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1.
Front Med (Lausanne) ; 9: 839389, 2022.
Article in English | MEDLINE | ID: covidwho-1753381

ABSTRACT

The present study investigated a SARS-CoV-2 infection in placenta and fetal samples from an early pregnancy miscarriage in Midwest Brazil. The Gamma variant was isolated and fully sequenced from the placenta sample, but not from fetal samples. Our findings highlight potential adverse perinatal outcomes caused by SARS-CoV-2 Gamma infection during pregnancy.

2.
Rev Bras Farmacogn ; 31(5): 658-666, 2021.
Article in English | MEDLINE | ID: covidwho-1649311

ABSTRACT

The novel coronavirus SARS-CoV-2 has been affecting the world, causing severe pneumonia and acute respiratory syndrome, leading people to death. Therefore, the search for anti-SARS-CoV-2 compounds is pivotal for public health. Natural products may present sources of bioactive compounds; among them, flavonoids are known in literature for their antiviral activity. Siparuna species are used in Brazilian folk medicine for the treatment of colds and flu. This work describes the isolation of 3,3',4'-tri-O-methyl-quercetin, 3,7,3',4'-tetra-O-methyl-quercetin (retusin), and 3,7-di-O-methyl-kaempferol (kumatakenin) from the dichloromethane extract of leaves of Siparuna cristata (Poepp. & Endl.) A.DC., Siparunaceae, using high-speed countercurrent chromatography in addition to the investigation of their inhibitory effect against SARS-CoV-2 viral replication. Retusin and kumatakenin inhibited SARS-CoV-2 replication in Vero E6 and Calu-3 cells, with a selective index greater than lopinavir/ritonavir and chloroquine, used as control. Flavonoids and their derivatives may stand for target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43450-021-00162-5.

3.
Viruses ; 14(2)2022 01 20.
Article in English | MEDLINE | ID: covidwho-1650717

ABSTRACT

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted public health and the world economy and fueled a worldwide race to approve therapeutic and prophylactic agents, but so far there are no specific antiviral drugs. Understanding the biology of the virus is the first step in structuring strategies to combat it, and in this context several studies have been conducted with the aim of understanding the replication mechanism of SARS-CoV-2 in vitro systems. In this work, studies using transmission and scanning electron microscopy and 3D electron microscopy modeling were performed with the goal of characterizing the morphogenesis of SARS-CoV-2 in Vero-E6 cells. Several ultrastructural changes were observed-such as syncytia formation, cytoplasmic membrane projections, lipid droplets accumulation, proliferation of double-membrane vesicles derived from the rough endoplasmic reticulum, and alteration of mitochondria. The entry of the virus into cells occurred through endocytosis. Viral particles were observed attached to the cell membrane and in various cellular compartments, and extrusion of viral progeny took place by exocytosis. These findings allow us to infer that Vero-E6 cells are highly susceptible to SARS-CoV-2 infection as described in the literature and their replication cycle is similar to that described with SARS-CoV and MERS-CoV in vitro models.


Subject(s)
Microscopy, Electron, Transmission/methods , Microscopy, Electron/methods , SARS-CoV-2/metabolism , SARS-CoV-2/ultrastructure , Animals , Cell Line , Chlorocebus aethiops , SARS-CoV-2/chemistry , Vero Cells , Virus Internalization , Virus Replication
4.
Cell ; 2022.
Article in English | EuropePMC | ID: covidwho-1601904

ABSTRACT

On the 24th November 2021 the sequence of a new SARS CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titres of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic as well as Alpha, Beta, Gamma, Delta are substantially reduced or fail to neutralize. Titres against Omicron are boosted by third vaccine doses and are high in cases both vaccinated and infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of a large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses, combining mutations conferring tight binding to ACE2 to unleash evolution driven by immune escape, leading to a large number of mutations in the ACE2 binding site which rebalance receptor affinity to that of early pandemic viruses. A comprehensive analysis of sera from vaccinees, convalescent patients infected previously by multiple variants and potent monoclonal antibodies from early in the COVID-19 pandemic reveals a substantial overall reduction the ability to neutralize the SARS-CoV-2 Omicron variant, which a third vaccine dose seems to ameliorate. Structural analyses of the Omicron RBD suggest a selective pressure enabling the virus bind ACE2 with increased affinity that is offset by other changes in the receptor binding motif that facilitates immune escape.

