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1.
Cell Death Dis ; 13(3): 235, 2022 03 14.
Article in English | MEDLINE | ID: covidwho-1740434

ABSTRACT

Coronavirus disease 2019 (COVID-19) has gained prominence as a global pandemic. Studies have suggested that systemic alterations persist in a considerable proportion of COVID-19 patients after hospital discharge. We used proteomic and metabolomic approaches to analyze plasma samples obtained from 30 healthy subjects and 54 COVID-19 survivors 6 months after discharge from the hospital, including 30 non-severe and 24 severe patients. Through this analysis, we identified 1019 proteins and 1091 metabolites. The differentially expressed proteins and metabolites were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Among the patients evaluated, 41% of COVID-19 survivors reported at least one clinical symptom and 26.5% showed lung imaging abnormalities at 6 months after discharge. Plasma proteomics and metabolomics analysis showed that COVID-19 survivors differed from healthy control subjects in terms of the extracellular matrix, immune response, and hemostasis pathways. COVID-19 survivors also exhibited abnormal lipid metabolism, disordered immune response, and changes in pulmonary fibrosis-related proteins. COVID-19 survivors show persistent proteomic and metabolomic abnormalities 6 months after discharge from the hospital. Hence, the recovery period for COVID-19 survivors may be longer.


Subject(s)
COVID-19/mortality , Metabolomics/methods , Patient Discharge/statistics & numerical data , Proteomics/methods , SARS Virus/pathogenicity , Female , Humans , Male , Middle Aged , Survivors , Time Factors
2.
Viruses ; 14(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1625346

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a major complication of the respiratory illness coronavirus disease 2019, with a death rate reaching up to 40%. The main underlying cause of ARDS is a cytokine storm that results in a dysregulated immune response. This review discusses the role of cytokines and chemokines in SARS-CoV-2 and its predecessors SARS-CoV and MERS-CoV, with particular emphasis on the elevated levels of inflammatory mediators that are shown to be correlated with disease severity. For this purpose, we reviewed and analyzed clinical studies, research articles, and reviews published on PubMed, EMBASE, and Web of Science. This review illustrates the role of the innate and adaptive immune responses in SARS, MERS, and COVID-19 and identifies the general cytokine and chemokine profile in each of the three infections, focusing on the most prominent inflammatory mediators primarily responsible for the COVID-19 pathogenesis. The current treatment protocols or medications in clinical trials were reviewed while focusing on those targeting cytokines and chemokines. Altogether, the identified cytokines and chemokines profiles in SARS-CoV, MERS-CoV, and SARS-CoV-2 provide important information to better understand SARS-CoV-2 pathogenesis and highlight the importance of using prominent inflammatory mediators as markers for disease diagnosis and management. Our findings recommend that the use of immunosuppression cocktails provided to patients should be closely monitored and continuously assessed to maintain the desirable effects of cytokines and chemokines needed to fight the SARS, MERS, and COVID-19. The current gap in evidence is the lack of large clinical trials to determine the optimal and effective dosage and timing for a therapeutic regimen.


Subject(s)
COVID-19/immunology , Adaptive Immunity , COVID-19/drug therapy , Chemokines/antagonists & inhibitors , Chemokines/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokines/antagonists & inhibitors , Cytokines/immunology , Humans , Immunity, Innate , Inflammation , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity
3.
Eur Rev Med Pharmacol Sci ; 25(22): 7162-7184, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1552083

ABSTRACT

The last two decades have witnessed the emergence of three deadly coronaviruses (CoVs) in humans: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are still no reliable and efficient therapeutics to manage the devastating consequences of these CoVs. Of these, SARS-CoV-2, the cause of the currently ongoing coronavirus disease 2019 (COVID-19) pandemic, has posed great global health concerns. The COVID-19 pandemic has resulted in an unprecedented crisis with devastating socio-economic and health impacts worldwide. This highlights the fact that CoVs continue to evolve and have the genetic flexibility to become highly pathogenic in humans and other mammals. SARS-CoV-2 carries a high genetic homology to the previously identified CoV (SARS-CoV), and the immunological and pathogenic characteristics of SARS-CoV-2, SARS-CoV, and MERS contain key similarities and differences that can guide therapy and management. This review presents salient and updated information on comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of SARS-CoV, MERS-CoV, and SARS-CoV-2; this can help in the design of more effective vaccines and therapeutics for countering these pathogenic CoVs.


