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1.
J Virol ; 95(13): e0019221, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1486499

ABSTRACT

Understanding factors that affect the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is central to combatting coronavirus disease 2019 (COVID-19). The virus surface spike protein of SARS-CoV-2 mediates viral entry into cells by binding to the ACE2 receptor on epithelial cells and promoting fusion. We found that Epstein-Barr virus (EBV) induces ACE2 expression when it enters the lytic replicative cycle in epithelial cells. By using vesicular stomatitis virus (VSV) particles pseudotyped with the SARS-CoV-2 spike protein, we showed that lytic EBV replication enhances ACE2-dependent SARS-CoV-2 pseudovirus entry. We found that the ACE2 promoter contains response elements for Zta, an EBV transcriptional activator that is essential for EBV entry into the lytic cycle of replication. Zta preferentially acts on methylated promoters, allowing it to reactivate epigenetically silenced EBV promoters from latency. By using promoter assays, we showed that Zta directly activates methylated ACE2 promoters. Infection of normal oral keratinocytes with EBV leads to lytic replication in some of the infected cells, induces ACE2 expression, and enhances SARS-CoV-2 pseudovirus entry. These data suggest that subclinical EBV replication and lytic gene expression in epithelial cells, which is ubiquitous in the human population, may enhance the efficiency and extent of SARS-CoV-2 infection of epithelial cells by transcriptionally activating ACE2 and increasing its cell surface expression. IMPORTANCE SARS-CoV-2, the coronavirus responsible for COVID-19, has caused a pandemic leading to millions of infections and deaths worldwide. Identifying the factors governing susceptibility to SARS-CoV-2 is important in order to develop strategies to prevent SARS-CoV-2 infection. We show that Epstein-Barr virus, which infects and persists in >90% of adult humans, increases susceptibility of epithelial cells to infection by SARS-CoV-2. EBV, when it reactivates from latency or infects epithelial cells, increases expression of ACE2, the cellular receptor for SARS-CoV-2, enhancing infection by SARS-CoV-2. Inhibiting EBV replication with antivirals may therefore decrease susceptibility to SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Epithelial Cells/virology , Herpesvirus 4, Human/physiology , SARS-CoV-2/physiology , Virus Internalization , Virus Replication , Angiotensin-Converting Enzyme 2/metabolism , Cell Line , DNA Methylation , Epithelial Cells/metabolism , Gene Expression Regulation , Humans , Promoter Regions, Genetic , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Trans-Activators/metabolism , Virus Activation
2.
Cell Host Microbe ; 29(2): 160-164, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-1385266

ABSTRACT

The emergence of alternate variants of SARS-CoV-2 due to ongoing adaptations in humans and following human-to-animal transmission has raised concern over the efficacy of vaccines against new variants. We describe human-to-animal transmission (zooanthroponosis) of SARS-CoV-2 and its implications for faunal virus persistence and vaccine-mediated immunity.


Subject(s)
COVID-19/veterinary , Communicable Diseases, Emerging/veterinary , SARS-CoV-2/pathogenicity , Zoonoses/transmission , Zoonoses/virology , Animals , COVID-19/immunology , COVID-19/transmission , COVID-19/virology , Communicable Diseases, Emerging/transmission , Communicable Diseases, Emerging/virology , Disease Reservoirs/veterinary , Disease Reservoirs/virology , Humans , Immunity , Viral Vaccines/immunology
3.
SAR QSAR Environ Res ; 32(6): 473-493, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1236142

ABSTRACT

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CLproinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CLpro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CLpro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CLpro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Coronavirus 3C Proteases/chemistry , Drug Design , Drug Discovery , Models, Molecular , Protease Inhibitors/chemistry , Quantitative Structure-Activity Relationship , SARS-CoV-2/enzymology
4.
J Med Virol ; 93(1): 275-299, 2021 01.
Article in English | MEDLINE | ID: covidwho-1206787

