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1.
Blood Adv ; 4(13): 2967-2978, 2020 07 14.
Article in English | MEDLINE | ID: covidwho-625455

ABSTRACT

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.


Subject(s)
Blood Platelets/virology , Influenza A virus/pathogenicity , Influenza, Human/complications , N-Acetylneuraminic Acid/metabolism , Polysaccharides/metabolism , Thrombocytopenia/etiology , Animals , Blood Platelets/metabolism , Blood Platelets/pathology , Disease Models, Animal , Ferrets , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza A Virus, H1N1 Subtype/physiology , Influenza A Virus, H3N2 Subtype/pathogenicity , Influenza A Virus, H3N2 Subtype/physiology , Influenza A Virus, H5N1 Subtype/pathogenicity , Influenza A Virus, H5N1 Subtype/physiology , Influenza A virus/physiology , Influenza, Human/metabolism , Influenza, Human/pathology , Influenza, Human/virology , Orthomyxoviridae Infections/complications , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Thrombocytopenia/metabolism , Thrombocytopenia/pathology , Thrombocytopenia/virology , Virus Internalization
2.
Nano Lett ; 20(7): 5367-5375, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-628240

ABSTRACT

Geometry-matching has been known to benefit the formation of stable biological interactions in natural systems. Herein, we report that the spiky nanostructures with matched topography to the influenza A virus (IAV) virions could be used to design next-generation advanced virus inhibitors. We demonstrated that nanostructures with spikes between 5 and 10 nm bind significantly better to virions than smooth nanoparticles, due to the short spikes inserting into the gaps of glycoproteins of the IAV virion. Furthermore, an erythrocyte membrane (EM) was coated to target the IAV, and the obtained EM-coated nanostructures could efficiently prevent IAV virion binding to the cells and inhibit subsequent infection. In a postinfection study, the EM-coated nanostructures reduced >99.9% virus replication at the cellular nontoxic dosage. We predict that such a combination of geometry-matching topography and cellular membrane coating will also push forward the development of nanoinhibitors for other virus strains, including SARS-CoV-2.


Subject(s)
Betacoronavirus/ultrastructure , Coronavirus Infections/virology , Nanostructures/ultrastructure , Pneumonia, Viral/virology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Binding Sites , Coronavirus Infections/drug therapy , Drug Design , Humans , Influenza A virus/drug effects , Influenza A virus/ultrastructure , Microscopy, Electron , Models, Biological , Nanotechnology , Pandemics , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/ultrastructure , Virus Internalization/drug effects
3.
Nat Commun ; 11(1): 4252, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-741685

ABSTRACT

The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. Here, we show that a defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alkaline peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , Influenza A virus/drug effects , Peptides/pharmacology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Cell Line , Endosomes/chemistry , Endosomes/drug effects , Female , Humans , Hydrogen-Ion Concentration , Influenza A virus/metabolism , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/metabolism , Peptides/chemistry , Peptides/metabolism , Peptides/therapeutic use , Protein Binding , Protein Conformation , Rhinovirus/drug effects , Rhinovirus/metabolism , Viral Load/drug effects , Virus Replication/drug effects
5.
Sci Immunol ; 5(49)2020 07 10.
Article in English | MEDLINE | ID: covidwho-639363

ABSTRACT

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1ß-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1ß-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immunophenotyping , Influenza A virus/immunology , Influenza, Human/immunology , Interferon Type I/metabolism , Pneumonia, Viral/immunology , Severity of Illness Index , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Coronavirus Infections/blood , Coronavirus Infections/virology , Female , Healthy Volunteers , Humans , Inflammation/immunology , Influenza, Human/blood , Influenza, Human/virology , Interleukin-1beta/metabolism , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/virology , RNA-Seq , Single-Cell Analysis , Transcriptome , Tumor Necrosis Factor-alpha/metabolism
7.
BMJ Case Rep ; 13(7)2020 Jul 01.
Article in English | MEDLINE | ID: covidwho-622599