Subject(s)
COVID-19/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Pathology, Molecular/methods , SARS Virus/genetics , SARS-CoV-2/genetics , Animals , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/transmission , Female , Global Health/economics , Humans , Male , Mammals , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Virulence
4.
mBio ; 12(5): e0234221, 2021 10 26.
Article in English | MEDLINE | ID: covidwho-1494971

ABSTRACT

The recent emergence and spread of zoonotic viruses highlights that animal-sourced viruses are the biggest threat to global public health. Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an HKU2-related bat coronavirus that was spilled over from Rhinolophus bats to swine, causing large-scale outbreaks of severe diarrhea disease in piglets in China. Unlike other porcine coronaviruses, SADS-CoV possesses broad species tissue tropism, including primary human cells, implying a significant risk of cross-species spillover. To explore host dependency factors for SADS-CoV as therapeutic targets, we employed genome-wide CRISPR knockout library screening in HeLa cells. Consistent with two independent screens, we identified the zinc finger DHHC-type palmitoyltransferase 17 (ZDHHC17 or ZD17) as an important host factor for SADS-CoV infection. Through truncation mutagenesis, we demonstrated that the DHHC domain of ZD17 that is involved in palmitoylation is important for SADS-CoV infection. Mechanistic studies revealed that ZD17 is required for SADS-CoV genomic RNA replication. Treatment of infected cells with the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly suppressed SADS-CoV infection. Our findings provide insight on SADS-CoV-host interactions and a potential therapeutic application. IMPORTANCE The recent emergence of deadly zoonotic viral diseases, including Ebola virus and SARS-CoV-2, emphasizes the importance of pandemic preparedness for the animal-sourced viruses with potential risk of animal-to-human spillover. Over the last 2 decades, three significant coronaviruses of bat origin, SARS-CoV, MERS-CoV, and SARS-CoV-2, have caused millions of deaths with significant economy and public health impacts. Lack of effective therapeutics against these coronaviruses was one of the contributing factors to such losses. Although SADS-CoV, another coronavirus of bat origin, was only known to cause fatal diarrhea disease in piglets, the ability to infect cells derived from multiple species, including human, highlights the potential risk of animal-to-human spillover. As part of our effort in pandemic preparedness, we explore SADS-CoV host dependency factors as targets for host-directed therapeutic development and found zinc finger DHHC-type palmitoyltransferase 17 is a promising drug target against SADS-CoV replication. We also demonstrated that a palmitoylation inhibitor, 2-bromopalmitate (2-BP), can be used as an inhibitor for SADS-CoV treatment.


Subject(s)
Acyltransferases/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Alphacoronavirus/pathogenicity , Nerve Tissue Proteins/metabolism , Acyltransferases/genetics , Adaptor Proteins, Signal Transducing/genetics , Alphacoronavirus/drug effects , Animals , COVID-19/metabolism , HeLa Cells , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Nerve Tissue Proteins/genetics , Palmitates/pharmacology , SARS Virus/drug effects , SARS Virus/pathogenicity , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Swine
5.
PLoS One ; 16(9): e0257965, 2021.
Article in English | MEDLINE | ID: covidwho-1443851

ABSTRACT

Many important questions remain regarding severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the viral pathogen responsible for COVID-19. These questions include the mechanisms explaining the high percentage of asymptomatic but highly infectious individuals, the wide variability in disease susceptibility, and the mechanisms of long-lasting debilitating effects. Bioinformatic analysis of four coronavirus datasets representing previous outbreaks (SARS-CoV-1 and MERS-CoV), as well as SARS-CoV-2, revealed evidence of diverse host factors that appear to be coopted to facilitate virus-induced suppression of interferon-induced innate immunity, promotion of viral replication and subversion and/or evasion of antiviral immune surveillance. These host factors merit further study given their postulated roles in COVID-19-induced loss of smell and brain, heart, vascular, lung, liver, and gut dysfunction.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , SARS-CoV-2/drug effects , Antiviral Agents/therapeutic use , COVID-19/metabolism , Coronavirus Infections/epidemiology , Databases, Factual , Host-Pathogen Interactions , Humans , Immune Evasion/immunology , Immunity, Innate/immunology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/drug effects , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Virus Replication/drug effects
6.
Mol Biol Evol ; 38(2): 702-715, 2021 01 23.
Article in English | MEDLINE | ID: covidwho-1387955

