RESUMEN
SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19. Our research, along with others', has demonstrated that mast cells (MCs) play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2. In previous study, we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice. Additionally, we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells, leading to subsequent lung injury. The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation, and inflammation in these regions could promote viral spread. MCs are widely distributed throughout the respiratory tract. Thus, in this study, we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium. Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2. MC degranulation caused lesions in trachea, and the formation of papillary hyperplasia was observed. Through transcriptome analysis in bronchial epithelial cells, we found that MC degranulation significantly altered multiple cellular signaling, particularly, leading to upregulated immune responses and inflammation. The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice. Taken together, our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions. Furthermore, our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation, thereby preventing tissue damage caused by hyper-inflammation.
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Bronquios , COVID-19 , Degranulación de la Célula , Mastocitos , SARS-CoV-2 , Tráquea , Animales , Mastocitos/virología , Mastocitos/inmunología , COVID-19/inmunología , COVID-19/virología , COVID-19/patología , Ratones , Tráquea/virología , Tráquea/patología , Bronquios/virología , Bronquios/patología , Humanos , Inflamación/virología , Células Epiteliales/virología , Modelos Animales de EnfermedadRESUMEN
Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure-function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.
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Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RTâqPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.
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Infección por el Virus Zika , Virus Zika , Masculino , Ratones , Animales , Virus Zika/genética , Niclosamida , Activación de Complemento , Análisis de Secuencia de ARNAsunto(s)
Inmunidad Humoral , Virosis , Humanos , Anticuerpos Antivirales , Adyuvantes InmunológicosRESUMEN
We identified a novel circovirus (human-associated circovirus 2 [HuCV2]) from the blood of 2 intravenous drug users in China who were infected with HIV-1, hepatitis C virus, or both. HuCV2 is most closely related to porcine circovirus 3. Our findings underscore the risk for HuCV2 and other emerging viruses among this population.
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Circovirus , Consumidores de Drogas , Abuso de Sustancias por Vía Intravenosa , Enfermedades de los Porcinos , Animales , Porcinos , Humanos , Circovirus/genética , Abuso de Sustancias por Vía Intravenosa/complicaciones , Abuso de Sustancias por Vía Intravenosa/epidemiología , China/epidemiología , Hepacivirus , Filogenia , Enfermedades de los Porcinos/epidemiologíaRESUMEN
Two-dimensional (2D) van der Waals heterostructures (VDWHs) containing a charge-density wave (CDW) and superconductivity (SC) have revealed rich tunability in their properties, which provide a new route for optimizing their novel exotic states. The interaction between SC and CDW is critical to its properties; however, understanding this interaction within VDWHs is very limited. A comprehensive in situ study and theoretical calculation on bulk 4Hb-TaSe2 VDWHs consisting of alternately stacking 1T-TaSe2 and 1H-TaSe2 monolayers are investigated under high pressure. Surprisingly, the superconductivity competes with the intralayer and adjacent-layer CDW order in 4Hb-TaSe2, which results in substantially and continually boosted superconductivity under compression. Upon total suppression of the CDW, the superconductivity in the individual layers responds differently to the charge transfer. Our results provide an excellent method to efficiently tune the interplay between SC and CDW in VDWHs and a new avenue for designing materials with tailored properties.
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The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.
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Tratamiento Farmacológico de COVID-19 , Nanoestructuras , Enzima Convertidora de Angiotensina 2 , Animales , Humanos , Ratones , Nanoestructuras/uso terapéutico , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Using a single atom to construct electronic components is a promising route for the microminiaturization of electronic instruments. However, effective control of the intrinsic property in a molecular/atomic prototype component is full of challenges. Here, we present that the intracell diffusion behavior of a target Ag single atom within a unit cell of Si reconstruction is controllably modulated by constructing Ag nanoclusters and arrays in the neighboring cells. Moreover, a three-bit digital comparator device is fabricated on the basis of the diffusion time of a Ag single atom that can be effectively regulated by using the intercoupling between the target Ag monomer and the surrounding metal arrays.
