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1.
Sci Transl Med ; 13(579)2021 02 03.
Article in English | MEDLINE | ID: covidwho-1112312

ABSTRACT

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain. Immune senescence and comorbidities in aging populations and immune dysregulation in populations living in low-resource settings may impede vaccine effectiveness. Distribution of vaccines among these populations where vaccine access is historically low remains challenging. In this Review, we address these challenges and provide strategies for ensuring that vaccines are developed and deployed for those most vulnerable.


Subject(s)
/immunology , /virology , Disease Susceptibility , /physiology , Animals , Disease Models, Animal , Humans , Phylogeny
2.
Mol Pharmacol ; 99(1): 17-28, 2021 01.
Article in English | MEDLINE | ID: covidwho-1109614

ABSTRACT

ACE2 has emerged as a double agent in the COVID-19 ordeal, as it is both physiologically protective and virally conducive. The identification of ACE2 in as many as 72 tissues suggests that extrapulmonary invasion and damage is likely, which indeed has already been demonstrated by cardiovascular and gastrointestinal symptoms. On the other hand, identifying ACE2 dysregulation in patients with comorbidities may offer insight as to why COVID-19 symptoms are often more severe in these individuals. This may be attributed to a pre-existing proinflammatory state that is further propelled with the cytokine storm induced by SARS-CoV-2 infection or the loss of functional ACE2 expression as a result of viral internalization. Here, we aim to characterize the distribution and role of ACE2 in various organs to highlight the scope of damage that may arise upon SARS-CoV-2 invasion. Furthermore, by examining the disruption of ACE2 in several comorbid diseases, we offer insight into potential causes of increased severity of COVID-19 symptoms in certain individuals. SIGNIFICANCE STATEMENT: Cell surface expression of ACE2 determines the tissue susceptibility for coronavirus infectious disease 2019 infection. Comorbid disease conditions altering ACE2 expression could increase the patient's vulnerability for the disease and its complications, either directly, through modulation of viral infection, or indirectly, through alteration of inflammatory status.


Subject(s)
/metabolism , /pathology , Animals , Humans , Pandemics , Severity of Illness Index
3.
PLoS Pathog ; 17(1): e1009287, 2021 01.
Article in English | MEDLINE | ID: covidwho-1105834

ABSTRACT

The COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from individuals that go on to become infected with SARS-CoV-2. Here, we utilized data from genetically diverse Collaborative Cross (CC) mice infected with SARS-CoV to determine whether baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. Our study serves as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.


Subject(s)
/immunology , /physiology , T-Lymphocytes/immunology , Animals , Female , Humans , Male , Mice , Mice, Inbred C57BL , Phenotype , Viral Load
5.
Rom J Morphol Embryol ; 61(2): 321-334, 2020.
Article in English | MEDLINE | ID: covidwho-1102794

ABSTRACT

Coronaviruses (CoVs) represent a family of viruses that have numerous animal hosts, and they cause severe respiratory, as well as systemic and enteric infections, in humans. Currently, there are limited antiviral strategies for treating patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The lack of specific antiviral medicines and SARS-CoV-2 vaccines continues to aggravate the situation. Natural product-based antiviral drugs have been used in the two previous CoV outbreaks: Middle East respiratory syndrome coronavirus (MERS-CoV) and the first SARS-CoV. This review emphasizes the role of natural and semisynthetic candidate molecules for coronavirus disease 2019 (COVID-19) prophylaxis and treatment. The experimental evidence suggests that nature could offer huge possibilities for treatment of the COVID-19 pandemic.


Subject(s)
/drug therapy , /prevention & control , Animals , Antiviral Agents/pharmacology , Humans , Pandemics , /isolation & purification
6.
J Infect Dis ; 223(2): 189-191, 2021 02 03.
Article in English | MEDLINE | ID: covidwho-1101844

ABSTRACT

Developers of severe acute respiratory syndrome coronavirus 2 vaccines should consider some of the lessons from a "new" vaccine introduced in 1921, namely bacille Calmette-Guérin.