ABSTRACT

There have been over seven million cases and almost 413 372 deaths globally due to the novel coronavirus (2019-nCoV) associated disease COVID-19, as of 11 June 2020. Phylogenetic analysis suggests that there is a common source for these infections. The overall sequence similarities between the spike protein of 2019-nCoV and that of SARS-CoV are known to be around 76% to 78% and 73% to 76% for the whole protein and receptor-binding domain (RBD), respectively. Thus, they have the potential to serve as the drug and/or vaccine candidate. However, the individual response against 2019-nCoV differs due to genetic variations in the human population. Understanding the variations in angiotensin-converting enzyme 2 (ACE2) and human leukocyte antigen (HLA) that may affect the severity of 2019-nCoV infection could help in identifying individuals at a higher risk from the COVID-19. A number of potential drugs/vaccines as well as antibody/cytokine-based therapeutics are in various developmental stages of preclinical/clinical trials against SARS-CoV, MERS-CoV, and 2019-nCoV with substantial cross-reactivity, and may be used against COVID-19. For diagnosis, the reverse-transcription polymerase chain reaction is the gold standard test for initial diagnosis of COVID-19. A kit based on serological tests are also recommended for investigating the spread of COVID-19 but this is challenging due to the antibodies cross-reactivity. This review comprehensively summarizes the recent reports available regarding the host-pathogen interaction, morphological and genomic structure of the virus, and the diagnostic techniques as well as the available potential therapeutics against COVID-19.


Subject(s)
COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/therapy , Host-Pathogen Interactions , SARS-CoV-2/genetics , Animals , Antibodies, Viral/immunology , Chiroptera/virology , Cross Reactions , Humans , Phylogeny , Receptors, Virus/chemistry , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics
5.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1203483

ABSTRACT

Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2/immunology , Single-Domain Antibodies , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/immunology , Antibodies, Viral/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Camelids, New World , Humans , Mice , Single-Domain Antibodies/immunology , Single-Domain Antibodies/pharmacology
6.
J Gen Virol ; 102(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1186013

ABSTRACT

SARS-CoV-2 is thought to have originated in the human population from a zoonotic spillover event. Infection in humans results in a variety of outcomes ranging from asymptomatic cases to the disease COVID-19, which can have significant morbidity and mortality, with over two million confirmed deaths worldwide as of January 2021. Over a year into the pandemic, sequencing analysis has shown that variants of SARS-CoV-2 are being selected as the virus continues to circulate widely within the human population. The predominant drivers of genetic variation within SARS-CoV-2 are single nucleotide polymorphisms (SNPs) caused by polymerase error, potential host factor driven RNA modification, and insertion/deletions (indels) resulting from the discontinuous nature of viral RNA synthesis. While many mutations represent neutral 'genetic drift' or have quickly died out, a subset may be affecting viral traits such as transmissibility, pathogenicity, host range, and antigenicity of the virus. In this review, we summarise the current extent of genetic change in SARS-CoV-2, particularly recently emerging variants of concern, and consider the phenotypic consequences of this viral evolution that may impact the future trajectory of the pandemic.


Subject(s)
Adaptation, Physiological/genetics , COVID-19/virology , SARS-CoV-2/genetics , Animals , Antigens, Viral/genetics , Antigens, Viral/immunology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/transmission , Humans , Immune Evasion/genetics , Mutation , RNA, Viral/biosynthesis , RNA, Viral/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Internalization , Virus Replication , Zoonoses/transmission , Zoonoses/virology
7.
Front Cell Dev Biol ; 9: 626821, 2021.
Article in English | MEDLINE | ID: covidwho-1175535

ABSTRACT

Deciphering the functional impact of genetic variation is required to understand phenotypic diversity and the molecular mechanisms of inherited disease and cancer. While millions of genetic variants are now mapped in genome sequencing projects, distinguishing functional variants remains a major challenge. Protein-coding variation can be interpreted using post-translational modification (PTM) sites that are core components of cellular signaling networks controlling molecular processes and pathways. ActiveDriverDB is an interactive proteo-genomics database that uses more than 260,000 experimentally detected PTM sites to predict the functional impact of genetic variation in disease, cancer and the human population. Using machine learning tools, we prioritize proteins and pathways with enriched PTM-specific amino acid substitutions that potentially rewire signaling networks via induced or disrupted short linear motifs of kinase binding. We then map these effects to site-specific protein interaction networks and drug targets. In the 2021 update, we increased the PTM datasets by nearly 50%, included glycosylation, sumoylation and succinylation as new types of PTMs, and updated the workflows to interpret inherited disease mutations. We added a recent phosphoproteomics dataset reflecting the cellular response to SARS-CoV-2 to predict the impact of human genetic variation on COVID-19 infection and disease course. Overall, we estimate that 16-21% of known amino acid substitutions affect PTM sites among pathogenic disease mutations, somatic mutations in cancer genomes and germline variants in the human population. These data underline the potential of interpreting genetic variation through the lens of PTMs and signaling networks. The open-source database is freely available at www.ActiveDriverDB.org.

