SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS...SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.展开更多
Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,s...Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform,which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads,without the need of culture-based amplification.High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak.We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine(F) from proline (P),in the first reported isolate of SARS-CoV-2,Wuhan-Hu-1.This 323F variant was present at a very high frequency in Northern Nevada.Structural modeling determined this mutation in the interface domain,which is important for the association of accessory proteins required for the polymerase.In conclusion,we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations,which is important for understanding the evolution and circulation of SARS-CoV-2variants of public health importance,while it circulates in humans.展开更多
We examined SARS-CoV-2(Covid-19)available treatments and prophylactic methods that included interventions associated with inhibiting the“type II transmembrane serine protease”(TMPRSS2)to limit the fusion between the...We examined SARS-CoV-2(Covid-19)available treatments and prophylactic methods that included interventions associated with inhibiting the“type II transmembrane serine protease”(TMPRSS2)to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors,or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication.We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders,yet,they serve as the viral points of entry,elevating the probability of infection.Human tissues’analysis reveals a higher ACE2 expression in adipose tissue,placing obesity-related conditions in the eye of the pandemic storm.It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues.Males manifest a relatively higher positive ACE2 correlations with certain immune cells in the lungs,thyroid,adrenals,liver and colon,while females evidence higher ACE2 correlations with immune cells in the heart.The remaining tissues’ACE2/immunity expressions are equivalent in both sexes,indicating that despite its preference for males,the threat of Covid-19 can easily target females.Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the“cytokine storm”,the aggravated immune response that indiscriminately perseveres,rampaging the host’s vital organs.Sedentary lifestyle,age-related hormonal imbalance,and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion,spotlighting the detrimental aftermath of metabolic dysfunction,and excess food consumption provoked by elevated cortisol and dysregulated appetite hormones.ACE 2 expression is suppressed in the skeletal muscle,rendering fitness and weight management an effective Covid-19 preventive intervention,along with social distancing,hygiene,and facial coverings.Physical activity,or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein(CRP),triglycerides,visceral fat,cortisol and the orexigenic hormone ghrelin,juxtaposed by optimal increases of IGF-1,skeletal muscle mass,Free T3,HDL,and the anorexic hormone leptin.展开更多
基金supported by grants from the National Major Sciences&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10733403 and 2018ZX10101001 to Z.X.,2018ZX10301401 to X.L. and Z.Z.)the National Natural Science Foundation of China(81930063,81971948,81772201,and 31670169 to J.W.,X.L.,Z.X.,and Z.Z.)+1 种基金the National Key R&D Program of China(2020YFA0707600)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2016-I2M-1-014 to J.W.).
文摘SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.
基金supported by University of Nevada, RenoDepartment of Microbiology & Immunology, UNR School of MedicineNevada IDeA Network of Biomedical Research Excellence (INBRE) from the National Institute of General Medical Sciences (GM 103440 and GM 104944) and from the National Institutes of Health。
文摘Patients with signs of COVID-19 were tested through diagnostic RT-PCR for SARS-CoV-2 using RNA extracted from the nasopharyngeal/nasal swabs.To determine the variants of SARS-CoV-2 circulating in the state of Nevada,specimens from 200 COVID-19 patients were sequenced through our robust sequencing platform,which enabled sequencing of SARS-CoV-2 from specimens with even very low viral loads,without the need of culture-based amplification.High genome coverage allowed the identification of single and multi-nucleotide variants in SARS-CoV-2 in the community and their phylogenetic relationships with other variants present during the same period of the outbreak.We report the occurrence of a novel mutation at 323aa (314aa of orf1b) of nsp12 (RNA-dependent RNA polymerase) changed to phenylalanine(F) from proline (P),in the first reported isolate of SARS-CoV-2,Wuhan-Hu-1.This 323F variant was present at a very high frequency in Northern Nevada.Structural modeling determined this mutation in the interface domain,which is important for the association of accessory proteins required for the polymerase.In conclusion,we report the introduction of specific SARS-CoV-2 variants at very high frequency in distinct geographic locations,which is important for understanding the evolution and circulation of SARS-CoV-2variants of public health importance,while it circulates in humans.
文摘We examined SARS-CoV-2(Covid-19)available treatments and prophylactic methods that included interventions associated with inhibiting the“type II transmembrane serine protease”(TMPRSS2)to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors,or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication.We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders,yet,they serve as the viral points of entry,elevating the probability of infection.Human tissues’analysis reveals a higher ACE2 expression in adipose tissue,placing obesity-related conditions in the eye of the pandemic storm.It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues.Males manifest a relatively higher positive ACE2 correlations with certain immune cells in the lungs,thyroid,adrenals,liver and colon,while females evidence higher ACE2 correlations with immune cells in the heart.The remaining tissues’ACE2/immunity expressions are equivalent in both sexes,indicating that despite its preference for males,the threat of Covid-19 can easily target females.Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the“cytokine storm”,the aggravated immune response that indiscriminately perseveres,rampaging the host’s vital organs.Sedentary lifestyle,age-related hormonal imbalance,and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion,spotlighting the detrimental aftermath of metabolic dysfunction,and excess food consumption provoked by elevated cortisol and dysregulated appetite hormones.ACE 2 expression is suppressed in the skeletal muscle,rendering fitness and weight management an effective Covid-19 preventive intervention,along with social distancing,hygiene,and facial coverings.Physical activity,or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein(CRP),triglycerides,visceral fat,cortisol and the orexigenic hormone ghrelin,juxtaposed by optimal increases of IGF-1,skeletal muscle mass,Free T3,HDL,and the anorexic hormone leptin.