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Electrónica , Plata , DifusiónRESUMEN
Intravenous drug users (IDUs) are a high-risk group for HIV-1, hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, which are the leading causes of death in IDUs. However, the plasma virome of IDUs and how it is influenced by above viral infections remain unclear. Using viral metagenomics, we determined the plasma virome of IDUs and its association with HIV-1, HCV, and/or HBV infections. Compared with healthy individuals, IDUs especially those with major viral infections had higher viral abundance and diversity. Anelloviridae dominated plasma virome. Coinfections of multiple anelloviruses were common, and anelloviruses from the same genus tended to coexist together. In this study, 4,487 anellovirus ORF1 sequences were identified, including 1,620 (36.1%) with less than 69% identity to any known sequences, which tripled the current number. Compared with healthy controls (HC), more anellovirus sequences were observed in neg-IDUs, and HIV-1, HCV, and/or HBV infections further expanded the sequence number in IDUs, which was characterized by the emergence of novel divergent taxons and blooms of resident anelloviruses. Pegivirus was mainly identified in infected IDUs. Five main pegivirus transmission clusters (TCs) were identified by phylogenetic analysis, suggesting a transmission link. Similar anellovirus profiles were observed in IDUs within the same TC, suggesting transmission of anellome among IDUs. Our data suggested that IDUs suffered higher plasma viral burden especially anelloviruses, which was associated with HIV-1, HCV, and/or HBV infections. Blooms in abundance and unprecedented diversity of anellovirus highlighted active evolution and replication of this virus in blood circulation, and an uncharacterized role it may engage with the host. IMPORTANCE Virome is associated with immune status and determines or influences disease progression through both pathogenic and resident viruses. Increased viral burden in IDUs especially those with major viral infections indicated the suboptimal immune status and high infection risks of these population. Blooms in abundance and unprecedented diversity of anellovirus highlighted its active evolution and replication in the blood circulation, and sensitive response to other viral infections. In addition, transmission cluster analysis revealed the transmission link of pegivirus among IDUs, and the individuals with transmission links shared similar anellome profiles. In-depth monitoring of the plasma virome in high-risk populations is not only needed for surveillance for emerging viruses and transmission networks of major and neglected bloodborne viruses, but also important for a better understanding of commensal viruses and their role it may engage with immune system.
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Anelloviridae , Consumidores de Drogas , Infecciones por VIH , VIH-1 , Hepatitis B , Hepatitis C , Abuso de Sustancias por Vía Intravenosa , Infecciones por VIH/complicaciones , VIH-1/genética , Hepacivirus/genética , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Virus de la Hepatitis B/genética , Hepatitis C/epidemiología , Humanos , Filogenia , Abuso de Sustancias por Vía Intravenosa/complicaciones , Abuso de Sustancias por Vía Intravenosa/epidemiología , ViromaRESUMEN
COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection, the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits. We recently demonstrated that mast cells (MCs) are an essential mediator of SARS-CoV-2-initiated hyperinflammation. We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury. In this study, we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo, and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice. Specifically, SARS-CoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury, while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption; predictably, the combination of antiviral drug remdesivir with the antihistamine loratadine, a histamine receptor 1 (HR1) antagonist, dampened viral replication and inflammation, thereby greatly reducing lung injury. Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Lesión Pulmonar , Enfermedades de los Roedores , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/veterinaria , Células Endoteliales , Antagonistas de los Receptores Histamínicos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/veterinaria , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/veterinaria , Ratones , Enfermedades de los Roedores/tratamiento farmacológico , SARS-CoV-2 , Glicoproteína de la Espiga del CoronavirusRESUMEN
SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.
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COVID-19/metabolismo , Degranulación de la Célula , Lesión Pulmonar/metabolismo , Mastocitos/metabolismo , Alveolos Pulmonares/metabolismo , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/genética , Línea Celular Tumoral , Femenino , Humanos , Lesión Pulmonar/genética , Lesión Pulmonar/virología , Macaca mulatta , Masculino , Ratones Endogámicos BALB C , Ratones Transgénicos , Alveolos Pulmonares/virología , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Recombinant viral vectors represent an important platform for vaccine delivery. Our recent studies have demonstrated distinct innate immune profiles in responding to viral vectors of different families (e.g., adenovirus versus poxvirus): while human Ad5 vector is minimally innate immune stimulatory, the poxviral vector ALVAC induces strong innate response and stimulates type I interferon (IFN) and inflammasome activation. However, the impact of the innate immune signaling on vaccine-induced adaptive immunity in viral vector vaccination is less clear. Here, we show that Modified Vaccinia Ankara (MVA), another poxviral vector, stimulated a type I IFN response in innate immune cells through cGAS-STING. Using MVA-HIV vaccine as a model, we found that type I IFN signaling promoted the generation of humoral immunity in MVA-HIV vaccination in vivo. Following vaccination, type I IFN receptor-knockout (IFNAR1-/-) mice produced significantly lower levels of total and HIV gp120-specific antibodies compared to wild-type (WT) mice. Consistent with the antibody response, a type I IFN signaling deficiency also led to reduced levels of plasma cells and memory-like B cells compared to WT mice. Furthermore, analysis of vaccine-induced CD4 T cells showed that type I IFN signaling also promoted the generation of a vaccine-specific CD4 T-cell response and a T follicular helper (Tfh) response in mice. Together, our data indicate a role for type I IFN signaling in promoting humoral immunity in poxviral vector vaccination. The study suggests that modulating type I IFN and its associated innate immune pathways will likely affect vaccine efficacy. IMPORTANCE Viral vectors, including MVA, are an important antigen delivery platform and have been commonly used in vaccine development. Understanding the innate host-viral vector interactions and their impact on vaccine-induced immunity is critical but understudied. Using MVA-HIV vaccination of WT and IFNAR1-/- mice as a model, we report that type I IFN signaling promotes humoral immunity in MVA vaccination, including vaccine-induced antibody, B-cell, and Tfh responses. Our findings provide insights that not only add to our basic understanding of host-viral vector interactions but also will aid in improving vaccine design by potentially modulating type I IFN and its associated innate immune pathways in viral vector vaccination.