8.
BMJ Open ; 11(4): e041619, 2021 04 09.
Article in English | MEDLINE | ID: covidwho-1175167

ABSTRACT

OBJECTIVES: To comprehensively map the existing evidence assessing the impact of travel-related control measures for containment of the SARS-CoV-2/COVID-19 pandemic. DESIGN: Rapid evidence map. DATA SOURCES: MEDLINE, Embase and Web of Science, and COVID-19 specific databases offered by the US Centers for Disease Control and Prevention and the WHO. ELIGIBILITY CRITERIA: We included studies in human populations susceptible to SARS-CoV-2/COVID-19, SARS-CoV-1/severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus/Middle East respiratory syndrome or influenza. Interventions of interest were travel-related control measures affecting travel across national or subnational borders. Outcomes of interest included infectious disease, screening, other health, economic and social outcomes. We considered all empirical studies that quantitatively evaluate impact available in Armenian, English, French, German, Italian and Russian based on the team's language capacities. DATA EXTRACTION AND SYNTHESIS: We extracted data from included studies in a standardised manner and mapped them to a priori and (one) post hoc defined categories. RESULTS: We included 122 studies assessing travel-related control measures. These studies were undertaken across the globe, most in the Western Pacific region (n=71). A large proportion of studies focused on COVID-19 (n=59), but a number of studies also examined SARS, MERS and influenza. We identified studies on border closures (n=3), entry/exit screening (n=31), travel-related quarantine (n=6), travel bans (n=8) and travel restrictions (n=25). Many addressed a bundle of travel-related control measures (n=49). Most studies assessed infectious disease (n=98) and/or screening-related (n=25) outcomes; we found only limited evidence on economic and social outcomes. Studies applied numerous methods, both inferential and descriptive in nature, ranging from simple observational methods to complex modelling techniques. CONCLUSIONS: We identified a heterogeneous and complex evidence base on travel-related control measures. While this map is not sufficient to assess the effectiveness of different measures, it outlines aspects regarding interventions and outcomes, as well as study methodology and reporting that could inform future research and evidence synthesis.


Subject(s)
COVID-19/prevention & control , Pandemics , Travel , Geography, Medical , Humans , Pandemics/prevention & control
9.
Front Genet ; 12: 581726, 2021.
Article in English | MEDLINE | ID: covidwho-1172965

ABSTRACT

In <20 years, we have witnessed three different epidemics with coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2 in human populations, causing widespread mortality. SARS-CoV-2, through its rapid global spread, has led to the pandemic that we call COVID-19. As of February 1, 2021, the global infections linked to SARS-CoV-2 stand at 103,503,340, with 2,236,960 deaths, and 75,108,099 recoveries. This review attempts to highlight host-pathogen interaction with particular emphasis on the role of epigenetic machinery in regulating the disease. Although researchers, since the start of the pandemic, have been intensely engaged in diverse areas to understand the mechanisms involved in SARS-CoV-2 infection to find answers that can bring about innovative ways to swiftly treat and prevent disease progression, this review provides an overview on how the host epigenetics is modulated and subverted by SARS-CoV-2 to enter the host cells and drive immunopathogenesis. Epigenetics is the study that combines genetic and non-genetic factors controlling phenotypic variation, which are primarily a consequence of external and environmental stimuli. These stimuli alter the activity of a gene without impinging on the DNA code. In viral-host interactions, DNA/RNA methylation, non-coding RNAs, chromatin remodeling, and histone modifications are known to regulate and modulate host gene expression patterns. Viruses such as Coronaviruses (an RNA virus) show intrinsic association with these processes. They have evolved the ability to tamper with host epigenetic machinery to interfere with immune sensing pathways to evade host immune response, thereby enhancing its replication and pathogenesis post-entry. These epigenetic alterations allow the virus to weaken the host's immune response to successfully spread infection. How this occurs, and what epigenetic mechanisms are altered is poorly understood both for coronaviruses and other respiratory RNA viruses. The review highlights several cutting-edge aspects of epigenetic work primarily pertinent to SARS-CoV-2, which has been published between 2019 and 2020 to showcase the current knowledge both in terms of success and failures and take lessons that will assist us in understanding the disease to develop better treatments suited to kill SARS-CoV-2.