ABSTRACT

Despite SARS-CoV and SARS-CoV-2 being equipped with highly similar protein arsenals, the corresponding zoonoses have spread among humans at extremely different rates. The specific characteristics of these viruses that led to such distinct outcomes remain unclear. Here, we apply proteome-wide comparative structural analysis aiming to identify the unique molecular elements in the SARS-CoV-2 proteome that may explain the differing consequences. By combining protein modeling and molecular dynamics simulations, we suggest nonconservative substitutions in functional regions of the spike glycoprotein (S), nsp1, and nsp3 that are contributing to differences in virulence. Particularly, we explain why the substitutions at the receptor-binding domain of S affect the structure-dynamics behavior in complexes with putative host receptors. Conservation of functional protein regions within the two taxa is also noteworthy. We suggest that the highly conserved main protease, nsp5, of SARS-CoV and SARS-CoV-2 is part of their mechanism of circumventing the host interferon antiviral response. Overall, most substitutions occur on the protein surfaces and may be modulating their antigenic properties and interactions with other macromolecules. Our results imply that the striking difference in the pervasiveness of SARS-CoV-2 and SARS-CoV among humans seems to significantly derive from molecular features that modulate the efficiency of viral particles in entering the host cells and blocking the host immune response.


Subject(s)
Molecular Dynamics Simulation , Proteomics , SARS Virus/chemistry , SARS Virus/pathogenicity , SARS-CoV-2/chemistry , SARS-CoV-2/pathogenicity , Viral Proteins/chemistry , Animals , Humans , Protein Domains , SARS Virus/metabolism , SARS-CoV-2/metabolism , Species Specificity , Viral Proteins/metabolism
7.
Int J Environ Res Public Health ; 17(5)2020 03 03.
Article in English | MEDLINE | ID: covidwho-1389345

ABSTRACT

Within last 17 years two widespread epidemics of severe acute respiratory syndrome (SARS) occurred in China, which were caused by related coronaviruses (CoVs): SARS-CoV and SARS-CoV-2. Although the origin(s) of these viruses are still unknown and their occurrences in nature are mysterious, some general patterns of their pathogenesis and epidemics are noticeable. Both viruses utilize the same receptor-angiotensin-converting enzyme 2 (ACE2)-for invading human bodies. Both epidemics occurred in cold dry winter seasons celebrated with major holidays, and started in regions where dietary consumption of wildlife is a fashion. Thus, if bats were the natural hosts of SARS-CoVs, cold temperature and low humidity in these times might provide conducive environmental conditions for prolonged viral survival in these regions concentrated with bats. The widespread existence of these bat-carried or -released viruses might have an easier time in breaking through human defenses when harsh winter makes human bodies more vulnerable. Once succeeding in making some initial human infections, spreading of the disease was made convenient with increased social gathering and holiday travel. These natural and social factors influenced the general progression and trajectory of the SARS epidemiology. However, some unique factors might also contribute to the origination of SARS in Wuhan. These factors are discussed in different scenarios in order to promote more research for achieving final validation.


