanidinas , Humanos , Inmunización Pasiva , Leucina/análogos & derivados , Leucina/farmacología , Pandemias , Peptidil-Dipeptidasa A/química , Receptores Virales/química , Receptores Virales/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Vesiculovirus/genética , Sueroterapia para COVID-19
11.
Cell ; 181(4): 865-876.e12, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32353252

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has highlighted the need for antiviral approaches that can target emerging viruses with no effective vaccines or pharmaceuticals. Here, we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN (prophylactic antiviral CRISPR in human cells), for viral inhibition that can effectively degrade RNA from SARS-CoV-2 sequences and live influenza A virus (IAV) in human lung epithelial cells. We designed and screened CRISPR RNAs (crRNAs) targeting conserved viral regions and identified functional crRNAs targeting SARS-CoV-2. This approach effectively reduced H1N1 IAV load in respiratory epithelial cells. Our bioinformatic analysis showed that a group of only six crRNAs can target more than 90% of all coronaviruses. With the development of a safe and effective system for respiratory tract delivery, PAC-MAN has the potential to become an important pan-coronavirus inhibition strategy.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Sistemas CRISPR-Cas , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , ARN Viral/antagonistas & inhibidores , Células A549 , Profilaxis Antibiótica/métodos , Secuencia de Bases , Betacoronavirus/genética , Betacoronavirus/crecimiento & desarrollo , COVID-19 , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Simulación por Computador , Secuencia Conservada , Coronavirus/efectos de los fármacos , Coronavirus/genética , Coronavirus/crecimiento & desarrollo , Infecciones por Coronavirus/tratamiento farmacológico , Proteínas de la Nucleocápside de Coronavirus , ARN Polimerasa Dependiente de ARN de Coronavirus , Células Epiteliales/virología , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Pulmón/patología , Pulmón/virología , Proteínas de la Nucleocápside/genética , Pandemias , Fosfoproteínas , Filogenia , Neumonía Viral/tratamiento farmacológico , ARN Polimerasa Dependiente del ARN/genética , SARS-CoV-2 , Proteínas no Estructurales Virales/genética
12.
Cell ; 176(5): 1026-1039.e15, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30712865

RESUMEN

Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Although the two antibodies studied blocked attachment to the host cell receptor, only the anti-SARS-CoV S antibody triggered fusogenic conformational changes via receptor functional mimicry. These results provide a structural framework for understanding coronavirus neutralization by human antibodies and shed light on activation of coronavirus membrane fusion, which takes place through a receptor-driven ratcheting mechanism.


Asunto(s)
Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/ultraestructura , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Chlorocebus aethiops , Coronavirus/metabolismo , Infecciones por Coronavirus/inmunología , Células HEK293 , Humanos , Inmunidad Humoral/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Imitación Molecular/inmunología , Unión Proteica , Receptores Virales/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Glicoproteína de la Espiga del Coronavirus/fisiología , Células Vero , Internalización del Virus
13.
Immunity ; 54(5): 1055-1065.e5, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33945786

RESUMEN

Efforts are being made worldwide to understand the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses because of different peptide conformations. T cell receptor (TCR) sequencing indicated that cross-reactivity was driven by private TCR repertoires with a bias for TRBV27 and a long CDR3ß loop. Our findings demonstrate the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Proteínas de la Nucleocápside de Coronavirus/inmunología , Epítopos Inmunodominantes/inmunología , SARS-CoV-2/inmunología , Secuencia de Aminoácidos , Coronavirus/clasificación , Coronavirus/inmunología , Proteínas de la Nucleocápside de Coronavirus/química , Reacciones Cruzadas , Epítopos de Linfocito T/química , Epítopos de Linfocito T/inmunología , Antígeno HLA-B7/química , Antígeno HLA-B7/genética , Antígeno HLA-B7/inmunología , Humanos , Epítopos Inmunodominantes/química , Memoria Inmunológica , Modelos Moleculares , Péptidos/química , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología
15.
Immunity ; 52(5): 734-736, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32392464

RESUMEN

The emergence and rapid global spread of SARS-CoV-2 mark the third such identification of a novel coronavirus capable of causing severe, potentially fatal disease in humans in the 21st century. As noted by Andersen et al. (Nature Medicine), the sequencing of proximal zoonotic ancestors to SARS-CoV-2 has aided in the identification of alleles that may contribute to the virus' virulence in humans.


Asunto(s)
Infecciones por Coronavirus , Coronavirus , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Betacoronavirus , COVID-19 , Humanos , Pandemias , Neumonía Viral , SARS-CoV-2
16.
Immunity ; 52(5): 731-733, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32325025

RESUMEN

Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis.