10.
BMC Microbiol ; 21(1): 89, 2021 03 23.
Article in English | MEDLINE | ID: covidwho-1148210

ABSTRACT

BACKGROUND: When a virus that has grown in a nonhuman host starts an epidemic in the human population, human cells may not provide growth conditions ideal for the virus. Therefore, the invasion of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which is usually prevalent in the bat population, into the human population is thought to have necessitated changes in the viral genome for efficient growth in the new environment. In the present study, to understand host-dependent changes in coronavirus genomes, we focused on the mono- and oligonucleotide compositions of SARS-CoV-2 genomes and investigated how these compositions changed time-dependently in the human cellular environment. We also compared the oligonucleotide compositions of SARS-CoV-2 and other coronaviruses prevalent in humans or bats to investigate the causes of changes in the host environment. RESULTS: Time-series analyses of changes in the nucleotide compositions of SARS-CoV-2 genomes revealed a group of mono- and oligonucleotides whose compositions changed in a common direction for all clades, even though viruses belonging to different clades should evolve independently. Interestingly, the compositions of these oligonucleotides changed towards those of coronaviruses that have been prevalent in humans for a long period and away from those of bat coronaviruses. CONCLUSIONS: Clade-independent, time-dependent changes are thought to have biological significance and should relate to viral adaptation to a new host environment, providing important clues for understanding viral host adaptation mechanisms.


Subject(s)
Base Composition , Evolution, Molecular , Genome, Viral , SARS-CoV-2/genetics , Animals , Chiroptera/virology , Humans , Oligonucleotides
11.
Pathog Glob Health ; 115(3): 151-167, 2021 05.
Article in English | MEDLINE | ID: covidwho-1082903

ABSTRACT

Before the 20th century many deaths in England, and most likely a majority, were caused by infectious diseases. The focus here is on the biggest killers, plague, typhus, smallpox, tuberculosis, cholera, typhoid, dysentery, childhood infections, pneumonia, and influenza. Many other infectious diseases including puerperal fever, relapsing fever, malaria, syphilis, meningitis, tetanus and gangrene caused thousands of deaths. This review of preventive measures, public health interventions and changes in behavior that reduced the risk of severe infections puts the response to recent epidemic challenges in historical perspective. Two new respiratory viruses have recently caused pandemics: an H1N1 influenza virus genetically related to pig viruses, and a bat-derived coronavirus causing COVID-19. Studies of infectious diseases emerging in human populations in recent decades indicate that the majority were zoonotic, and many of the causal pathogens had a wildlife origin. As hunter-gatherers, humans contracted pathogens from other species, and then from domesticated animals and rodents when they began to live in settled communities based on agriculture. In the modern world of large inter-connected urban populations and rapid transport, the risk of global transmission of new infectious diseases is high. Past and recent experience indicates that surveillance, prevention and control of infectious diseases are critical for global health. Effective interventions are required to control activities that risk dangerous pathogens transferring to humans from wild animals and those reared for food.


Subject(s)
Communicable Disease Control/history , Communicable Diseases/history , Animals , Communicable Diseases/epidemiology , Communicable Diseases/microbiology , Communicable Diseases/virology , History, 15th Century , History, 16th Century , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , History, 21st Century , History, Ancient , History, Medieval , Humans , Public Health/history
12.
Cell Host Microbe ; 29(2): 160-164, 2021 02 10.
Article in English | MEDLINE | ID: covidwho-1064929

ABSTRACT

The emergence of alternate variants of SARS-CoV-2 due to ongoing adaptations in humans and following human-to-animal transmission has raised concern over the efficacy of vaccines against new variants. We describe human-to-animal transmission (zooanthroponosis) of SARS-CoV-2 and its implications for faunal virus persistence and vaccine-mediated immunity.


