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2.
Sustainability ; 13(23):13379, 2021.
Article in English | ProQuest Central | ID: covidwho-1559143

ABSTRACT

Under the background of higher education reform, undergraduate tourism students’ professional identity may play an important role in affecting students’ learning engagement and the sustainable development of tourism higher education. Data were collected from 551 Chinese undergraduate tourism students to investigate the potential relationships between professional identity and learning engagement. Based on the theory of social identity, professional identity is perceived as a progressive, dynamic process including professional cognition, professional appraisal, and professional emotion. The data were analyzed using structural equation modeling (SEM), and the findings confirmed that professional identity was in positive correlation with employee engagement. Furthermore, the results showed that professional cognition has positive influences on professional appraisal, professional emotion, and learning engagement, and professional appraisal has positive influences on professional emotion and learning engagement. In addition, the mediating effects of professional appraisal and professional emotion between professional cognition and learning engagement were analyzed, respectively. This study contributes to the understanding of the impacts of tourism students’ professional identity on learning engagement. Both theoretical and practical implications are provided.

3.
Preprint in English | EuropePMC | ID: ppcovidwho-295639

ABSTRACT

S100A8 and S100A9 are members of the Alarmin family;these proteins are abundantly expressed in neutrophils and form a heterodimer complex. Recently, both proteins were identified as novel biomarkers of SARS-CoV-2 infection and were shown to play key roles in inducing an aggressive inflammatory response by mediating the release of large amounts of pro-inflammatory cytokines, called the “cytokine storm.” Although co-infection with SARS-CoV-2 in people living with HIV-1 may result in an immunocompromised status, the role of the S100A8/A9 complex in HIV-1 replication in primary T cells and macrophages is still unclear. Here, we evaluated the roles of the proteins in HIV replication to elucidate their functions. We found that the complex had no impact on virus replication in both cell types;however, the subunits of S100A8 and S100A9 inhibits HIV in macrophages. These findings provide important insights into the regulation of HIV viral loads in SARS-CoV2 co-infection.

4.
Front Cell Dev Biol ; 9: 696662, 2021.
Article in English | MEDLINE | ID: covidwho-1528812

ABSTRACT

A better understanding of the role of T cells in the immune response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is helpful not only for vaccine development but also for the treatment of COVID-19 patients. In this study, we determined the existence of SARS-CoV-2-specific T cells in the blood of COVID-19 convalescents. Meanwhile, the specific T cell response in the non-RBD region was stronger than in the RBD region. We also found that SARS-CoV-2 S-specific reactive CD4+ T cells exhibited higher frequency than CD8+ T cells in recovered COVID-19 patients, with greater number of corresponding epitopes presented. Importantly, we isolated the SARS-CoV-2-specific CD4+ T cell receptors (TCRs) and inserted the TCRs into allogenic CD4+ T cells. These TCR-T cells can be activated by SARS-CoV-2 spike peptide and produce IFN-γ in vitro. These results might provide valuable information for the development of vaccines and new therapies against COVID-19.

5.
China CDC Wkly ; 3(46): 967-972, 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1513532

ABSTRACT

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emergent coronavirus of natural origin and caused the coronavirus disease (COVID-19) pandemic. The study of its natural origin and host range is of particular importance for source tracing, monitoring of this virus, and prevention of recurrent infections. One major approach is to test the binding ability of the viral receptor gene ACE2 from various hosts to SARS-CoV-2 spike protein, but it is time-consuming and labor-intensive to cover a large collection of species. Methods: In this paper, we applied state-of-the-art machine learning approaches and created a pipeline reaching >87% accuracy in predicting binding between different ACE2 and SARS-CoV-2 spike. Results: We further validated our prediction pipeline using 2 independent test sets involving >50 bat species and achieved >78% accuracy. A large-scale screening of 204 mammal species revealed 144 species (or 61%) were susceptible to SARS-CoV-2 infections, highlighting the importance of intensive monitoring and studies in mammalian species. Discussion: In short, our study employed machine learning models to create an important tool for predicting potential hosts of SARS-CoV-2 and achieved the highest precision to our knowledge in experimental validation. This study also predicted that a wide range of mammals were capable of being infected by SARS-CoV-2.