Asunto(s)
Quirópteros , Coronavirus , Animales , Betacoronavirus , COVID-19 , Infecciones por Coronavirus , Síndrome de Liberación de Citoquinas , Pandemias , Neumonía Viral , SARS-CoV-2 , Internalización del Virus
17.
Immunity ; 53(5): 1095-1107.e3, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33128877

RESUMEN

Developing effective strategies to prevent or treat coronavirus disease 2019 (COVID-19) requires understanding the natural immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used an unbiased, genome-wide screening technology to determine the precise peptide sequences in SARS-CoV-2 that are recognized by the memory CD8+ T cells of COVID-19 patients. In total, we identified 3-8 epitopes for each of the 6 most prevalent human leukocyte antigen (HLA) types. These epitopes were broadly shared across patients and located in regions of the virus that are not subject to mutational variation. Notably, only 3 of the 29 shared epitopes were located in the spike protein, whereas most epitopes were located in ORF1ab or the nucleocapsid protein. We also found that CD8+ T cells generally do not cross-react with epitopes in the four seasonal coronaviruses that cause the common cold. Overall, these findings can inform development of next-generation vaccines that better recapitulate natural CD8+ T cell immunity to SARS-CoV-2.


Asunto(s)
Betacoronavirus/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adulto , Anciano , Betacoronavirus/aislamiento & purificación , COVID-19 , Convalecencia , Coronavirus/inmunología , Infecciones por Coronavirus/diagnóstico , Proteínas de la Nucleocápside de Coronavirus , Mapeo Epitopo , Epítopos de Linfocito T , Femenino , Humanos , Epítopos Inmunodominantes , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Proteínas de la Nucleocápside/inmunología , Pandemias , Fosfoproteínas , Neumonía Viral/diagnóstico , Poliproteínas , SARS-CoV-2 , Proteínas Virales/inmunología , Adulto Joven
18.
Immunity ; 52(4): 583-589, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32259480

RESUMEN

SARS-CoV-2, the causal agent of COVID-19, first emerged in late 2019 in China. It has since infected more than 870,000 individuals and caused more than 43,000 deaths globally. Here, we discuss therapeutic and prophylactic interventions for SARS-CoV-2 with a focus on vaccine development and its challenges. Vaccines are being rapidly developed but will likely come too late to affect the first wave of a potential pandemic. Nevertheless, critical lessons can be learned for the development of vaccines against rapidly emerging viruses. Importantly, SARS-CoV-2 vaccines will be essential to reducing morbidity and mortality if the virus establishes itself in the population.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/prevención & control , Desarrollo de Medicamentos , Pandemias/prevención & control , Neumonía Viral/prevención & control , Vacunas Virales , Animales , Betacoronavirus/inmunología , COVID-19 , Vacunas contra la COVID-19 , China , Ensayos Clínicos como Asunto , Coronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Modelos Animales de Enfermedad , Humanos , Neumonía Viral/epidemiología , SARS-CoV-2 , Factores de Tiempo , Vacunas Virales/uso terapéutico
19.
EMBO J ; 43(2): 151-167, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38200146

RESUMEN

Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms of translation regulation during coronaviral infections is critical for developing antiviral therapies and preventing viral spread. Translation of the viral single-stranded RNA genome in the host cell cytoplasm is an essential step in the life cycle of coronaviruses, which affects the cellular mRNA translation landscape in many ways. Here we discuss various viral strategies of translation control, including how members of the Betacoronavirus genus shut down host cell translation and suppress host innate immune functions, as well as the role of the viral non-structural protein 1 (Nsp1) in the process. We also outline the fate of viral RNA, considering stress response mechanisms triggered in infected cells, and describe how unique viral RNA features contribute to programmed ribosomal -1 frameshifting, RNA editing, and translation shutdown evasion.


Asunto(s)
Infecciones por Coronavirus , Coronavirus , Animales , Humanos , Coronavirus/genética , Infecciones por Coronavirus/genética , Betacoronavirus/fisiología , Antivirales/farmacología , ARN Viral/genética
20.
Nature ; 602(7895): 142-147, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35082445

RESUMEN

Public databases contain a planetary collection of nucleic acid sequences, but their systematic exploration has been inhibited by a lack of efficient methods for searching this corpus, which (at the time of writing) exceeds 20 petabases and is growing exponentially1. Here we developed a cloud computing infrastructure, Serratus, to enable ultra-high-throughput sequence alignment at the petabase scale. We searched 5.7 million biologically diverse samples (10.2 petabases) for the hallmark gene RNA-dependent RNA polymerase and identified well over 105 novel RNA viruses, thereby expanding the number of known species by roughly an order of magnitude. We characterized novel viruses related to coronaviruses, hepatitis delta virus and huge phages, respectively, and analysed their environmental reservoirs. To catalyse the ongoing revolution of viral discovery, we established a free and comprehensive database of these data and tools. Expanding the known sequence diversity of viruses can reveal the evolutionary origins of emerging pathogens and improve pathogen surveillance for the anticipation and mitigation of future pandemics.


Asunto(s)
Nube Computacional , Bases de Datos Genéticas , Virus ARN/genética , Virus ARN/aislamiento & purificación , Alineación de Secuencia/métodos , Virología/métodos , Viroma/genética , Animales , Archivos , Bacteriófagos/enzimología , Bacteriófagos/genética , Biodiversidad , Coronavirus/clasificación , Coronavirus/enzimología , Coronavirus/genética , Evolución Molecular , Virus de la Hepatitis Delta/enzimología , Virus de la Hepatitis Delta/genética , Humanos , Modelos Moleculares , Virus ARN/clasificación , Virus ARN/enzimología , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/genética , Programas Informáticos
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