5.
Int J Infect Dis ; 114: 58-61, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1487754

ABSTRACT

We describe a case of prolonged COVID-19 caused by the SARS-CoV-2 Gamma variant in a fully vaccinated healthcare worker, 387 days after an infection caused by lineage B.1.1.33. Infections were confirmed by whole-genome sequencing and corroborated by the detection of neutralizing antibodies in convalescent serum samples. Considering the permanent exposure of this healthcare worker to SARS-CoV-2, the waning immunity after the first infection, the low efficacy of the inactivated vaccine at preventing COVID-19, the immune escape of the Gamma variant (VOC), and the burden of post-COVID syndrome, this individual would have benefited from an additional dose of a heterologous vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Brazil , COVID-19/complications , COVID-19/therapy , Humans , Immunization, Passive , Reinfection , Vaccines, Inactivated
6.
Cells ; 10(9)2021 08 26.
Article in English | MEDLINE | ID: covidwho-1374306

ABSTRACT

The cellular immune response plays an important role in COVID-19, caused by SARS-CoV-2. This feature makes use of in vitro models' useful tools to evaluate vaccines and biopharmaceutical effects. Here, we developed a two-step model to evaluate the cellular immune response after SARS-CoV-2 infection-induced or spike protein stimulation in peripheral blood mononuclear cells (PBMC) from both unexposed and COVID-19 (primo-infected) individuals (Step1). Moreover, the supernatants of these cultures were used to evaluate its effects on lung cell lines (A549) (Step2). When PBMC from the unexposed were infected by SARS-CoV-2, cytotoxic natural killer and nonclassical monocytes expressing inflammatory cytokines genes were raised. The supernatant of these cells can induce apoptosis of A549 cells (mock vs. Step2 [mean]: 6.4% × 17.7%). Meanwhile, PBMCs from primo-infected presented their memory CD4+ T cells activated with a high production of IFNG and antiviral genes. Supernatant from past COVID-19 subjects contributed to reduce apoptosis (mock vs. Step2 [ratio]: 7.2 × 1.4) and to elevate the antiviral activity (iNOS) of A549 cells (mock vs. Step2 [mean]: 31.5% × 55.7%). Our findings showed features of immune primary cells and lung cell lines response after SARS-CoV-2 or spike protein stimulation that can be used as an in vitro model to study the immunity effects after SARS-CoV-2 antigen exposure.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity, Cellular , Models, Biological , SARS-CoV-2/physiology , Adult , Alveolar Epithelial Cells/virology , COVID-19/blood , COVID-19/genetics , Cytokines/genetics , Cytokines/metabolism , Female , Gene Expression Regulation , Humans , Immunologic Memory/immunology , Killer Cells, Natural/immunology , Leukocytes, Mononuclear/virology , Male , Middle Aged , Phenotype , T-Lymphocytes/immunology , Virus Replication/physiology , Young Adult
8.
Cell ; 184(11): 2939-2954.e9, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1343152

ABSTRACT

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Binding Sites , COVID-19/therapy , COVID-19/virology , Cell Line , Humans , Immune Evasion , Immunization, Passive , Mutation , Protein Binding , Protein Domains , SARS-CoV-2/genetics , Sequence Deletion , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Vaccines/immunology
9.
Cell ; 184(16): 4220-4236.e13, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1272328

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antigen-Antibody Complex/chemistry , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Chlorocebus aethiops , Crystallography, X-Ray , Humans , Immunization, Passive , Neutralization Tests , Protein Domains/immunology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
10.
Emerg Infect Dis ; 27(7): 1789-1794, 2021 07.
Article in English | MEDLINE | ID: covidwho-1197530

ABSTRACT

A 37-year-old healthcare worker from the northeastern region of Brazil experienced 2 clinical episodes of coronavirus disease. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by reverse transcription PCR in samples collected 116 days apart. Whole-genome sequencing revealed that the 2 infections were caused by the most prevalent lineage in Brazil, B.1.1.33, and the emerging lineage P.2. The first infection occurred in June 2020; Bayesian analysis suggests reinfection at some point during September 14-October 11, 2020, a few days before the second episode of coronavirus disease. Of note, P.2 corresponds to an emergent viral lineage in Brazil that contains the mutation E484K in the spike protein. The P.2 lineage was initially detected in the state of Rio de Janeiro, and since then it has been found throughout the country. Our findings suggest not only a reinfection case but also geographic dissemination of the emerging Brazil clade P.2.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Bayes Theorem , Brazil/epidemiology , Humans , Reinfection
11.
Front Microbiol ; 11: 615280, 2020.
Article in English | MEDLINE | ID: covidwho-1120950

ABSTRACT

A previous study demonstrates that most of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Brazilian strains fell in three local clades that were introduced from Europe around late February 2020. Here we investigated in more detail the origin of the major and most widely disseminated SARS-CoV-2 Brazilian lineage B.1.1.33. We recovered 190 whole viral genomes collected from 13 Brazilian states from February 29 to April 31, 2020 and combined them with other B.1.1 genomes collected globally. Our genomic survey confirms that lineage B.1.1.33 is responsible for a variable fraction of the community viral transmissions in Brazilian states, ranging from 2% of all SARS-CoV-2 genomes from Pernambuco to 80% of those from Rio de Janeiro. We detected a moderate prevalence (5-18%) of lineage B.1.1.33 in some South American countries and a very low prevalence (<1%) in North America, Europe, and Oceania. Our study reveals that lineage B.1.1.33 evolved from an ancestral clade, here designated B.1.1.33-like, that carries one of the two B.1.1.33 synapomorphic mutations. The B.1.1.33-like lineage may have been introduced from Europe or arose in Brazil in early February 2020 and a few weeks later gave origin to the lineage B.1.1.33. These SARS-CoV-2 lineages probably circulated during February 2020 and reached all Brazilian regions and multiple countries around the world by mid-March, before the implementation of air travel restrictions in Brazil. Our phylodynamic analysis also indicates that public health interventions were partially effective to control the expansion of lineage B.1.1.33 in Rio de Janeiro because its median effective reproductive number (R e ) was drastically reduced by about 66% during March 2020, but failed to bring it to below one. Continuous genomic surveillance of lineage B.1.1.33 might provide valuable information about epidemic dynamics and the effectiveness of public health interventions in some Brazilian states.