6.
National Bureau of Economic Research Working Paper Series ; No. 27733, 2020.
Article in English | NBER, Grey literature | ID: grc-748521

ABSTRACT

Banking-system shutdowns during contractions scar economies. Four times in the last forty years, governors suspended payments from state-insured depository institutions. Suspensions of payments in Nebraska (1983), Ohio (1985), and Maryland (1985), which were short and occurred during expansions, had little measurable impact on macroeconomic aggregates. Rhode Island’s payments crisis (1991), which was prolonged and occurred during a recession, lengthened and deepened the downturn. Unemployment increased. Output declined, possibly permanently relative to what might have been. We document these effects using a novel Bayesian method for synthetic control that characterizes the principal types of uncertainty in this form of analysis. Our findings suggest policies that ensure banks continue to process payments during contractions – including the bailouts of financial institutions in 2008 and the unprecedented support of the financial system during the COVID crisis – have substantial value.

7.
Nat Commun ; 12(1): 6304, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1500462

ABSTRACT

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/chemistry , Antibodies, Viral/administration & dosage , Antibodies, Viral/chemistry , Binding Sites , COVID-19/pathology , COVID-19/virology , Epitopes , Humans , Mice , Mice, Transgenic , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Viral Load/drug effects , Weight Loss/drug effects
8.
Aging (Albany NY) ; 13(20): 23442-23458, 2021 10 29.
Article in English | MEDLINE | ID: covidwho-1498162

ABSTRACT

OBJECTIVE: Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized. DESIGN: In this retrospective cohort study, the epidemiological, demographic, laboratory, treatment and outcome information of 1,515 COVID-19 patients with available longitudinal amylase records collected from electronic medical system were analyzed to assess the prevalence and clinical significance of hyperamylasemia in this infection. Associated variables with hyperamylasemia in COVID-19 were also analyzed. RESULTS: Of 1,515 patients, 196 (12.9%) developed hyperamylasemia, among whom 19 (1.3%) greater than 3 times upper limit of normal (ULN) and no clinical acute pancreatitis was seen. Multivariable ordered logistic regression implied older age, male, chronic kidney disease, several medications (immunoglobin, systemic corticosteroids, and antifungals), increased creatinine might be associated with hyperamylasemia during hospitalization. Restricted cubic spline analysis indicated hyperamylasemia had a J-shaped association with all-cause mortality and the estimated hazard ratio per standard deviation was 2.85 (2.03-4.00) above ULN. Based on the multivariable mixed-effect cox or logistic regression model taking hospital sites as random effects, elevated serum amylase during hospitalization was identified as an independent risk factor associated with in-hospital death and intensive complications, including sepsis, cardiac injury, acute respiratory distress syndrome, and acute kidney injury. CONCLUSIONS: Elevated serum amylase was independently associated with adverse clinical outcomes in COVID-19 patients. Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.


Subject(s)
Amylases/blood , COVID-19/diagnosis , Hospital Mortality , Hyperamylasemia/complications , SARS-CoV-2/isolation & purification , Acute Disease , Aged , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Female , Hospitalization/statistics & numerical data , Humans , Hyperamylasemia/blood , Male , Middle Aged , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics
9.
Nat Commun ; 12(1): 6103, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475296

ABSTRACT

Multiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. However, there is yet a lack of understanding of the molecular basis for the interactions between the human ACE2 (hACE2) receptor and these VOCs. Here we examined several VOCs including Alpha, Beta, and Gamma, and demonstrate that five variants receptor-binding domain (RBD) increased binding affinity for hACE2, and four variants pseudoviruses increased entry into susceptible cells. Crystal structures of hACE2-RBD complexes help identify the key residues facilitating changes in hACE2 binding affinity. Additionally, soluble hACE2 protein efficiently prevent most of the variants pseudoviruses. Our findings provide important molecular information and may help the development of novel therapeutic and prophylactic agents targeting these emerging mutants.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/isolation & purification , Angiotensin-Converting Enzyme 2/ultrastructure , Animals , Cell Line, Tumor , Crystallography, X-Ray , HEK293 Cells , Humans , Molecular Dynamics Simulation , Mutation , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Recombinant Proteins/ultrastructure , SARS-CoV-2/genetics , Sf9 Cells , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/isolation & purification , Spike Glycoprotein, Coronavirus/ultrastructure , Spodoptera , Surface Plasmon Resonance , Virus Attachment , Virus Internalization
10.
iScience ; 24(11): 103256, 2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1464739