ABSTRACT

Since December 2019, coronavirus disease 2019 (COVID-19) has been an international public health emergency. The possibility of COVID-19 should be considered primarily in patients with new-onset fever or respiratory tract symptoms. However, these symptoms can occur with other viral respiratory illnesses. We reported a case of severe acute respiratory syndrome coronavirus 2 and influenza A virus coinfection. During the epidemic, the possibility of COVID-19 should be considered regardless of positive findings for other pathogens.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Influenza A virus/isolation & purification , Influenza, Human/complications , Influenza, Human/diagnosis , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Amides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Coinfection , Coronavirus Infections/drug therapy , Diagnosis, Differential , Glucocorticoids/therapeutic use , Humans , Influenza, Human/economics , Lung/diagnostic imaging , Male , Middle Aged , Pandemics , Pneumonia, Viral/drug therapy , Pregnenediones/therapeutic use , Pyrazines/therapeutic use , Radiography , Real-Time Polymerase Chain Reaction
8.
Viruses ; 12(7)2020 06 28.
Article in English | MEDLINE | ID: covidwho-627994

ABSTRACT

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (IAV), and norovirus (NV) are highly contagious pathogens that threaten human health. Here we focused on the antiviral potential of the medicinal herb, Saxifraga spinulosa (SS). Water-soluble extracts of SS were prepared, and their virus-inactivating activity was evaluated against the human virus pathogens SARS-CoV-2 and IAV; we also examined virucidal activity against feline calicivirus and murine norovirus, which are surrogates for human NV. Among our findings, we found that SS-derived gallocatechin gallate compounds were capable of inactivating all viruses tested. Interestingly, a pyrogallol-enriched fraction (Fr 1C) inactivated all viruses more rapidly and effectively than did any of the component compounds used alone. We found that 25 µg/mL of Fr 1C inactivated >99.6% of SARS-CoV-2 within 10 s (reduction of ≥2.33 log10 TCID50/mL). Fr 1C resulted in the disruption of viral genomes and proteins as determined by gel electrophoresis, electron microscopy, and reverse transcription-PCR. Taken together, our results reveal the potential of Fr 1C for development as a novel antiviral disinfectant.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Influenza A virus/drug effects , Norovirus/drug effects , Plant Extracts/pharmacology , Plants, Medicinal , Saxifragaceae , Betacoronavirus/ultrastructure , Calicivirus, Feline/drug effects , Electrophoresis, Polyacrylamide Gel , Genome, Viral/drug effects , Hemagglutination Tests , Humans , Microscopy, Electron, Transmission , Reverse Transcriptase Polymerase Chain Reaction , Viral Proteins/drug effects
13.
Int J Infect Dis ; 96: 154-156, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-307695

ABSTRACT

Respiratory viruses are a major cause of mortality worldwide and in France, where they cause several thousands of deaths every year. University Hospital Institute-Méditerranée Infection performs real-time surveillance of all diagnoses of infections and associated deaths in public hospitals in Marseille, Southeastern France. This study compared mortality associated with diagnoses of respiratory viruses during the colder months of 2018-2019 and 2019-2020 (week 47-week 14). In 2018-2019, 73 patients (0.17% of 42,851 hospitalized patients) died after being diagnosed with a respiratory virus; 40 and 13 deaths occurred in patients diagnosed with influenza A virus and respiratory syncytial virus (RSV), respectively. In 2019-2020, 50 patients (0.10% of 49,043 patients hospitalized) died after being diagnosed with a common respiratory virus; seven and seven deaths occurred in patients diagnosed with influenza A virus and RSV, respectively. Additionally, 55 patients died after being diagnosed with SARS-CoV-2. The proportion of respiratory virus-associated deaths among hospitalized patients was thus significantly lower for common respiratory viruses in 2019-2020 than in 2018-2019 (102 versus 170 per 100,000 hospitalized patients; p = 0.003), primarily as a consequence of a decrease in influenza A virus (-83%) and RSV (-46%)-associated deaths. Overall, the proportion of respiratory virus-associated deaths among hospitalized patients was higher, but not significantly, in 2019-2020 than in 2018-2019 (214 versus 170 per 100,000 hospitalized patients; p = 0.08, Yates-corrected Chi-square test). These findings put into perspective the death burden of SARS-CoV-2 infections in this geographical area.