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Vacunas contra el SIDA/inmunología , Vectores Genéticos/inmunología , Interferón Tipo I/inmunología , Desarrollo de Vacunas/métodos , Virus Vaccinia/inmunología , Animales , Humanos , Inmunidad Humoral , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células THP-1 , Eficacia de las VacunasRESUMEN
Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.
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Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Microambiente Celular/inmunología , Pulmón/inmunología , Receptores CXCR3/inmunología , SARS-CoV-2/inmunología , Enzima Convertidora de Angiotensina 2/inmunología , Animales , Linfocitos T CD8-positivos/patología , COVID-19/patología , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/patología , Interferón-alfa/inmunología , Interleucina-6/inmunología , Pulmón/patología , Pulmón/virología , Macaca mulatta , MasculinoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.
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Antihipertensivos/uso terapéutico , COVID-19/complicaciones , Captopril/uso terapéutico , Hipertensión/complicaciones , Enfermedades Pulmonares/tratamiento farmacológico , SARS-CoV-2 , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antihipertensivos/farmacología , Captopril/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/virología , Ratones , Replicación Viral/efectos de los fármacosRESUMEN
Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.
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Antivirales/metabolismo , COVID-19/patología , Proteínas de la Envoltura de Coronavirus/metabolismo , Síndrome de Dificultad Respiratoria/etiología , SARS-CoV-2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Antivirales/química , Antivirales/uso terapéutico , Apoptosis , COVID-19/complicaciones , COVID-19/virología , Proteínas de la Envoltura de Coronavirus/antagonistas & inhibidores , Proteínas de la Envoltura de Coronavirus/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Semivida , Humanos , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutagénesis Sitio-Dirigida , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidad , Bazo/metabolismo , Bazo/patología , Carga Viral , Virulencia , Tratamiento Farmacológico de COVID-19RESUMEN
The global outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as of 8 May 2021, has surpassed 150 700 000 infections and 3 279 000 deaths worldwide. Evidence indicates that SARS-CoV-2 RNA can be detected on particulate matter (PM), and COVID-19 cases are correlated with levels of air pollutants. However, the mechanisms of PM involvement in the spread of SARS-CoV-2 remain poorly understood. Here, we found that PM exposure increased the expression level of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in several epithelial cells and increased the adsorption of the SARS-CoV-2 spike protein. Instillation of PM in a hACE2 mouse model significantly increased the expression of ACE2 and Tmprss2 and viral replication in the lungs. Furthermore, PM exacerbated the pulmonary lesions caused by SARS-CoV-2 infection in the hACE2 mice. In conclusion, our study demonstrated that PM is an epidemiological factor of COVID-19, emphasizing the necessity of wearing anti-PM masks to cope with this global pandemic.
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Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/inducido químicamente , COVID-19/inmunología , Material Particulado/efectos adversos , SARS-CoV-2 , Adsorción/efectos de los fármacos , Animales , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/inmunología , Células Epiteliales/metabolismo , Ratones , Ratones Endogámicos , Material Particulado/química , ARN Viral/análisis , SARS-CoV-2/genética , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become an unprecedented global health emergency. At present, SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research. Here, we showed that northern pig-tailed macaques ( Macaca leonina, NPMs) supported SARS-CoV-2 replication. Furthermore, compared with rhesus macaques, NPMs showed rapid viral clearance in lung tissues, nose swabs, throat swabs, and rectal swabs, which may be due to higher expression of interferon (IFN)-α in lung tissue. However, the rapid viral clearance was not associated with good outcome. In the second week post infection, NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques. These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.
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COVID-19/inmunología , COVID-19/virología , Macaca nemestrina , SARS-CoV-2/inmunología , Animales , Modelos Animales de Enfermedad , Interferón-alfa/análisis , Interleucina-1beta/análisis , Interleucina-6/análisis , Pulmón/inmunología , Pulmón/virología , Nariz/virología , Faringe/virología , ARN Viral/análisis , Recto/virología , SARS-CoV-2/genéticaRESUMEN
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.