ABSTRACT

Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) driven by viruses or bacteria, as well as in numerous immune-mediated disorders. Histone citrullination by the enzyme peptidylarginine deiminase 4 (PAD4) and the consequent decondensation of chromatin are hallmarks in the induction of NETs. Nevertheless, additional histone modifications that may govern NETosis are largely overlooked. Herein, we show that histone deacetylases (HDACs) play critical roles in driving NET formation in human and mouse neutrophils. HDACs belonging to the zinc-dependent lysine deacetylases family are necessary to deacetylate histone H3, thus allowing the activity of PAD4 and NETosis. Of note, HDAC inhibition in mice protects against microbial-induced pneumonia and septic shock, decreasing NETosis and inflammation. Collectively, our findings illustrate a new fundamental step that governs the release of NETs and points to HDAC inhibitors as therapeutic agents that may be used to protect against ARDS and sepsis.

12.
Medicine (Baltimore) ; 100(34): e27016, 2021 Aug 27.
Article in English | MEDLINE | ID: covidwho-1376351

ABSTRACT

ABSTRACT: Nursing students are the main force of future nursing development, and their hope and death anxiety are important aspects of their coping styles and clinical practice.The present study examined the relationships between hope, death anxiety and simplified coping style scores of nursing students during the outbreak of COVID-19.Between February and April 2020, a cross-sectional descriptive study was performed using a Sojump online survey, and 870 nursing students completed the herth hope (HH), death anxiety scale (DAS) and simplified coping style questionnaire. The data were analyzed using t-tests, one-way analysis of variance (ANOVA), and multiple linear regression in SPSS 23.0 (IBM Corp, Armonk, NY).The average HH, DAS and active and passive coping scores of the 870 nursing students were 3.07 ±â€Š0.32, 3.01 ±â€Š0.37, 2.84 ±â€Š0.48, and 2.25 ±â€Š0.50, respectively. Participants with contact experience with individuals with suspected or confirmed COVID-19 were more likely to adopt passive coping styles than students without contact experience (t = 5.019, P = .025). Being older and having higher inner positive readiness and expectancy, a lower inner sense of temporality and future, and lower time awareness were predictors of passive coping styles (P < .05). Living in cities (vs towns) and having a higher inner positive readiness and expectancy, a higher inner sense of temporality and future and lower cognition of death were predictors of active coping styles (P < .05).The findings of this study suggest that hope and death anxiety are important aspects of the coping styles of nursing students. Nursing educators should emphasize the role of hope, further deepen the death education mode, and perform scientific and reasonable death education programmes to reduce the death anxiety level of nursing students to promote their coping styles in crisis.


Subject(s)
Adaptation, Psychological , Anxiety/epidemiology , Attitude to Death , COVID-19/epidemiology , Hope , Students, Nursing/psychology , Adolescent , Adult , Cross-Sectional Studies , Female , Humans , Male , SARS-CoV-2 , Young Adult
13.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Article in English | MEDLINE | ID: covidwho-1307382