Subject(s)
Coronavirus Infections , Peptidyl-Dipeptidase A , Pneumonia, Viral , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , China/epidemiology , Chiroptera , Coronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Disease Outbreaks , Humans , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Seasons , Severe Acute Respiratory Syndrome/transmission , Social Conditions , Travel , Zoonoses
9.
Head Neck ; 42(7): 1392-1396, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1384168

ABSTRACT

The severe acute respiratory syndrome (SARS)-CoV-2 pandemic continues to produce a large number of patients with chronic respiratory failure and ventilator dependence. As such, surgeons will be called upon to perform tracheotomy for a subset of these chronically intubated patients. As seen during the SARS and the SARS-CoV-2 outbreaks, aerosol-generating procedures (AGP) have been associated with higher rates of infection of medical personnel and potential acceleration of viral dissemination throughout the medical center. Therefore, a thoughtful approach to tracheotomy (and other AGPs) is imperative and maintaining traditional management norms may be unsuitable or even potentially harmful. We sought to review the existing evidence informing best practices and then develop straightforward guidelines for tracheotomy during the SARS-CoV-2 pandemic. This communication is the product of those efforts and is based on national and international experience with the current SARS-CoV-2 pandemic and the SARS epidemic of 2002/2003.


Subject(s)
Clinical Decision-Making , Coronavirus Infections/epidemiology , Hospital Mortality/trends , Pandemics/statistics & numerical data , Pneumonia, Viral/epidemiology , Severe Acute Respiratory Syndrome/therapy , Tracheotomy/methods , COVID-19 , Coronavirus Infections/prevention & control , Critical Care/methods , Elective Surgical Procedures/methods , Elective Surgical Procedures/statistics & numerical data , Emergencies , Female , Follow-Up Studies , Humans , Intensive Care Units/statistics & numerical data , Internationality , Intubation, Intratracheal , Male , Occupational Health , Pandemics/prevention & control , Patient Safety , Pneumonia, Viral/prevention & control , Respiration, Artificial/methods , Risk Assessment , SARS Virus/pathogenicity , Survival Rate , Time Factors , Treatment Outcome , United States/epidemiology , Ventilator Weaning/methods
10.
Brief Bioinform ; 22(2): 1175-1196, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343624

ABSTRACT

The novel coronavirus (2019-nCoV) has recently emerged, causing COVID-19 outbreaks and significant societal/global disruption. Importantly, COVID-19 infection resembles SARS-like complications. However, the lack of knowledge about the underlying genetic mechanisms of COVID-19 warrants the development of prospective control measures. In this study, we employed whole-genome alignment and digital DNA-DNA hybridization analyses to assess genomic linkage between 2019-nCoV and other coronaviruses. To understand the pathogenetic behavior of 2019-nCoV, we compared gene expression datasets of viral infections closest to 2019-nCoV with four COVID-19 clinical presentations followed by functional enrichment of shared dysregulated genes. Potential chemical antagonists were also identified using protein-chemical interaction analysis. Based on phylogram analysis, the 2019-nCoV was found genetically closest to SARS-CoVs. In addition, we identified 562 upregulated and 738 downregulated genes (adj. P ≤ 0.05) with SARS-CoV infection. Among the dysregulated genes, SARS-CoV shared ≤19 upregulated and ≤22 downregulated genes with each of different COVID-19 complications. Notably, upregulation of BCL6 and PFKFB3 genes was common to SARS-CoV, pneumonia and severe acute respiratory syndrome, while they shared CRIP2, NSG1 and TNFRSF21 genes in downregulation. Besides, 14 genes were common to different SARS-CoV comorbidities that might influence COVID-19 disease. We also observed similarities in pathways that can lead to COVID-19 and SARS-CoV diseases. Finally, protein-chemical interactions suggest cyclosporine, resveratrol and quercetin as promising drug candidates against COVID-19 as well as other SARS-like viral infections. The pathogenetic analyses, along with identified biomarkers, signaling pathways and chemical antagonists, could prove useful for novel drug development in the fight against the current global 2019-nCoV pandemic.


