RESUMEN
SARS-CoV-2 is an enveloped virus responsible for the COVID-19 pandemic. Despite recent advances in the structural elucidation of SARS-CoV-2 proteins, the detailed architecture of the intact virus remains to be unveiled. Here we report the molecular assembly of the authentic SARS-CoV-2 virus using cryoelectron tomography (cryo-ET) and subtomogram averaging (STA). Native structures of the S proteins in pre- and postfusion conformations were determined to average resolutions of 8.7-11 Å. Compositions of the N-linked glycans from the native spikes were analyzed by mass spectrometry, which revealed overall processing states of the native glycans highly similar to that of the recombinant glycoprotein glycans. The native conformation of the ribonucleoproteins (RNPs) and their higher-order assemblies were revealed. Overall, these characterizations revealed the architecture of the SARS-CoV-2 virus in exceptional detail and shed light on how the virus packs its â¼30-kb-long single-segmented RNA in the â¼80-nm-diameter lumen.
Asunto(s)
Betacoronavirus/fisiología , Betacoronavirus/ultraestructura , Ensamble de Virus , Animales , Chlorocebus aethiops , Microscopía por Crioelectrón , Humanos , Espectrometría de Masas , Modelos Moleculares , Conformación Proteica , SARS-CoV-2 , Células Vero , Proteínas Virales/química , Proteínas Virales/ultraestructura , Cultivo de VirusRESUMEN
COVID-19 has spread worldwide since 2019 and is now a severe threat to public health. We previously identified the causative agent as a novel SARS-related coronavirus (SARS-CoV-2) that uses human angiotensin-converting enzyme 2 (hACE2) as the entry receptor. Here, we successfully developed a SARS-CoV-2 hACE2 transgenic mouse (HFH4-hACE2 in C3B6 mice) infection model. The infected mice generated typical interstitial pneumonia and pathology that were similar to those of COVID-19 patients. Viral quantification revealed the lungs as the major site of infection, although viral RNA could also be found in the eye, heart, and brain in some mice. Virus identical to SARS-CoV-2 in full-genome sequences was isolated from the infected lung and brain tissues. Last, we showed that pre-exposure to SARS-CoV-2 could protect mice from severe pneumonia. Our results show that the hACE2 mouse would be a valuable tool for testing potential vaccines and therapeutics.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/patología , Modelos Animales de Enfermedad , Ratones Transgénicos , Neumonía Viral/patología , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/virología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos/genética , Pandemias , Peptidil-Dipeptidasa A/genética , SARS-CoV-2 , Tropismo Viral , Pérdida de PesoRESUMEN
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Inmunidad Innata , Inmunomodulación , Neumonía Viral/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Animales , Vacuna BCG/inmunología , COVID-19 , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/transmisión , Humanos , Inmunidad Innata/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Linfopenia/patología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Pandemias , Neumonía Viral/patología , Neumonía Viral/fisiopatología , Neumonía Viral/transmisión , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/patología , Replicación ViralRESUMEN
Coronavirus disease 2019 (COVID-19) is a novel respiratory illness caused by SARS-CoV-2. Viral entry is mediated through viral spike protein and host ACE2 enzyme interaction. Most cases are mild; severe disease often involves cytokine storm and organ failure. Therapeutics including antivirals, immunomodulators, and vaccines are in development. To view this SnapShot, open or download the PDF.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Animales , Betacoronavirus/clasificación , Betacoronavirus/genética , COVID-19 , Prueba de COVID-19 , Vacunas contra la COVID-19 , Técnicas de Laboratorio Clínico/métodos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/transmisión , Humanos , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/terapia , Neumonía Viral/transmisión , SARS-CoV-2 , Vacunas Virales/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
SARS-CoV-2 infection displays immense inter-individual clinical variability, ranging from silent infection to lethal disease. The role of human genetics in determining clinical response to the virus remains unclear. Studies of outliers-individuals remaining uninfected despite viral exposure and healthy young patients with life-threatening disease-present a unique opportunity to reveal human genetic determinants of infection and disease.