Subject(s)
Betacoronavirus , Coronavirus Infections/mortality , Influenza A virus , Influenza, Human/epidemiology , Pneumonia, Viral/mortality , Respiratory Syncytial Virus Infections/epidemiology , Child, Preschool , Female , France/epidemiology , Humans , Infant , Male , Middle Aged , Pandemics , Time Factors
14.
Microbes Infect ; 22(6-7): 236-244, 2020.
Article in English | MEDLINE | ID: covidwho-244991

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to sweep the world, causing infection of millions and death of hundreds of thousands. The respiratory disease that it caused, COVID-19 (stands for coronavirus disease in 2019), has similar clinical symptoms with other two CoV diseases, severe acute respiratory syndrome and Middle East respiratory syndrome (SARS and MERS), of which causative viruses are SARS-CoV and MERS-CoV, respectively. These three CoVs resulting diseases also share many clinical symptoms with other respiratory diseases caused by influenza A viruses (IAVs). Since both CoVs and IAVs are general pathogens responsible for seasonal cold, in the next few months, during the changing of seasons, clinicians and public heath may have to distinguish COVID-19 pneumonia from other kinds of viral pneumonia. This is a discussion and comparison of the virus structures, transmission characteristics, clinical symptoms, diagnosis, pathological changes, treatment and prevention of the two kinds of viruses, CoVs and IAVs. It hopes to provide information for practitioners in the medical field during the epidemic season.


Subject(s)
Coronavirus Infections/diagnosis , Influenza, Human/diagnosis , Pneumonia, Viral/diagnosis , Respiratory Tract Infections/virology , Seasons , Age Factors , Animals , Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Humans , Influenza A virus/pathogenicity , Influenza, Human/complications , Influenza, Human/prevention & control , Influenza, Human/transmission , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Public Health , Respiratory Tract Infections/transmission , SARS Virus/pathogenicity , Severe Acute Respiratory Syndrome/diagnosis , Severe Acute Respiratory Syndrome/virology
15.
PLoS One ; 15(5): e0233117, 2020.
Article in English | MEDLINE | ID: covidwho-244945

ABSTRACT

Severe acute respiratory illness (SARI) is a major cause of death and morbidity in low- and middle-income countries, however, the etiologic agents are often undetermined due to the lack of molecular diagnostics in hospitals and clinics. To examine evidence for select viral infections among patients with SARI in northern Vietnam, we studied 348 nasopharyngeal samples from military and civilian patients admitted to 4 hospitals in the greater Hanoi area from 2017-2019. Initial screening for human respiratory viral pathogens was performed in Hanoi, Vietnam at the National Institute of Hygiene and Epidemiology (NIHE) or the Military Institute of Preventative Medicine (MIPM), and an aliquot was shipped to Duke-NUS Medical School in Singapore for validation. Patient demographics were recorded and used to epidemiologically describe the infections. Among military and civilian cases of SARI, 184 (52.9%) tested positive for one or more respiratory viruses. Influenza A virus was the most prevalent virus detected (64.7%), followed by influenza B virus (29.3%), enterovirus (3.8%), adenovirus (1.1%), and coronavirus (1.1%). Risk factor analyses demonstrated an increased risk of influenza A virus detection among military hospital patients (adjusted OR, 2.0; 95% CI, 1.2-3.2), and an increased risk of influenza B virus detection among patients enrolled in year 2017 (adjusted OR, 7.9; 95% CI, 2.7-22.9). As influenza A and B viruses were commonly associated with SARI and are treatable, SARI patients entering these hospitals would benefit if the hospitals were able to adapt onsite molecular diagnostics.


Subject(s)
Pneumonia/epidemiology , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/virology , Adolescent , Adult , Coronavirus/isolation & purification , Enterovirus/isolation & purification , Female , Humans , Influenza A virus/isolation & purification , Influenza B virus/isolation & purification , Influenza, Human/epidemiology , Influenza, Human/virology , Male , Middle Aged , Military Facilities/statistics & numerical data , Pneumonia/virology , Vietnam/epidemiology , Young Adult
16.
Int J Infect Dis ; 96: 154-156, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-240907