Subject(s)
COVID-19/virology , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Case-Control Studies , Comorbidity , Genome, Viral , Humans , MicroRNAs/metabolism , SARS Virus/genetics , Transcription Factors/metabolism
12.
Salud Publica Mex ; 63(1, ene-feb): 109-119, 2020 Dec 22.
Article in Spanish | MEDLINE | ID: covidwho-1310298

ABSTRACT

Objetivo. Describir la evidencia sobre la presencia e infectividad de SARS-CoV-2 y otros coronavirus en aguas residuales y su potencial uso como herramienta de vigilancia epidemiológica. Material y métodos. Búsqueda de publicaciones en PubMed y medRxiv desde enero 2003 hasta el 8 de junio de 2020 de acuerdo con la guía de revisiones rápidas de Cochrane. Resultados. Se incluyeron 29 publicaciones. El ARN de SARS-CoV-2 no infectivo se encontró en agua residual hospitalaria, agua residual cruda, tratada y lodos de plantas de tratamiento. Los niveles cuantitativos de ARN viral en agua residual presentan relación con el número de casos de Covid-19. SARS-CoV-1 y otros coronavirus permanecieron infectivos en agua residual cruda hasta por dos días. Conclusiones. Hasta esta revisión no existe evidencia sobre la presencia de virus infectivos de SARS-CoV-2 en agua residual cruda o tratada. La cuantificación de ARN de SARS-CoV-2 en agua residual es útil para la vigilancia epidemiológica.


Subject(s)
RNA, Viral/isolation & purification , SARS-CoV-2/isolation & purification , Waste Water/virology , Wastewater-Based Epidemiological Monitoring , Coronavirus/isolation & purification , Coronavirus/pathogenicity , Mexico , SARS Virus/isolation & purification , SARS Virus/pathogenicity , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Virulence , Water Microbiology
13.
IUBMB Life ; 73(8): 1005-1015, 2021 08.
Article in English | MEDLINE | ID: covidwho-1291220

ABSTRACT

The kidney is one of the main targets attacked by viruses in patients with a coronavirus infection. Until now, SARS-CoV-2 has been identified as the seventh member of the coronavirus family capable of infecting humans. In the past two decades, humankind has experienced outbreaks triggered by two other extremely infective members of the coronavirus family; the MERS-CoV and the SARS-CoV. According to several investigations, SARS-CoV causes proteinuria and renal impairment or failure. The SARS-CoV was identified in the distal convoluted tubules of the kidney of infected patients. Also, renal dysfunction was observed in numerous cases of MERS-CoV infection. And recently, during the 2019-nCoV pandemic, it was found that the novel coronavirus not only induces acute respiratory distress syndrome (ARDS) but also can induce damages in various organs including the liver, heart, and kidney. The kidney tissue and its cells are targeted massively by the coronaviruses due to the abundant presence of ACE2 and Dpp4 receptors on kidney cells. These receptors are characterized as the main route of coronavirus entry to the victim cells. Renal failure due to massive viral invasion can lead to undesirable complications and enhanced mortality rate, thus more attention should be paid to the pathology of coronaviruses in the kidney. Here, we have provided the most recent knowledge on the coronaviruses (SARS, MERS, and COVID19) pathology and the mechanisms of their impact on the kidney tissue and functions.


Subject(s)
COVID-19/mortality , Coronavirus Infections/mortality , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/mortality , Viral Tropism/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Dipeptidyl Peptidase 4/genetics , Dipeptidyl Peptidase 4/metabolism , Gene Expression Regulation , Humans , Kidney/metabolism , Kidney/pathology , Kidney/virology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/metabolism , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS Virus/genetics , SARS Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Severity of Illness Index , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Survival Analysis
14.
Nat Biomed Eng ; 5(7): 666-677, 2021 07.
Article in English | MEDLINE | ID: covidwho-1241951

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for rapid and sensitive protein detection and quantification in simple and robust formats for widespread point-of-care applications. Here, we report on nanobody-functionalized organic electrochemical transistors with a modular architecture for the rapid quantification of single-molecule-to-nanomolar levels of specific antigens in complex bodily fluids. The sensors combine a solution-processable conjugated polymer in the transistor channel and high-density and orientation-controlled bioconjugation of nanobody-SpyCatcher fusion proteins on disposable gate electrodes. The devices provide results after 10 min of exposure to 5 µl of unprocessed samples, maintain high specificity and single-molecule sensitivity in human saliva and serum, and can be reprogrammed to detect any protein antigen if a corresponding specific nanobody is available. We used the sensors to detect green fluorescent protein, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) spike proteins, and for the COVID-19 screening of unprocessed clinical nasopharyngeal swab and saliva samples with a wide range of viral loads.