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2), presents an urgent health crisis. More recently, an increasing number of mutated strains of SARS-CoV-2 have been identified globally. Such mutations, especially those on the spike glycoprotein to render its higher binding affinity to human angiotensin-converting enzyme II (hACE2) receptors, not only resulted in higher transmission of SARS-CoV-2 but also raised serious concerns regarding the efficacies of vaccines against mutated viruses. Since ACE2 is the virus-binding protein on human cells regardless of viral mutations, we design hACE2-containing nanocatchers (NCs) as the competitor with host cells for virus binding to protect cells from SARS-CoV-2 infection. The hACE2-containing NCs, derived from the cellular membrane of genetically engineered cells stably expressing hACE2, exhibited excellent neutralization ability against pseudoviruses of both wild-type SARS-CoV-2 and the D614G variant. To prevent SARS-CoV-2 infections in the lung, the most vulnerable organ for COVID-19, we develop an inhalable formulation by mixing hACE2-containing NCs with mucoadhesive excipient hyaluronic acid, the latter of which could significantly prolong the retention of NCs in the lung after inhalation. Excitingly, inhalation of our formulation could lead to potent pseudovirus inhibition ability in hACE2-expressing mouse model, without imposing any appreciable side effects. Importantly, our inhalable hACE2-containing NCs in the lyophilized formulation would allow long-term storage, facilitating their future clinical use. Thus, this work may provide an alternative tactic to inhibit SARS-CoV-2 infections even with different mutations, exhibiting great potential for treatment of the ongoing COVID-19 epidemic.


Subject(s)
COVID-19/prevention & control , Nanostructures/administration & dosage , SARS-CoV-2/drug effects , Adhesives/administration & dosage , Adhesives/chemistry , Adhesives/pharmacokinetics , Administration, Inhalation , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cryoprotective Agents/chemistry , Drug Storage , Epithelial Cells/metabolism , Excipients/administration & dosage , Excipients/chemistry , Excipients/pharmacokinetics , HEK293 Cells , Humans , Hyaluronic Acid/administration & dosage , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacokinetics , Lung/drug effects , Lung/metabolism , Lung/virology , Mice , Mice, Transgenic , Nanostructures/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Virus Attachment/drug effects
14.
Genes Dis ; 2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1293799

ABSTRACT

Despite the growing knowledge of T cell responses in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Here, with a predicted peptide library from SARS-CoV-2 S and N proteins, restricted to three of the most prominent HLA-A alleles in the Asian population, we found that specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients (15/20). A total of 15 SARS-CoV-2 epitopes from the S and N proteins were identified, and among them, 3 dominant epitopes were further characterized. We found that an epitope from the N protein, N361-369 (KTFPPTEPK), was the most dominant epitope from our selected peptide library. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity that were independent of the CD8 co-receptor. These TCRs exhibited complementary cross-reactivity to several presently reported N361-369 mutant variants, as to the wild-type epitope. Further, the natural functions of these TCRs in the cytotoxic immunity against SARS-CoV-2 were determined with dendritic cells (DCs) and the lung organoid model. We found that the N361-369 epitope could be normally processed and endogenously presented by these different types of antigen presenting cells, to elicit successful activation and effective cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, and illuminated potential ways of viral clearance in COVID-19 patients. These results indicate that utilizing CD8-independent TCRs against SARS-CoV-2-associated antigens may provide functional superiority that is beneficial for the adoptive cell immunotherapies based on natural or genetically engineered T cells. Additionally, this information is highly relevant for the development of the next-generation vaccines with protections against continuously emerged SARS-CoV-2 mutant strains.

15.
Cell ; 184(13): 3438-3451.e10, 2021 06 24.
Article in English | MEDLINE | ID: covidwho-1275185

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Binding Sites/physiology , COVID-19/metabolism , Chiroptera/virology , SARS-CoV-2/pathogenicity , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , COVID-19/immunology , Chiroptera/immunology , Chiroptera/metabolism , Host Specificity/immunology , Humans , Phylogeny , Protein Binding/physiology , Receptors, Virus/metabolism , SARS-CoV-2/immunology , Sequence Alignment
16.
Vaccines (Basel) ; 9(6)2021 Jun 14.
Article in English | MEDLINE | ID: covidwho-1270134