Subject(s)
COVID-19/veterinary , Communicable Diseases, Emerging/veterinary , SARS-CoV-2/pathogenicity , Zoonoses/transmission , Zoonoses/virology , Animals , COVID-19/immunology , COVID-19/transmission , COVID-19/virology , Communicable Diseases, Emerging/transmission , Communicable Diseases, Emerging/virology , Disease Reservoirs/veterinary , Disease Reservoirs/virology , Humans , Immunity , Viral Vaccines/immunology
13.
J Infect Dev Ctries ; 14(12): 1374-1379, 2020 12 31.
Article in English | MEDLINE | ID: covidwho-1000366

ABSTRACT

INTRODUCTION: Coronavirus infectious disease 2019 (COVID-19) is currently one of the most important public health crises affecting the global human population. It continues to spread widely, as the world still lacks specific treatments and a vaccine for the virus. The scenario of COVID-19 in Yemen seems obscure due to the lack of adequate data, therefore, we developed an electronic questionnaire and distributed it online among Yemeni people. The aim of this study was to understand the COVID-19 epidemiological situation in Yemen better since there is currently limited published data and limited availability of COVID-19 testing. METHODOLOGY: A 34-question web-based survey was distributed on social media outlets targeting people in Yemen. Data aggregation, analysis, and visualization were performed using Tableau and Microsoft Excel. RESULTS: 2,341 individuals reported symptoms concerning for COVID-19 infection, with 25.4% reporting a chronic medical condition. Diabetes, hypertension, asthma, and immune deficiency were associated with increased severity of the disease, while obesity, cardiovascular disease, kidney disease, and liver disease were not. Only 37 individuals (1.6%) had a confirmatory COVID-19 PCR test. The presence of high fever, dyspnea, chest pain, and dysphagia were symptoms that tended to be correlated to worse clinical outcomes. CONCLUSIONS: This study provides some important information about the early overspread of COVID-19 within the Yemeni community in May, June, and July of 2020. It shows that online questionnaires may help in collecting data about pandemics in resource-limited countries where testing availability is limited.


Subject(s)
COVID-19/epidemiology , COVID-19/transmission , Surveys and Questionnaires , Adult , COVID-19/physiopathology , COVID-19 Nucleic Acid Testing , Comorbidity , Female , Humans , Male , SARS-CoV-2/genetics , Severity of Illness Index , Social Media , Yemen/epidemiology , Young Adult
14.
Front Pediatr ; 8: 584694, 2020.
Article in English | MEDLINE | ID: covidwho-993402

ABSTRACT

The ongoing pandemic of COVID-19, which is caused by the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), constituted significant public health concerns and impacted the human populations with massive economic and social burdens worldwide. The disease is known to infect people of all ages, including children, adults, and the elderly. Although several reports about pediatric COVID-19 were seen in the literature, we believe that the epidemiology and pathology of the infection described in these reports are not conclusive. Therefore, in this scientific communication, a narrative review study was performed to shed some light on the characteristic epidemiological features and clinical phenotypes of pediatric COVID-19. In this report, we had compiled and presented the different epidemiological features of the disease related to the age of infection, virus acquisition, explanations of the low infectivity rates, and consequences of infections. The discriminatory clinical manifestations of the disease in children were also addressed and discussed in this review. The search included the data published from the date of the start of the pandemic in December 2019 up to October 2020. Our literature search revealed that children of all ages, including neonates, had been infected by the virus. Despite the fact that pediatric COVID-19 is less common to occur, as compared to the disease in adults, the infected children usually manifest the disease symptomatology in benign form. Asymptomatic and symptomatic adult patients are the primary source of the virus to the children. Intrauterine transmission of the virus and breastfeeding infections to the neonates were hypothesized in some studies but ruled out since they were not confirmed. Intensive review and discussion warranting the low infection rates and benign conditions of COVID-19 in children were also made in this study. As documented in many studies, the infectivity, morbidity, and mortality rates of the disease among the children populations are much lower than those in adults. They also seem to be lower than those observed during SARS-CoV and MERS-CoV epidemics. The described clinical phenotypes of COVID-19 in children do not differ much from those of adults, and complications of the disease seem to be associated with comorbidities.

