Dear Editor,As of 5 July,2020,approximately 20,162,000 confirmed cases of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),have been reported globally,i...Dear Editor,As of 5 July,2020,approximately 20,162,000 confirmed cases of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),have been reported globally,including an estimated 740,000 deaths.Although the clinical manifestations of COVID-19 are heterogeneous,viral infection and pathological changes in the respiratory system,especially the lungs,still represent common characteristics of COVID-19.The nose,served as the entrance to the respiratory system,seems to produce absent or minimal symptoms of nasal congestion or rhinorrhea during SRAS-CoV-2 infection,while other viral rhinitis(i.e.,adenovirus,rhinovirus,influenza virus,etc.)are characterized by typical nasal symptoms,including nasal congestion,rhinorrhea,and sneezing.Recent studies suggest that,despite a lack of other nasal symptoms,anosmia is an important sign of early-stage COVID-19(Lechien et al.,2020).展开更多
As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respi...As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection. To examine the effect of age on death, we established a SARSCoV-2 infection model in Chinese rhesus macaques(Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b^+ and CD8^+ cells in lungs at one-week post infection(wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b^+ cells, and persistent infiltration of CD8^+ cells in the lungs at 2 wpi. In addition,peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.展开更多
Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controll...Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here,different aged Chinese tree shrews(adult group, 1 year old;old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days postinoculation(dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3,5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase(AST) and blood urea nitrogen(BUN). Histological analysis of lung tissues from animals at 3 dpi(adult group) and 7 dpi(old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.展开更多
Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are ...Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research.Here,we showed that northern pig-tailed macaques(Macaca leonina,NPMs)supported SARS-CoV-2 replication.Furthermore,compared with rhesus macaques,NPMs showed rapid viral clearance in lung tissues,nose swabs,throat swabs,and rectal swabs,which may be due to higher expression of interferon(IFN)-αin lung tissue.However,the rapid viral clearance was not associated with good outcome.In the second week post infection,NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques.These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.展开更多
Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infe...Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.展开更多
Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first ...Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first identified in Colombia in January 2021,was classified as a variant of interest(VOI)and designated as Mu by the World Health Organization(WHO)in August 2021.However,its infectivity and resistance to neutralizing antibodies remain largely unknown.Here,in comparison to Delta,the Mu variant showed an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies.Nevertheless,Mu demonstrated less infectivity than Delta,implying a biological trade-off between viral transmission and immune escape.This study strongly calls for urgent evaluation of the protective efficacy of current COVID-19 vaccines against the Mu variant.Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are of concern regarding control of the global COVID-19 pandemic(Wang et al.,2021).The SARS-CoV-2 B.1.621 variant was first identified in Colombia in January 2021.Considering its epidemiological prevalence,the WHO defined B.1.621(named Mu)as a VOI on 30 August 2021.As of September 2021,the WHO has classified four variants of concern(VOC),i.e.,Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2),and two VOI,i.e.,Lambda(C.37)and Mu(B.1.621)(Supplementary Figure S1A).展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)is the etiologic agent responsible for the global coronavirus disease 2019(COVID-19)pandemic.Numerous studies have demonstrated that cardiovascular disease m...Severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)is the etiologic agent responsible for the global coronavirus disease 2019(COVID-19)pandemic.Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression.In the present study,we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-Co V-2.Results revealed that SARS-Co V-2 replication was delayed in hypertensive mouse lungs.In contrast,SARS-Co V-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-Co V-2-infected normotensive mice.展开更多
DEAR EDITOR,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pandemic remains an important global public health issue. In this study, we unexpectedly found that wildtype Sprague-Dawley(SD) rats can be i...DEAR EDITOR,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pandemic remains an important global public health issue. In this study, we unexpectedly found that wildtype Sprague-Dawley(SD) rats can be infected with the SARS-CoV-2 prototype. Our results showed direct experimental evidence of the infectivity of SARS-CoV-2 infection, subsequent pathogenicity, and protection against reinfection in rats.展开更多