Subject(s)
BCG Vaccine/immunology , /prevention & control , /immunology , Animals , BCG Vaccine/administration & dosage , /virology , Humans , Pandemics/prevention & control , Randomized Controlled Trials as Topic , Tuberculosis/immunology , Tuberculosis/prevention & control
7.
Physiol Rep ; 9(2): e14707, 2021 01.
Article in English | MEDLINE | ID: covidwho-1100461

ABSTRACT

The COVID-19 has originated from Wuhan, China, in December 2019 and has been affecting the public health system, society, and economy in an unheard-of manner. There is no specific treatment or vaccine available for COVID-19. Previous data showed that men are more affected than women by COVID-19, then we hypothesized whether sex hormones could be protecting the female organism against the infection. VERO E6 cells have been commonly used as in vitro model for SARS-CoV-2 infection. In our experimental approach, we have treated VERO E6 cells with 17ß-estradiol to evaluate the modulation of SARS-CoV-2 infection in this cell line. Here we demonstrated that estrogen protein receptors ERα, ERß, and GPER1 are expressed by VERO E6 cells and could be used to study the effects of this steroid hormone. Previous and 24-hours post-infection, cells treated with 17ß-estradiol revealed a reduction in the viral load. Afterward, we found that SARS-CoV-2 infection per se results in ACE2 and TMPRSS2 increased gene expression in VERO E6-cell, which could be generating a cycle of virus infection in host cells. The estrogen treatment reduces the levels of the TMPRSS2, which are involved with SARS-CoV-2 infectiveness capacity, and hence, reducing the pathogenicity/genesis. These data suggest that estrogen could be a potential therapeutic target promoting cell protection against SARS-CoV-2. This opens new possibilities for further studies on 17ß-estradiol in human cell lines infected by SARS-CoV-2 and at least in part, explain why men developed a more severe COVID-19 compared to women.


Subject(s)
Antiviral Agents/pharmacology , Estradiol/pharmacology , /drug effects , /genetics , Animals , /virology , Chlorocebus aethiops , Host-Pathogen Interactions , Receptors, Virus/genetics , Receptors, Virus/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Vero Cells
10.
Front Immunol ; 11: 616595, 2020.
Article in English | MEDLINE | ID: covidwho-1094165

ABSTRACT

By December 2020, the COVID-19 pandemic had caused more than 74 million confirmed cases and 1.6 million related deaths around the world. However, only a few drugs have been approved in certain areas and for use in conditional patients, and the vaccine candidates were only recently approved or authorized for emergency use without being fully implemented worldwide, suggesting that we are yet to reach effective control of the current outbreak as its uninhibited transmission continues precariously. Over the past few months, several therapeutic candidates have been proven ineffective in large clinical trials, while some other agents exhibited promising preliminary results. Meanwhile, the investigation of SARS-CoV-2-specific antivirals is underway. Despite still being preclinical, these agents could be beneficial for the long-term control of COVID-19 and deserve more research focus. In this article, we update the current status of therapeutic candidates that have been examined for COVID-19 management, including the virus-targeting inhibitors and host-targeting agents, with their antiviral efficacy in vitro, in vivo, and in clinical studies. Finally, we highlight the current challenges and future prospect of developing potent therapeutic agents against COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , /physiology , Animals , Humans , Pandemics , Virus Replication/drug effects
11.
Front Immunol ; 11: 594963, 2020.
Article in English | MEDLINE | ID: covidwho-1094164

ABSTRACT

When viruses infect cells, they almost invariably cause metabolic changes in the infected cell as well as in several host cell types that react to the infection. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Several examples are discussed in this review, which include effects on energy metabolism, glutaminolysis and fatty acid metabolism. The response of the immune system also involves metabolic changes and manipulating these may change the outcome of infection. This could include changing the status of herpesviruses infections from productive to latency. The consequences of viral infections which include coronavirus disease 2019 (COVID-19), may also differ in patients with metabolic problems, such as diabetes mellitus (DM), obesity, and endocrine diseases. Nutrition status may also affect the pattern of events following viral infection and examples that impact on the pattern of human and experimental animal viral diseases and the mechanisms involved are discussed. Finally, we discuss the so far few published reports that have manipulated metabolic events in-vivo to change the outcome of virus infection. The topic is expected to expand in relevance as an approach used alone or in combination with other therapies to shape the nature of virus induced diseases.


Subject(s)
/metabolism , Herpesviridae Infections/metabolism , Herpesviridae/physiology , Obesity/metabolism , /physiology , Animals , Energy Metabolism , Herpesviridae Infections/complications , Humans , Immunity , Lipid Metabolism , Nutritional Physiological Phenomena , Obesity/complications , Pandemics , Virus Latency
12.
Methods Mol Biol ; 2273: 131-138, 2021.
Article in English | MEDLINE | ID: covidwho-1092090