12.
Cephalalgia ; 40(13): 1452-1458, 2020 11.
Article in English | MEDLINE | ID: covidwho-1088417

ABSTRACT

BACKGROUND: Headache is a frequent complaint in COVID-19 patients. However, no detailed information on headache characteristics is provided in these reports. Our objective is to describe the characteristics of headache and the cerebrospinal fluid (CSF) profile in COVID-19 patients, highlighting the cases of isolated intracranial hypertension. METHODS: In this cross-sectional study, we selected COVID-19 patients who underwent lumbar puncture due to neurological complaints from April to May 2020. We reviewed clinical, imaging, and laboratory data of patients with refractory headache in the absence of other encephalitic or meningitic features. CSF opening pressures higher than 250 mmH2O were considered elevated, and from 200 to 250 mmH2O equivocal. RESULTS: Fifty-six COVID-19 patients underwent lumbar puncture for different neurological conditions. A new, persistent headache that prompted a CSF analysis was diagnosed in 13 (23.2%). The pain was throbbing, holocranial or bilateral in the majority of patients. All patients had normal CSF analysis and RT-qPCR for SARS-CoV-2 was negative in all samples. Opening pressure >200 mmH2O was present in 11 patients and, in six of these, > 250 mmH2O. 6/13 patients had complete improvement of the pain, five had partial improvement, and two were left with a daily persistent headache. CONCLUSIONS: In a significant proportion of COVID-19 patients, headache was associated to intracranial hypertension in the absence of meningitic or encephalitic features. Coagulopathy associated with COVID-19 could be an explanation, but further studies including post-mortem analysis of areas of production and CSF absorption (choroid plexuses and arachnoid granulations) are necessary to clarify this issue.


Subject(s)
Coronavirus Infections/complications , Intracranial Hypertension/virology , Pneumonia, Viral/complications , Adult , Aged , Betacoronavirus , COVID-19 , Cerebrospinal Fluid Pressure , Coronavirus Infections/cerebrospinal fluid , Cross-Sectional Studies , Female , Headache/cerebrospinal fluid , Headache/etiology , Humans , Intracranial Hypertension/cerebrospinal fluid , Intracranial Hypertension/epidemiology , Male , Middle Aged , Pandemics , Pneumonia, Viral/cerebrospinal fluid , Retrospective Studies , SARS-CoV-2 , Spinal Puncture
13.
Int J Environ Res Public Health ; 17(24)2020 12 10.
Article in English | MEDLINE | ID: covidwho-965102

ABSTRACT

SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. Disease clinical manifestations range from asymptomatic to severe multiple organ damage. SARS-CoV-2 uses ACE2 as a cellular receptor, which is abundantly expressed in the small intestine, allowing viral replication in the gastrointestinal tract. Viral RNA has been detected in the stool of COVID-19 patients and viable viruses had been isolated in some of these samples. Thus, a putative role of SARS-CoV-2 fecal-oral transmission has been argued. SARS-CoV-2 is shed in human excreta and further disposed in the sewerage or in the environment, in poor basic sanitation settings. Wastewater-based epidemiology (WBE) is a valuable population level approach for monitoring viral pathogens and has been successfully used in different contexts. This review summarizes the current global experience on SARS-CoV-2 WBE in distinct continents and viral detection in polluted surface water. The advantages and concerns of this strategy for SARS-CoV-2 surveillance are discussed. Outcomes suggest that WBE is a valuable early warning alert and a helpful complementary surveillance tool to subside public health response, to tailor containment and mitigation measures and to determine target populations for testing. In poor sanitation settings, contaminated rivers could be alternatively used as a source for environmental surveillance.


Subject(s)
COVID-19/epidemiology , Pandemics , Wastewater-Based Epidemiological Monitoring , Humans , SARS-CoV-2/isolation & purification , Sanitation , Waste Water/virology
14.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Article in English | MEDLINE | ID: covidwho-810756

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Atazanavir Sulfate/pharmacology , Betacoronavirus/drug effects , Cytokines/metabolism , Ritonavir/pharmacology , Animals , Atazanavir Sulfate/chemistry , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , COVID-19 , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Therapy, Combination , Humans , Inflammation/metabolism , Inflammation/virology , Lopinavir/pharmacology , Molecular Docking Simulation , Monocytes/virology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Protease Inhibitors/pharmacology , SARS-CoV-2 , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
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