15.
Cells ; 9(12)2020 12 04.
Article in English | MEDLINE | ID: covidwho-965318

ABSTRACT

Human herpesvirus 6 (HHV-6) is a ß-herpesvirus that is highly prevalent in the human population. HHV-6 comprises two recognized species (HHV-6A and HHV-6B). Despite different cell tropism and disease association, HHV-6A/B show high genome homology and harbor the conserved U94 gene, which is limited to HHV-6 and absent in all the other human herpesviruses. U94 has key functions in the virus life cycle and associated diseases, having demonstrated or putative roles in virus replication, integration, and reactivation. During natural infection, U94 elicits an immune response, and the prevalence and extent of the anti-U94 response are associated with specific diseases. Notably, U94 can entirely reproduce some virus effects at the cell level, including inhibition of cell migration, induction of cytokines and HLA-G expression, and angiogenesis inhibition, supporting a direct U94 role in the development of HHV-6-associated diseases. Moreover, specific U94 properties, such as the ability to modulate angiogenesis pathways, have been exploited to counteract cancer development. Here, we review the information available on this key HHV-6 gene, highlighting its potential uses.


Subject(s)
Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/immunology , Roseolovirus Infections/virology , Viral Proteins/physiology , Animals , Cell Line , Cell Movement , Cytokines/metabolism , Genome, Viral , HLA-G Antigens/metabolism , Humans , Immune System , Mice , Neovascularization, Pathologic , Rats , Roseolovirus Infections/epidemiology , Viral Proteins/genetics , Virus Integration , Virus Replication
16.
Rev Francoph Lab ; 2020(526): 32-39, 2020 Nov.
Article in French | MEDLINE | ID: covidwho-915753

ABSTRACT

Four coronaviruses cause frequent and most often mild respiratory infections in humans: HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU 1. In addition to these endemic human coronaviruses, three new coronaviruses of zoonotic origin have emerged in the human population over the past 20 years. SARS-CoV (-1) appeared in 2003, MERS-CoV appeared in 2012, and SARS-CoV-2 appeared in 20l9. These three coronaviruses are the causative agents of a severe respiratory syndrome. The epidemic of the severe acute respiratory syndrome (SARS) due to SARS-CoV-l affected approximately 8,000 individuals and caused approximately 800 deaths but was brought under control within a few months. MERS-CoV has caused more than 2,500 cases since 20l2 with a mortality of around 35 %. SARS-CoV-2 is currently responsible for a major pandemic with significant mortality in the elderly or in patients with underlying diseases.

17.
Nat Rev Immunol ; 20(11): 709-713, 2020 11.
Article in English | MEDLINE | ID: covidwho-834892

ABSTRACT

Immunity is a multifaceted phenomenon. For T cell-mediated memory responses to SARS-CoV-2, it is relevant to consider their impact both on COVID-19 disease severity and on viral spread in a population. Here, we reflect on the immunological and epidemiological aspects and implications of pre-existing cross-reactive immune memory to SARS-CoV-2, which largely originates from previous exposure to circulating common cold coronaviruses. We propose four immunological scenarios for the impact of cross-reactive CD4+ memory T cells on COVID-19 severity and viral transmission. For each scenario, we discuss its implications for the dynamics of herd immunity and on projections of the global impact of SARS-CoV-2 on the human population, and assess its plausibility. In sum, we argue that key potential impacts of cross-reactive T cell memory are already incorporated into epidemiological models based on data of transmission dynamics, particularly with regard to their implications for herd immunity. The implications of immunological processes on other aspects of SARS-CoV-2 epidemiology are worthy of future study.