The global outbreak of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),as of 8 May 2021,has surpassed 150700000 infections and 3279000 deaths worldwide...The global outbreak of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),as of 8 May 2021,has surpassed 150700000 infections and 3279000 deaths worldwide.Evidence indicates that SARS-CoV-2 RNA can be detected on particulate matter(PM),and COVID-19 cases are correlated with levels of air pollutants.However,the mechanisms of PM involvement in the spread of SARS-CoV-2 remain poorly understood.Here,we found that PM exposure increased the expression level of angiotensin-converting enzyme 2(ACE2)and transmembrane serine protease 2(TMPRSS2)in several epithelial cells and increased the adsorption of the SARS-CoV-2 spike protein.Instillation of PM in a hACE2 mouse model significantly increased the expression of ACE2 and Tmprss2 and viral replication in the lungs.Furthermore,PM exacerbated the pulmonary lesions caused by SARS-CoV-2 infection in the hACE2 mice.In conclusion,our study demonstrated that PM is an epidemiological factor of COVID-19,emphasizing the necessity of wearing anti-PM masks to cope with this global pandemic.展开更多
The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant...The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.展开更多
Dear editor,The pandemic of coronavirus disease-19(COVID-19)has lasted for more than three years,causing lots of extra death and posing a serious threat to public health.This pandemic swept the last global safety isla...Dear editor,The pandemic of coronavirus disease-19(COVID-19)has lasted for more than three years,causing lots of extra death and posing a serious threat to public health.This pandemic swept the last global safety island in a matter of months,coinciding with the switch of zero-COVID policy of China.The causative agent,SARS-CoV-2,spreads globally and then lurks in the population with sporadic outbreaks in local areas.Meanwhile,the sequelae of convalescent COVID-19 patients receded slowly.The pantissue tropism of SARS-CoV-2 results in a wide range of symptoms in patients,including cardiovascular disorders.Cardiac complications occur in 20%–44%of hospitalized patients,which is an independent risk factor for COVID-19 mortality(Ma et al.,2022;Patone et al.,2022).Survivors of acute COVID-19 also have a substantial risk of cardiovascular disease burden lasting up to one year(Xie et al.,2022).展开更多
Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is ef...Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.展开更多
Dear Editor,The coronavirus disease 2019(COVID-19)pandemic presents a severe threat to public health and the global economy and the direct origin of the causative agent severe acute respiratory syndrome coronavirus 2(...Dear Editor,The coronavirus disease 2019(COVID-19)pandemic presents a severe threat to public health and the global economy and the direct origin of the causative agent severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)remains unresolved(WHO 2020).The outbreak in China was successfully contained by the implementation of a strict quarantine strategy,however sporadic outbreaks still occurred and were associated with trade markets in Beijing and Dalian cities.The COVID-19 outbreak in Beijing was traced to contaminated salmon meat sold at the Xinfadi market,Beijing,China(Chinese CDC 2020)。展开更多
The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or r...The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or reemerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics,pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2(hACE2)transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.展开更多
Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared...Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared imnnunopathological changes in young and old rhesus macaques(RMs)before and after SARS-CoV-2 infection at the tissue level.Quantitative analysis of multiplex immunofluoresce nee staining images of formali n-fixed paraffi n-embedded(FFPE)sections showed that SARS-CoV-2 infectio n specifically induced elevated levels of apoptosis,autophagy,and nuclear factor kappa-B(NF-kB)activation of angiotensirv convert!ng enzyme 2(ACE2)+cells,and increased interferon a(IFN-a)-and interleukin 6(IL-6)-secreting cells and C-X-C motif chemokine receptor 3(CXCR3)+cells in lung tissue of old RMs.This pathological pattern,which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens,was significantly correlated with the systemic accumulation of CXCR3+cells in lungs,spleens,and peripheral blood.Furthermore,the ratio of CXCR3+to T-box protein expression in T cell(T-bet)+(CXCR3+/T-bet+ratio)in CD8+cells may be used as a predictor of severe COVID-19.These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+cells in predicting severe COVID-19.展开更多
Dear editor,To date,a number of clinically approved drugs have been evaluated for potential to treat coronavirus disease 2019(COVID-19),such as lopinavir/ritonavir,hydroxychloroquine,cobicistat,and darunavir.Some of t...Dear editor,To date,a number of clinically approved drugs have been evaluated for potential to treat coronavirus disease 2019(COVID-19),such as lopinavir/ritonavir,hydroxychloroquine,cobicistat,and darunavir.Some of these drugs have been proven to be effective in vitro;however,clinical trials showed that none of these compounds led to a significant improvement in symptoms or length of hospitalization.Thus,it is essential and more reliable to start from a defined target to ide ntify can didate drugs.展开更多
基金supported by the National Key Research and Development Program of China(2020YFC0842000).