ABSTRACT

The current coronavirus disease-19 (COVID-19) pandemic, caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), underscores the threat posed by newly emerging viruses. The understanding of the mechanisms driving early infection events, that are crucial for the exponential spread of the disease, is mandatory and can be significantly implemented generating 3D in vitro models as experimental platforms to investigate the infection substrates and how the virus invades and ravages the tissues.We here describe a protocol for the creation of a synthetic hydrogel-based 3D culture system that mimics in vitro the complex architectures and mechanical cues distinctive of the upper airway epithelia. We then expose the in vitro generated 3D nasal and tracheal epithelia to gold nanoparticles (AuNPs) that display the typical shape and size distinctive of SARS-CoV-2 and of the majority of Coronaviridae presently known.The infection platform here described provides an efficient and highly physiological in vitro model that reproduces the host-pathogen early interactions, using virus-mimicking nanoparticles, and offers a flexible tool to study virus entry into the cell. At the same time, it reduces the risk of accidental infection/spillovers for researchers, which represents a crucial aspect when dealing with a virus that is highly contagious, virulent, and even deadly.


Subject(s)
/metabolism , Cell Culture Techniques/methods , Epithelial Cells/cytology , Nanoparticles/metabolism , Respiratory Mucosa/cytology , Animals , Cell Line , Chlorocebus aethiops , Epithelial Cells/virology , Gold , Humans , Metal Nanoparticles/chemistry , Molecular Mimicry/immunology , Nose/virology , Respiratory Mucosa/virology , /pathogenicity , Trachea/virology , Vero Cells , Virus Internalization
13.
Nat Commun ; 12(1): 1112, 2021 02 18.
Article in English | MEDLINE | ID: covidwho-1091491

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.


Subject(s)
/diagnosis , Interleukin-3/blood , Animals , Chemokine CXCL12/immunology , Dendritic Cells/cytology , Disease Models, Animal , Female , Germany , Humans , Immunity, Innate , Interferons/blood , Lung/immunology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Prospective Studies , Severity of Illness Index , T-Lymphocytes/cytology , Viral Load
15.
Microbiome ; 9(1): 51, 2021 02 20.
Article in English | MEDLINE | ID: covidwho-1090608

ABSTRACT

BACKGROUND: The detection of pathogens in clinical and environmental samples using high-throughput sequencing (HTS) is often hampered by large amounts of background information, which is especially true for viruses with small genomes. Enormous sequencing depth can be necessary to compile sufficient information for identification of a certain pathogen. Generic HTS combining with in-solution capture enrichment can markedly increase the sensitivity for virus detection in complex diagnostic samples. METHODS: A virus panel based on the principle of biotinylated RNA baits was developed for specific capture enrichment of epizootic and zoonotic viruses (VirBaits). The VirBaits set was supplemented by a SARS-CoV-2 predesigned bait set for testing recent SARS-CoV-2-positive samples. Libraries generated from complex samples were sequenced via generic HTS (without enrichment) and afterwards enriched with the VirBaits set. For validation, an internal proficiency test for emerging epizootic and zoonotic viruses (African swine fever virus, Ebolavirus, Marburgvirus, Nipah henipavirus, Rift Valley fever virus) was conducted. RESULTS: The VirBaits set consists of 177,471 RNA baits (80-mer) based on about 18,800 complete viral genomes targeting 35 epizootic and zoonotic viruses. In all tested samples, viruses with both DNA and RNA genomes were clearly enriched ranging from about 10-fold to 10,000-fold for viruses including distantly related viruses with at least 72% overall identity to viruses represented in the bait set. Viruses showing a lower overall identity (38% and 46%) to them were not enriched but could nonetheless be detected based on capturing conserved genome regions. The internal proficiency test supports the improved virus detection using the combination of HTS plus targeted enrichment but also points to the risk of cross-contamination between samples. CONCLUSIONS: The VirBaits approach showed a high diagnostic performance, also for distantly related viruses. The bait set is modular and expandable according to the favored diagnostics, health sector, or research question. The risk of cross-contamination needs to be taken into consideration. The application of the RNA-baits principle turned out to be user friendly, and even non-experts can easily use the VirBaits workflow. The rapid extension of the established VirBaits set adapted to actual outbreak events is possible as shown for SARS-CoV-2. Video abstract.