ABSTRACT

OBJECTIVES: To investigate the differences in vaccine hesitancy and preference of the currently available COVID-19 vaccines between two countries, namely, China and the United States (U.S.). METHOD: A cross-national survey was conducted in both China and the United States, and discrete choice experiments, as well as Likert scales, were utilized to assess vaccine preference and the underlying factors contributing to vaccination acceptance. Propensity score matching (PSM) was performed to enable a direct comparison between the two countries. RESULTS: A total of 9077 (5375 and 3702 from China and the United States, respectively) respondents completed the survey. After propensity score matching, over 82.0% of respondents from China positively accepted the COVID-19 vaccination, while 72.2% of respondents from the United States positively accepted it. Specifically, only 31.9% of Chinese respondents were recommended by a doctor to have COVID-19 vaccination, while more than half of the U.S. respondents were recommended by a doctor (50.2%), local health board (59.4%), or friends and families (64.8%). The discrete choice experiments revealed that respondents from the United States attached the greatest importance to the efficacy of COVID-19 vaccines (44.41%), followed by the cost of vaccination (29.57%), whereas those from China held a different viewpoint, that the cost of vaccination covered the largest proportion in their trade-off (30.66%), and efficacy ranked as the second most important attribute (26.34%). Additionally, respondents from China tended to be much more concerned about the adverse effect of vaccination (19.68% vs. 6.12%) and have a lower perceived severity of being infected with COVID-19. CONCLUSION: Although the overall acceptance and hesitancy of COVID-19 vaccination in both countries are high, underpinned distinctions between these countries were observed. Owing to the differences in COVID-19 incidence rates, cultural backgrounds, and the availability of specific COVID-19 vaccines in the two countries, vaccine rollout strategies should be nation-dependent.

17.
International Journal of Social Research Methodology ; : 1-7, 2021.
Article in English | Taylor & Francis | ID: covidwho-1258693
18.
EMBO J ; 40(16): e107786, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1239217

ABSTRACT

Pangolins have been suggested as potential reservoir of zoonotic viruses, including SARS-CoV-2 causing the global COVID-19 outbreak. Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Additionally, cryo-EM structures of GX/P2V/2017 and GD/1/2019 RBDs in complex with hACE2 show their molecular binding in modes similar to SARS-CoV-2 RBD. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. These findings suggest that these two pangolin CoVs may infect humans, highlighting the necessity of further surveillance of pangolin CoVs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Betacoronavirus/physiology , Pangolins/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/chemistry , Animals , Binding Sites , HEK293 Cells , Hedgehogs/virology , Host Specificity , Humans , Mice , Models, Molecular , Phylogeny , Protein Binding , Protein Conformation , Rats , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
19.
Nano Lett ; 21(10): 4394-4402, 2021 05 26.
Article in English | MEDLINE | ID: covidwho-1230861

ABSTRACT

The high demand for acute kidney injury (AKI) therapy calls the development of multifunctional nanomedicine for renal management with programmable pharmacokinetics. Here, we developed a renal-accumulating DNA nanodevice with exclusive kidney retention for longitudinal protection of AKI in different stages in a renal ischemia-reperfusion (I/R) model. Due to the prolonged kidney retention time (>12 h), the ROS-sensitive nucleic acids of the nanodevice could effectively alleviate oxidative stress by scavenging ROS in stage I, and then the anticomplement component 5a (aC5a) aptamer loaded nanodevice could sequentially suppress the inflammatory responses by blocking C5a in stage II, which is directly related to the cytokine storm. This sequential therapy provides durable and pathogenic treatment of kidney dysfunction based on successive pathophysiological events induced by I/R, which holds great promise for renal management and the suppression of the cytokine storm in more broad settings including COVID-19.


Subject(s)
Acute Kidney Injury , COVID-19 , Reperfusion Injury , Acute Kidney Injury/drug therapy , Acute Kidney Injury/metabolism , Humans , Kidney/metabolism , Oxidative Stress , Reperfusion Injury/drug therapy , SARS-CoV-2
20.
Immunity ; 54(6): 1186-1199.e7, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1207036

ABSTRACT

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.


Subject(s)
Host-Pathogen Interactions , Immunity, Cellular , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Receptor, Notch4/metabolism , Signal Transduction , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Amphiregulin/pharmacology , Animals , Biomarkers , Cytokines/metabolism , Disease Models, Animal , Disease Susceptibility , Host-Pathogen Interactions/immunology , Humans , Immunohistochemistry , Immunomodulation/drug effects , Inflammation Mediators/metabolism , Influenza A virus/physiology , Lung/immunology , Lung/metabolism , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Pneumonia, Viral/pathology , Receptor, Notch4/antagonists & inhibitors , Receptor, Notch4/genetics , Severity of Illness Index
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