文摘Dear Editor,As of 5 July,2020,approximately 20,162,000 confirmed cases of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),have been reported globally,including an estimated 740,000 deaths.Although the clinical manifestations of COVID-19 are heterogeneous,viral infection and pathological changes in the respiratory system,especially the lungs,still represent common characteristics of COVID-19.The nose,served as the entrance to the respiratory system,seems to produce absent or minimal symptoms of nasal congestion or rhinorrhea during SRAS-CoV-2 infection,while other viral rhinitis(i.e.,adenovirus,rhinovirus,influenza virus,etc.)are characterized by typical nasal symptoms,including nasal congestion,rhinorrhea,and sneezing.Recent studies suggest that,despite a lack of other nasal symptoms,anosmia is an important sign of early-stage COVID-19(Lechien et al.,2020).
基金This work was supported by the National Key Research and Development Program of China(2020YFC0842000)。
文摘As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection. To examine the effect of age on death, we established a SARSCoV-2 infection model in Chinese rhesus macaques(Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b^+ and CD8^+ cells in lungs at one-week post infection(wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b^+ cells, and persistent infiltration of CD8^+ cells in the lungs at 2 wpi. In addition,peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.
基金partly supported by the National Key R&D Program of China(2020YFC0842000 to Y.T.Z.)National Natural Science Foundation of China(U1902215 to Y.G.Y.)+2 种基金National Science and Technology Major Projects of Infectious Disease Funds(2017ZX10304402 to Y.T.Z.)Yunnan Province(2018FB046 to D.D.Y.)CAS“Light of West China”Program(xbzg-zdsys-201909to Y.G.Y.and Y.T.Z.)。
文摘Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here,different aged Chinese tree shrews(adult group, 1 year old;old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days postinoculation(dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3,5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase(AST) and blood urea nitrogen(BUN). Histological analysis of lung tissues from animals at 3 dpi(adult group) and 7 dpi(old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.
基金This work was partly supported by the National Key R&D Program of China(2020YFC0842000)National Science and Technology Major Projects of Infectious Disease Funds(2017ZX10304402,2018ZX10301406-003)+1 种基金the National Natural Science Foundation of China(U1802284,U1902210)National Resource Center for Non-Human Primates。
文摘Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health emergency.At present,SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 research.Here,we showed that northern pig-tailed macaques(Macaca leonina,NPMs)supported SARS-CoV-2 replication.Furthermore,compared with rhesus macaques,NPMs showed rapid viral clearance in lung tissues,nose swabs,throat swabs,and rectal swabs,which may be due to higher expression of interferon(IFN)-αin lung tissue.However,the rapid viral clearance was not associated with good outcome.In the second week post infection,NPMs developed persistent or even more severe inflammation and body injury compared with rhesus macaques.These results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.
基金supported by the National Basic Research Program of China(2020YFA0804000,2020YFC0842000,2020YFA0112200,2021YFC2301703)Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100)+6 种基金Special Associate Research Program of the Chinese Academy of Sciences(E1290601)National Natural Science Foundation of China(32122037,81891001,32192411,32100512,U1902215)Collaborative Research Fund of the Chinese Institute for Brain Research,Beijing(2020-NKX-PT-03)CAS Project for Young Scientists in Basic Research(YSBR-013)Young Elite Scientist Sponsorship Program by the China Association for Science and Technology(2020QNRC001)National Resource Center for Non-Human Primates。
文摘Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs.However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.
基金This work was supported by start-up funding from the Kunming Institute of Zoology,Chinese Academy of Sciences to J.X.Z.