Subject(s)
Biosensing Techniques/methods , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Nanotechnology/methods , SARS Virus/pathogenicity , COVID-19/virology , Humans , Single-Domain Antibodies/immunology
15.
NPJ Syst Biol Appl ; 7(1): 21, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1241950

ABSTRACT

COVID-19 is an infection caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), which has caused a global outbreak. Current research efforts are focused on the understanding of the molecular mechanisms involved in SARS-CoV-2 infection in order to propose drug-based therapeutic options. Transcriptional changes due to epigenetic regulation are key host cell responses to viral infection and have been studied in SARS-CoV and MERS-CoV; however, such changes are not fully described for SARS-CoV-2. In this study, we analyzed multiple transcriptomes obtained from cell lines infected with MERS-CoV, SARS-CoV, and SARS-CoV-2, and from COVID-19 patient-derived samples. Using integrative analyses of gene co-expression networks and de-novo pathway enrichment, we characterize different gene modules and protein pathways enriched with Transcription Factors or Epifactors relevant for SARS-CoV-2 infection. We identified EP300, MOV10, RELA, and TRIM25 as top candidates, and more than 60 additional proteins involved in the epigenetic response during viral infection that has therapeutic potential. Our results show that targeting the epigenetic machinery could be a feasible alternative to treat COVID-19.


Subject(s)
COVID-19/genetics , Epigenesis, Genetic/genetics , SARS-CoV-2/genetics , Transcriptome/genetics , COVID-19/virology , Gene Expression Profiling , Humans , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/genetics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Signal Transduction/genetics
16.
Int Rev Immunol ; 40(1-2): 5-53, 2021.
Article in English | MEDLINE | ID: covidwho-1236148

ABSTRACT

Coronavirus infections are responsible for mild, moderate, and severe infections in birds and mammals. These were first isolated in humans as causal microorganisms responsible for common cold. The 2002-2003 SARS epidemic caused by SARS-CoV and 2012 MERS epidemic (64 countries affected) caused by MERS-CoV showed their acute and fatal side. These two CoV infections killed thousands of patients infected worldwide. However, WHO has still reported the MERS case in December 2019 in middle-eastern country (Saudi Arabia), indicating the MERS epidemic has not ended completely yet. Although we have not yet understood completely these two CoV epidemics, a third most dangerous and severe CoV infection has been originated in the Wuhan city, Hubei district of China in December 2019. This CoV infection called COVID-19 or SARS-CoV2 infection has now spread to 210 countries and territories around the world. COVID-19 has now been declared a pandemic by the World Health Organization (WHO). It has infected more than 16.69 million people with more than 663,540 deaths across the world. Thus the current manuscript aims to describe all three (SARS, MERS, and COVID-19) in terms of their causal organisms (SARS-CoV, MERS-CoV, and SARS-CoV2), similarities and differences in their clinical symptoms, outcomes, immunology, and immunopathogenesis, and possible future therapeutic approaches.


Subject(s)
COVID-19/pathology , Coronaviridae/ultrastructure , Middle East Respiratory Syndrome Coronavirus/immunology , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/pathology , Animals , COVID-19/diagnosis , COVID-19/mortality , Camelus/virology , Chiroptera/virology , Coronaviridae/classification , Disease Reservoirs/virology , Disease Susceptibility/virology , Humans , Middle East Respiratory Syndrome Coronavirus/pathogenicity , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/mortality , Virus Replication/physiology
17.
Epidemiol Infect ; 149: e96, 2021 04 14.
Article in English | MEDLINE | ID: covidwho-1182771

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is pandemic. Prevention and control strategies require an improved understanding of SARS-CoV-2 dynamics. We did a rapid review of the literature on SARS-CoV-2 viral dynamics with a focus on infective dose. We sought comparisons of SARS-CoV-2 with other respiratory viruses including SARS-CoV-1 and Middle East respiratory syndrome coronavirus. We examined laboratory animal and human studies. The literature on infective dose, transmission and routes of exposure was limited specially in humans, and varying endpoints were used for measurement of infection. Despite variability in animal studies, there was some evidence that increased dose at exposure correlated with higher viral load clinically, and severe symptoms. Higher viral load measures did not reflect coronavirus disease 2019 severity. Aerosol transmission seemed to raise the risk of more severe respiratory complications in animals. An accurate quantitative estimate of the infective dose of SARS-CoV-2 in humans is not currently feasible and needs further research. Our review suggests that it is small, perhaps about 100 particles. Further work is also required on the relationship between routes of transmission, infective dose, co-infection and outcomes.