ABSTRACT

Respiratory viruses are a major cause of mortality worldwide and in France, where they cause several thousands of deaths every year. University Hospital Institute-Méditerranée Infection performs real-time surveillance of all diagnoses of infections and associated deaths in public hospitals in Marseille, Southeastern France. This study compared mortality associated with diagnoses of respiratory viruses during the colder months of 2018-2019 and 2019-2020 (week 47-week 14). In 2018-2019, 73 patients (0.17% of 42,851 hospitalized patients) died after being diagnosed with a respiratory virus; 40 and 13 deaths occurred in patients diagnosed with influenza A virus and respiratory syncytial virus (RSV), respectively. In 2019-2020, 50 patients (0.10% of 49,043 patients hospitalized) died after being diagnosed with a common respiratory virus; seven and seven deaths occurred in patients diagnosed with influenza A virus and RSV, respectively. Additionally, 55 patients died after being diagnosed with SARS-CoV-2. The proportion of respiratory virus-associated deaths among hospitalized patients was thus significantly lower for common respiratory viruses in 2019-2020 than in 2018-2019 (102 versus 170 per 100,000 hospitalized patients; p = 0.003), primarily as a consequence of a decrease in influenza A virus (-83%) and RSV (-46%)-associated deaths. Overall, the proportion of respiratory virus-associated deaths among hospitalized patients was higher, but not significantly, in 2019-2020 than in 2018-2019 (214 versus 170 per 100,000 hospitalized patients; p = 0.08, Yates-corrected Chi-square test). These findings put into perspective the death burden of SARS-CoV-2 infections in this geographical area.


Subject(s)
Betacoronavirus , Coronavirus Infections/mortality , Influenza A virus , Influenza, Human/epidemiology , Pneumonia, Viral/mortality , Respiratory Syncytial Virus Infections/epidemiology , Child, Preschool , Female , France/epidemiology , Humans , Infant , Male , Middle Aged , Pandemics , Time Factors
17.
Sci Rep ; 10(1): 7635, 2020 05 06.
Article in English | MEDLINE | ID: covidwho-196615

ABSTRACT

Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.


Subject(s)
Influenza A virus/growth & development , Organoselenium Compounds , Serine Endopeptidases/genetics , Cell Line , DNA Footprinting , Drug Discovery , G-Quadruplexes , Gene Expression Regulation/drug effects , Humans , Influenza A virus/physiology , Organoselenium Compounds/chemistry , Organoselenium Compounds/pharmacology , Promoter Regions, Genetic , Transcription, Genetic
18.
Nature ; 582(7811): 277-282, 2020 06.
Article in English | MEDLINE | ID: covidwho-164175

ABSTRACT

The great majority of globally circulating pathogens go undetected, undermining patient care and hindering outbreak preparedness and response. To enable routine surveillance and comprehensive diagnostic applications, there is a need for detection technologies that can scale to test many samples1-3 while simultaneously testing for many pathogens4-6. Here, we develop Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (CARMEN), a platform for scalable, multiplexed pathogen detection. In the CARMEN platform, nanolitre droplets containing CRISPR-based nucleic acid detection reagents7 self-organize in a microwell array8 to pair with droplets of amplified samples, testing each sample against each CRISPR RNA (crRNA) in replicate. The combination of CARMEN and Cas13 detection (CARMEN-Cas13) enables robust testing of more than 4,500 crRNA-target pairs on a single array. Using CARMEN-Cas13, we developed a multiplexed assay that simultaneously differentiates all 169 human-associated viruses with at least 10 published genome sequences and rapidly incorporated an additional crRNA to detect the causative agent of the 2020 COVID-19 pandemic. CARMEN-Cas13 further enables comprehensive subtyping of influenza A strains and multiplexed identification of dozens of HIV drug-resistance mutations. The intrinsic multiplexing and throughput capabilities of CARMEN make it practical to scale, as miniaturization decreases reagent cost per test by more than 300-fold. Scalable, highly multiplexed CRISPR-based nucleic acid detection shifts diagnostic and surveillance efforts from targeted testing of high-priority samples to comprehensive testing of large sample sets, greatly benefiting patients and public health9-11.


Subject(s)
CRISPR-Associated Proteins/metabolism , CRISPR-Cas Systems/genetics , Microfluidic Analytical Techniques/methods , Virus Diseases/diagnosis , Virus Diseases/virology , Animals , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , Drug Resistance, Viral/genetics , Genome, Viral/genetics , HIV/classification , HIV/genetics , HIV/isolation & purification , Humans , Influenza A virus/classification , Influenza A virus/genetics , Influenza A virus/isolation & purification , Microfluidic Analytical Techniques/instrumentation , RNA, Guide/genetics , Sensitivity and Specificity
19.
Emerg Infect Dis ; 26(8): 1928-1930, 2020 08.
Article in English | MEDLINE | ID: covidwho-133184
20.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Article in English | MEDLINE | ID: covidwho-47305
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