Subject(s)
Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Coronaviridae Infections/prevention & control , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Adaptive Immunity/drug effects , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , COVID-19 , COVID-19 Vaccines , Coronaviridae/drug effects , Coronaviridae/immunology , Coronaviridae Infections/epidemiology , Coronaviridae Infections/immunology , Coronaviridae Infections/virology , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cross Reactions , Humans , Immunity, Herd/drug effects , Immunologic Memory , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Rhinovirus/drug effects , Rhinovirus/immunology , SARS-CoV-2 , Viral Vaccines/administration & dosage , Viral Vaccines/biosynthesis
18.
J Mol Model ; 26(8): 200, 2020 Jul 07.
Article in English | MEDLINE | ID: covidwho-650087

ABSTRACT

Beta-lactamase (ampC) in general causes the onset of antibiotic resistance in pathogenic bacteria against the ß-lactam antibiotics. Morganella morganii which belongs to the Proteae tribe of the Enterobacteriaceae family is a Gram-negative bacillus. Gram-negative bacteria are the key problematic agents among the human population in overexpressing resistance against ß-lactam antibiotics. These ß-lactam antibiotics being experimentally well studied still lack the key information and mechanism for their resistance. The structural information of the ampC protein is unknown and poorly studied; hence, it is the need of the hour to find effective inhibitors against it. In our study, the prediction of the three-dimensional structure of ampC protein from Morganella morganii was performed using a comparative modelling approach. The predicted structure was energetically stabilized and functional conformations were mapped through 100-ns molecular dynamics simulation runs. Also, Ramachandran plot shows the model to be stereo-chemically stable with most residues found under core allowed regions. Drug screening with several experimentally tested inhibitors was then confirmed to check the activity against ampC protein using an AutoDock tool. The results suggested OncoglabrinolC molecule as the best inhibitor (out of 21 drug molecules) with a binding affinity of - 11.44 kcal/mol. Anti-bacterial/anti-parasitic inhibitors have not only been used against bacterial infections, but later reports have also shown them to work against deadly viruses such as SARS-CoV2. This key structural and inhibitory information is certain to help in the discovery of specific and potent substitute therapeutic drugs and the development of experimental procedures against human infection.


Subject(s)
Anti-Bacterial Agents/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , beta-Lactamase Inhibitors/chemistry , beta-Lactamases/chemistry , Anti-Bacterial Agents/pharmacology , Base Sequence , Binding Sites , Chemical Phenomena , Drug Discovery , Drug Evaluation, Preclinical , Humans , Ligands , Mutation , Protein Binding , Protein Conformation , beta-Lactamase Inhibitors/pharmacology , beta-Lactamases/genetics
19.
Front Immunol ; 11: 2033, 2020.
Article in English | MEDLINE | ID: covidwho-760861

ABSTRACT

Immune dysfunction and aberrant cytokine storms often lead to rapid exacerbation of the disease during late infection stages in SARS-CoV and MERS-CoV patients. However, the underlying immunopathology mechanisms are not fully understood, and there has been little progress in research regarding the development of vaccines, anti-viral drugs, and immunotherapy. The newly discovered SARS-CoV-2 (2019-nCoV) is responsible for the third coronavirus pandemic in the human population, and this virus exhibits enhanced pathogenicity and transmissibility. SARS-CoV-2 is highly genetically homologous to SARS-CoV, and infection may result in a similar clinical disease (COVID-19). In this review, we provide detailed knowledge of the pathogenesis and immunological characteristics of SARS and MERS, and we present recent findings regarding the clinical features and potential immunopathogenesis of COVID-19. Host immunological characteristics of these three infections are summarised and compared. We aim to provide insights and scientific evidence regarding the pathogenesis of COVID-19 and therapeutic strategies targeting this disease.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , Pneumonia, Viral/pathology , SARS Virus/immunology , Severe Acute Respiratory Syndrome/immunology , COVID-19 , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/pathology
20.
Front Pharmacol ; 11: 1214, 2020.
Article in English | MEDLINE | ID: covidwho-732851

ABSTRACT

SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired substantial knowledge of this virus and the clinical course of COVID-19 progression. Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Initial case reports indicated many succumb to COVID-19 of hypoxic respiratory failure due to ARDS. However, ensuing studies revealed an atypical, immune cell-sequestered, vasculature-inflamed state leading to multiorgan thrombotic complications and end organ failure likely due to hyperinflammatory host responses. This Perspective focuses on a potential mechanism for a key COVID-19 disease progression turning point related to vascular and airway inflammation. The leukotriene lipid mediators have been overlooked with discussion centering on cytokine storms unleashing the deadly form of COVID-19. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo® controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair®).

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