文摘Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and Lambda.The B.1.621 variant,first identified in Colombia in January 2021,was classified as a variant of interest(VOI)and designated as Mu by the World Health Organization(WHO)in August 2021.However,its infectivity and resistance to neutralizing antibodies remain largely unknown.Here,in comparison to Delta,the Mu variant showed an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies.Nevertheless,Mu demonstrated less infectivity than Delta,implying a biological trade-off between viral transmission and immune escape.This study strongly calls for urgent evaluation of the protective efficacy of current COVID-19 vaccines against the Mu variant.Variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are of concern regarding control of the global COVID-19 pandemic(Wang et al.,2021).The SARS-CoV-2 B.1.621 variant was first identified in Colombia in January 2021.Considering its epidemiological prevalence,the WHO defined B.1.621(named Mu)as a VOI on 30 August 2021.As of September 2021,the WHO has classified four variants of concern(VOC),i.e.,Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2),and two VOI,i.e.,Lambda(C.37)and Mu(B.1.621)(Supplementary Figure S1A).
基金supported by the National Key R&D Program of China(2020YFC0842000)National Natural Science Foundation of China(81960662)Science and Technology Department of Yunnan Province(202001AS070034)。
文摘Severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)is the etiologic agent responsible for the global coronavirus disease 2019(COVID-19)pandemic.Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression.In the present study,we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-Co V-2.Results revealed that SARS-Co V-2 replication was delayed in hypertensive mouse lungs.In contrast,SARS-Co V-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-Co V-2-infected normotensive mice.
基金supported by the National Natural Science Foundation of China(U1902215 to Y.G.Y.,32070569 to L.X.)Applied Basic Research Foundation of Yunnan Province(202001AS070023 to D.Y.)+1 种基金Key Project of the CAS“Light of West China”Program(to D.Y.)。
文摘DEAR EDITOR,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pandemic remains an important global public health issue. In this study, we unexpectedly found that wildtype Sprague-Dawley(SD) rats can be infected with the SARS-CoV-2 prototype. Our results showed direct experimental evidence of the infectivity of SARS-CoV-2 infection, subsequent pathogenicity, and protection against reinfection in rats.
基金This work was supported by the National Natural Science Foundation of China(NSFC)(31900331,32070444)Science and Technology Department of Yunnan Province(202001AW070019)+2 种基金Chinese Academy of Sciences“Light of West China”Program and Youth Innovation Promotion Association(2019378)to L.J.and the NSFC(21761142002)Chinese Academy of Sciences(XDB31000000,SAJC201606 and KGFZD-135-17-011)Yunnan Province(2019-YT-053 and 2019ZF003)to R.L.and the NSFC(91643206)to W.J.D。
文摘The global outbreak of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),as of 8 May 2021,has surpassed 150700000 infections and 3279000 deaths worldwide.Evidence indicates that SARS-CoV-2 RNA can be detected on particulate matter(PM),and COVID-19 cases are correlated with levels of air pollutants.However,the mechanisms of PM involvement in the spread of SARS-CoV-2 remain poorly understood.Here,we found that PM exposure increased the expression level of angiotensin-converting enzyme 2(ACE2)and transmembrane serine protease 2(TMPRSS2)in several epithelial cells and increased the adsorption of the SARS-CoV-2 spike protein.Instillation of PM in a hACE2 mouse model significantly increased the expression of ACE2 and Tmprss2 and viral replication in the lungs.Furthermore,PM exacerbated the pulmonary lesions caused by SARS-CoV-2 infection in the hACE2 mice.In conclusion,our study demonstrated that PM is an epidemiological factor of COVID-19,emphasizing the necessity of wearing anti-PM masks to cope with this global pandemic.
基金supported in part by grants from the National Natural Science Foundation of China(82151218,81971548)National Key Research and Development Program of China(2021YFC2301703,2021YFC2301303,2022YFC2303700)+1 种基金Yunnan Key Research and Development Program(202103AC100005,202103AQ100001,202102AA310055,China)CAS“Light of West China”。
文摘The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.
文摘Dear editor,The pandemic of coronavirus disease-19(COVID-19)has lasted for more than three years,causing lots of extra death and posing a serious threat to public health.This pandemic swept the last global safety island in a matter of months,coinciding with the switch of zero-COVID policy of China.The causative agent,SARS-CoV-2,spreads globally and then lurks in the population with sporadic outbreaks in local areas.Meanwhile,the sequelae of convalescent COVID-19 patients receded slowly.The pantissue tropism of SARS-CoV-2 results in a wide range of symptoms in patients,including cardiovascular disorders.Cardiac complications occur in 20%–44%of hospitalized patients,which is an independent risk factor for COVID-19 mortality(Ma et al.,2022;Patone et al.,2022).Survivors of acute COVID-19 also have a substantial risk of cardiovascular disease burden lasting up to one year(Xie et al.,2022).