Subject(s)
COVID-19/transmission , SARS-CoV-2/pathogenicity , Viral Load , Adenoviridae/pathogenicity , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Communicable Disease Control , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Cricetinae , Enterovirus/pathogenicity , Ferrets , Humans , Macaca mulatta , Mice , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Orthomyxoviridae/pathogenicity , Respiratory Syncytial Viruses/pathogenicity , Rhinovirus/pathogenicity , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/transmission , Severe Acute Respiratory Syndrome/virology , Virus Diseases/epidemiology , Virus Diseases/transmission , Virus Diseases/virology
18.
Nature ; 594(7862): 246-252, 2021 06.
Article in English | MEDLINE | ID: covidwho-1180252

ABSTRACT

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-ß pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Host-Pathogen Interactions , Proteome/metabolism , Proteomics , SARS Virus/pathogenicity , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/metabolism , Animals , Antiviral Agents/pharmacology , Autophagy/drug effects , COVID-19/immunology , COVID-19/virology , Cell Line , Datasets as Topic , Drug Evaluation, Preclinical , Host-Pathogen Interactions/immunology , Humans , Matrix Metalloproteinase Inhibitors/pharmacology , Phosphorylation , Protein Interaction Maps , Protein Kinase Inhibitors/pharmacology , Protein Processing, Post-Translational , Proteome/chemistry , SARS Virus/immunology , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Transforming Growth Factor beta/metabolism , Ubiquitination , Viral Proteins/chemistry , Viral Proteins/metabolism , Viroporin Proteins/metabolism
19.
Rev Med Virol ; 31(6): e2225, 2021 11.
Article in English | MEDLINE | ID: covidwho-1095682

ABSTRACT

Convalescent plasma therapy (CPT) has been investigated as a treatment for COVID-19. This review evaluates CPT in COVID-19 and other viral respiratory diseases, including severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and influenza. PubMed and Google scholar databases were used to collect eligible publications until 8 December 2020. Meta-analysis used Mantel-Haenszel risk ratio (RR) with 95% confidence interval (CI) and pooled analysis for individual patient data with inverse variance weighted average. The study is registered at PROSPERO with the number of CRD4200270579. Forty-four studies with 36,716 participants were included in the pooled analysis and 20 studies in the meta-analysis. Meta-analysis showed reduction of mortality (RR 0.57, 95% CI [0.43, 0.76], z = 3.86 [p < 0.001], I2  = 44% [p = 0.03]) and higher number of discharged patients (RR 2.53, 95% CI [1.72, 3.72], z = 4.70 [p < 0.001], I2  = 3% [p = 0.39]) in patients receiving CPT compared to standard care alone. A possible mechanism of action is prompt reduction in viral titre. Serious transfusion-related adverse events were reported to be less than 1% of cases, suggesting the overall safety of CPT; nevertheless, the number of patients participating in the studies was still limited. It is also important to notice that in all the studies, the majority of patients were also given other medications, such as antivirals, antibiotics and corticosteroid; furthermore, randomized controlled studies involving more patients and in combination with other treatment modalities are urgently needed.


Subject(s)
COVID-19/therapy , Coronavirus Infections/therapy , Influenza, Human/therapy , Severe Acute Respiratory Syndrome/therapy , Adrenal Cortex Hormones/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , Combined Modality Therapy/methods , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Humans , Immunization, Passive , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , Influenza, Human/immunology , Influenza, Human/mortality , Influenza, Human/virology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , RNA, Viral/antagonists & inhibitors , RNA, Viral/genetics , RNA, Viral/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/mortality , Severe Acute Respiratory Syndrome/virology , Survival Analysis , Treatment Outcome
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