Asunto(s)
Infecciones por Coronavirus/genética , Infecciones por Coronavirus/inmunología , Predisposición Genética a la Enfermedad , Neumonía Viral/genética , Neumonía Viral/inmunología , Factores de Edad , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Resistencia a la Enfermedad , Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/inmunología , Variación Genética , Genoma Humano , Interacciones Huésped-Patógeno , Humanos , Infecciones/genética , Infecciones/inmunología , Infecciones/fisiopatología , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , SARS-CoV-2RESUMEN
The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.
Asunto(s)
Betacoronavirus/química , Peptidil-Dipeptidasa A/química , Glicoproteína de la Espiga del Coronavirus/química , Internalización del Virus , Secuencia de Aminoácidos , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/fisiología , Epítopos , Humanos , Modelos Moleculares , Peptidil-Dipeptidasa A/metabolismo , Filogenia , Dominios Proteicos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/química , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , SARS-CoV-2 , Alineación de Secuencia , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts an interprotomer contact and that the conformation is shifted toward an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.
Asunto(s)
Betacoronavirus/fisiología , Betacoronavirus/ultraestructura , Glicoproteína de la Espiga del Coronavirus/fisiología , Glicoproteína de la Espiga del Coronavirus/ultraestructura , Enzima Convertidora de Angiotensina 2 , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Células Cultivadas , Infecciones por Coronavirus/virología , Femenino , Variación Genética , Células HEK293 , Humanos , Masculino , Modelos Moleculares , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Conformación Proteica , Procesamiento Proteico-Postraduccional , Receptores de Coronavirus , Receptores Virales/metabolismo , SARS-CoV-2 , Especificidad de la EspecieRESUMEN
The SARS-CoV-2 pandemic has caused extreme human suffering and economic harm. We generated and characterized a new mouse-adapted SARS-CoV-2 virus that captures multiple aspects of severe COVID-19 disease in standard laboratory mice. This SARS-CoV-2 model exhibits the spectrum of morbidity and mortality of COVID-19 disease as well as aspects of host genetics, age, cellular tropisms, elevated Th1 cytokines, and loss of surfactant expression and pulmonary function linked to pathological features of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). This model can rapidly access existing mouse resources to elucidate the role of host genetics, underlying molecular mechanisms governing SARS-CoV-2 pathogenesis, and the protective or pathogenic immune responses related to disease severity. The model promises to provide a robust platform for studies of ALI and ARDS to evaluate vaccine and antiviral drug performance, including in the most vulnerable populations (i.e., the aged) using standard laboratory mice.
Asunto(s)
Lesión Pulmonar Aguda/patología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Animales , Betacoronavirus/aislamiento & purificación , Betacoronavirus/fisiología , COVID-19 , Línea Celular , Quimiocinas/sangre , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Humanos , Pulmón/patología , Pulmón/fisiología , Pulmón/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/virología , Síndrome de Dificultad Respiratoria/patología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Tasa de SupervivenciaRESUMEN
The SARS-CoV-2 pandemic that causes COVID-19 respiratory syndrome has caused global public health and economic crises, necessitating rapid development of vaccines and therapeutic countermeasures. The world-wide response to the COVID-19 pandemic has been unprecedented with government, academic, and private partnerships working together to rapidly develop vaccine and antibody countermeasures. Many of the technologies being used are derived from prior government-academic partnerships for response to other emerging infections.
Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Vacunas Virales/inmunología , Vacunas contra el SIDA/inmunología , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Betacoronavirus/fisiología , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/inmunología , Humanos , Colaboración Intersectorial , Neumonía Viral/inmunología , SARS-CoV-2 , Vacunas Virales/química , Tratamiento Farmacológico de COVID-19RESUMEN
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide "megapools," circulating SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in â¼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike, and N proteins each accounted for 11%-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a, and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in â¼40%-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating "common cold" coronaviruses and SARS-CoV-2.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Epítopos de Linfocito T , Neumonía Viral/inmunología , Betacoronavirus/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19 , Vacunas contra la COVID-19 , Convalecencia , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Reacciones Cruzadas , Humanos , Leucocitos Mononucleares/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/metabolismo , Neumonía Viral/virología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/metabolismo , Proteínas Virales/metabolismo , Vacunas Virales/inmunologíaRESUMEN
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Virus ARN/inmunología , Animales , COVID-19 , Células Cultivadas , Quimiocinas/genética , Quimiocinas/inmunología , Infecciones por Coronavirus/genética , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Inflamación/virología , Interferones/genética , Interferones/inmunología , Pandemias , Neumonía Viral/genética , Virus ARN/clasificación , SARS-CoV-2 , Transcripción GenéticaRESUMEN
There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , Enterocitos/metabolismo , Células Caliciformes/metabolismo , Interferón Tipo I/metabolismo , Mucosa Nasal/citología , Peptidil-Dipeptidasa A/genética , Adolescente , Células Epiteliales Alveolares/inmunología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/fisiología , COVID-19 , Línea Celular , Células Cultivadas , Niño , Infecciones por Coronavirus/virología , Enterocitos/inmunología , Células Caliciformes/inmunología , Infecciones por VIH/inmunología , Humanos , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Pulmón/citología , Pulmón/patología , Macaca mulatta , Ratones , Mycobacterium tuberculosis , Mucosa Nasal/inmunología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Receptores Virales/genética , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Análisis de la Célula Individual , Tuberculosis/inmunología , Regulación hacia ArribaRESUMEN
We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.
Asunto(s)
Betacoronavirus/fisiología , Heparitina Sulfato/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/aislamiento & purificación , Sitios de Unión , COVID-19 , Línea Celular , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Heparina/química , Heparina/metabolismo , Heparitina Sulfato/química , Humanos , Riñón/metabolismo , Pulmón/metabolismo , Simulación de Dinámica Molecular , Pandemias , Peptidil-Dipeptidasa A/química , Neumonía Viral/patología , Neumonía Viral/virología , Unión Proteica , Dominios Proteicos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/aislamiento & purificación , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Internalización del VirusRESUMEN
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.
Asunto(s)
Betacoronavirus/fisiología , Vacunas contra la COVID-19/inmunología , Infecciones por Coronavirus/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Secuencia Conservada/genética , Evolución Molecular , Humanos , Inmunización , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Unión Proteica , Dominios Proteicos/genética , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Desarrollo de VacunasRESUMEN
The World Health Organization has declared SARS-CoV-2 virus outbreak a worldwide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free, and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in eight newly discharged patients. Follow-up analysis on another cohort of six patients 2 weeks post discharge also revealed high titers of immunoglobulin G (IgG) antibodies. In all 14 patients tested, 13 displayed serum-neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It also has implications in developing an effective vaccine to SARS-CoV-2 infection.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Inmunidad Celular , Inmunidad Humoral , Neumonía Viral/inmunología , Adulto , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19 , Convalecencia , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/patología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Animales , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/terapia , Susceptibilidad a Enfermedades , Humanos , Inmunidad Innata , Memoria Inmunológica , Inflamación/inmunología , Inflamación/virología , Linfocitos/inmunología , Células Mieloides/inmunología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/patología , Neumonía Viral/terapia , SARS-CoV-2RESUMEN
Respiratory viruses affect us throughout our lives, from infancy to old age, causing illnesses ranging from a common cold to severe pneumonia. They belong to several virus families, and although many features of infection with these diverse viruses are shared, some have unique characteristics. Here we explain what happens when we are infected by respiratory viruses, including SARS-CoV-2, which causes COVID-19.
Asunto(s)
Infecciones por Coronavirus/fisiopatología , Neumonía Viral/fisiopatología , Sistema Respiratorio/fisiopatología , Inmunidad Adaptativa , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Humanos , Inmunidad Innata , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/terapia , Neumonía Viral/virología , Sistema Respiratorio/inmunología , Sistema Respiratorio/virología , SARS-CoV-2 , Fenómenos Fisiológicos de los Virus , Virus/clasificaciónRESUMEN
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/genéticaRESUMEN
The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.