基金supported by the Natural Science Foundation of Shanghai (21ZR1475600)Science and Technology Commission of Shanghai Municipality (20431900100)+4 种基金Shanghai Science and Technology Committee (19430750100)National Key R&D Program of China (2016YFA0502301 and 2021YFC2301204)Drug development for the newly emerging viral infectious diseases (SIMM010107)Fundamental Research Funds for the Central Universities (2022ZFJH003)Zhejiang Provincial Key Research&Development Program of China (2021C03043 and No.2021C03039).
文摘Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.
基金supported by the Key Program of Chinese Academy of Sciences(KJZD-SW-L11 to Z.L.S.)the Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(XDB29010102 and XDA19090118 to Y.H.B.)+4 种基金COVID-19 emergency project of CAS(2020YJFK-Z-0149)the National Key R&D Program of China(2020YFC0842000 to Y.T.Z.)the National Natural Science Foundation of China(NSFC32041010 to Y.H.B.)the NSFC Outstanding Young Scholars(31822055 to Y.H.B.)Youth Innovation Promotion Association of CAS(2017122 to Y.H.B.,2019328 to X.L.Y.)。
文摘Dear Editor,The coronavirus disease 2019(COVID-19)pandemic presents a severe threat to public health and the global economy and the direct origin of the causative agent severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)remains unresolved(WHO 2020).The outbreak in China was successfully contained by the implementation of a strict quarantine strategy,however sporadic outbreaks still occurred and were associated with trade markets in Beijing and Dalian cities.The COVID-19 outbreak in Beijing was traced to contaminated salmon meat sold at the Xinfadi market,Beijing,China(Chinese CDC 2020)。
基金supported by the Major Science and Technique Programs in Yunnan Province(grant No.202102AA310055)the Bureau of Frontier Sciences and Education,CAS(grant no.QYZDJ-SSW-SMC005 to Y.G.Y.)+2 种基金the Key project of the CAS“Light of West China”Program(to D.Y.)Yunnan Province(202001AS070023 to D.Y.)Yunnan Fundamental Research Projects(grant No.202201AW070020 to J.Z.)
文摘The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally,from B.1.17(Alpha), B.1.351(Beta), P.1(Gamma), B.1.617.2(Delta) to B.1.1.529(Omicron). The emerging or reemerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics,pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2(hACE2)transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.
基金supported by the National Key Research and Development Program of China(2020YFC0842000,2020YFC0847000).
文摘Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared imnnunopathological changes in young and old rhesus macaques(RMs)before and after SARS-CoV-2 infection at the tissue level.Quantitative analysis of multiplex immunofluoresce nee staining images of formali n-fixed paraffi n-embedded(FFPE)sections showed that SARS-CoV-2 infectio n specifically induced elevated levels of apoptosis,autophagy,and nuclear factor kappa-B(NF-kB)activation of angiotensirv convert!ng enzyme 2(ACE2)+cells,and increased interferon a(IFN-a)-and interleukin 6(IL-6)-secreting cells and C-X-C motif chemokine receptor 3(CXCR3)+cells in lung tissue of old RMs.This pathological pattern,which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens,was significantly correlated with the systemic accumulation of CXCR3+cells in lungs,spleens,and peripheral blood.Furthermore,the ratio of CXCR3+to T-box protein expression in T cell(T-bet)+(CXCR3+/T-bet+ratio)in CD8+cells may be used as a predictor of severe COVID-19.These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+cells in predicting severe COVID-19.
基金supported by grants from the Emergency Project of West China Hospital(number HX-2019-nCoV-025)the Program from Chongqing Education Commission(number KYYJ202010).
文摘Dear editor,To date,a number of clinically approved drugs have been evaluated for potential to treat coronavirus disease 2019(COVID-19),such as lopinavir/ritonavir,hydroxychloroquine,cobicistat,and darunavir.Some of these drugs have been proven to be effective in vitro;however,clinical trials showed that none of these compounds led to a significant improvement in symptoms or length of hospitalization.Thus,it is essential and more reliable to start from a defined target to ide ntify can didate drugs.