Subject(s)
/isolation & purification , Viruses/isolation & purification , Zoonoses/diagnosis , Animals , DNA, Viral/genetics , Genome, Viral , Humans , RNA, Viral/genetics , Viruses/classification
16.
Front Immunol ; 11: 624411, 2020.
Article in English | MEDLINE | ID: covidwho-1090416

ABSTRACT

SARS-CoV-2 is wreaking havoc around the world. To get the world back on track, hundreds of vaccines are under development. A deeper understanding of how the immune system responds to SARS-CoV-2 re-infection will certainly help. Studies have highlighted various aspects of T cell response in resolving acute infection and preventing re-infections. Lung resident memory T (TRM) cells are sentinels in the secondary immune response. They are mostly differentiated from effector T cells, construct specific niches and stay permanently in lung tissues. If the infection recurs, locally activated lung TRM cells can elicit rapid immune response against invading pathogens. In addition, they can significantly limit tumor growth or lead to pathologic immune responses. Vaccines targeting TRM cells are under development, with the hope to induce stable and highly reactive lung TRM cells through mucosal administration or "prime-and-pull" strategy. In this review, we will summarize recent advances in lung TRM cell generation and maintenance, explore their roles in different diseases and discuss how these cells may guide the development of future vaccines targeting infectious disease, cancer, and pathologic immune response.


Subject(s)
/immunology , Immunotherapy, Adoptive/methods , Lung/immunology , Neoplasms/immunology , T-Lymphocytes/immunology , Vaccines/immunology , Animals , Humans , Immunologic Memory , Lymphocyte Activation , T-Lymphocytes/transplantation
17.
PLoS Negl Trop Dis ; 15(2): e0009109, 2021 02.
Article in English | MEDLINE | ID: covidwho-1088657

ABSTRACT

Public health institutions with sectorized structure and low integration among field teams, old-fashioned practices such as paper-based storage system, and poorly qualified health agents have limited ability to conduct accurate surveillance and design effective timely interventions. Herein, we describe the steps taken by the Zoonosis Control Center of Foz do Iguaçu (CCZ-Foz) in the last 23 years to move from an archaic and sectorized structure to a modern and timely surveillance program embracing zoonotic diseases, venomous animal injuries, and vector-borne diseases epidemiology under the One Health approach. The full implementation of the One Health approach was based on 5 axes: (1) merging sectorized field teams; (2) adoption of digital solutions; (3) health agents empowerment and permanent capacitation; (4) social mobilization; and (5) active surveys. By doing so, notifications related to zoonotic diseases and venomous animals increased 10 and 21 times, respectively, with no impairment on arbovirus surveillance (major concern in the city). Open sources database (PostgreSQL) and software (QGis) are daily updated and create real-time maps to support timely decisions. The adoption of One Health approach increased preparedness for endemic diseases and reemerging and emerging threats such as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).


Subject(s)
Bites and Stings/epidemiology , Epidemiological Monitoring , One Health , Vector Borne Diseases/epidemiology , Zoonoses/epidemiology , Animals , Brazil , Databases, Factual , Geographic Information Systems , Humans , Organizations/organization & administration
18.
Mol Cancer ; 20(1): 33, 2021 02 16.
Article in English | MEDLINE | ID: covidwho-1088597

ABSTRACT

mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases.


Subject(s)
Vaccines, Synthetic/therapeutic use , Animals , Gene Transfer Techniques , Humans , Immunity, Humoral , Immunotherapy , RNA Stability , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
19.
mSphere ; 6(1)2021 02 17.
Article in English | MEDLINE | ID: covidwho-1088203

ABSTRACT

Many viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV), have a structure consisting of spikes protruding from an underlying spherical surface. Research in biological and colloidal sciences has revealed secrets of why spikes exist on virus surfaces. Specifically, the spikes favor virus attachment on surfaces via receptor-specific interactions (RSIs), mediate the membrane fusion, and determine or change viral tropism. The spikes also facilitate viruses to approach surfaces before attachment and subsequently escape back to the environment if RSIs do not occur (i.e., easy come and easy go). Therefore, virus spikes create the paradox of having a large capacity for binding with cells (high infectivity) and meanwhile great mobility in the environment. Such structure-function relationships have important implications for the fabrication of virus-like particles and analogous colloids (e.g., hedgehog- and raspberry-like particles) for applications such as the development of antiviral vaccines and drug delivery.


Subject(s)
/transmission , /pathogenicity , Spike Glycoprotein, Coronavirus/metabolism , Animals , HIV/metabolism , HIV/pathogenicity , HIV Infections/transmission , Humans , Viral Proteins/metabolism , Viral Tropism/physiology , Virus Internalization
20.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Article in English | MEDLINE | ID: covidwho-1087557

ABSTRACT

Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mp ro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC50) value below 100 µM in inhibiting Mp ro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting Mp ro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti-SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC50) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.


Subject(s)
Antiviral Agents/pharmacology , Bepridil/pharmacology , Drug Discovery , /drug effects , A549 Cells , Animals , Chlorocebus aethiops , Humans , Molecular Docking Simulation , Molecular Structure , Small Molecule Libraries , Vero Cells
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