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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335275

ABSTRACT

While SARS-CoV-2 pathogenesis has been intensively investigated, the host mechanisms of viral clearance and inflammation resolution are still elusive because of the ethical limitation of human studies based on COVID-19 convalescents. Here we infected Syrian hamsters by authentic SARS-CoV-2 and built an ideal model to simulate the natural recovery process of SARS-CoV-2 infection from severe pneumonia 1,2 . We developed and applied a spatial transcriptomic sequencing technique with subcellular resolution and tissue-scale extensibility, i.e. , Stereo-seq 3 , together with single-cell RNA sequencing (scRNA-seq), to the entire lung lobes of 45 hamsters and obtained an elaborate map of the pulmonary spatiotemporal changes from acute infection, severe pneumonia to the late viral clearance and inflammation resolution. While SARS-CoV-2 infection caused massive damages to the hamster lungs, including naïve T cell infection and deaths related to lymphopenia, we identified a group of monocyte-derived proliferating Slamf9 + Spp1 + macrophages, which were SARS-CoV-2 infection-inducible and cell death-resistant, recruiting neutrophils to clear viruses together. After viral clearance, the Slamf9 + Spp1 + macrophages differentiated into Trem2 + and Fbp1 + macrophages, both responsible for inflammation resolution and replenishment of alveolar macrophages. The existence of this specific macrophage subpopulation and its descendants were validated by RNAscope in hamsters, immunofluorescence in hACE2 mice, and public human autopsy scRNA-seq data of COVID-19 patients. The spatiotemporal landscape of SARS-CoV-2 infection in hamster lungs and the identification of Slamf9 + Spp1 + macrophages that is pivotal to viral clearance and inflammation resolution are important to better understand the critical molecular and cellular players of COVID-19 host defense and also develop potential interventions of COVID-19 immunopathology.

3.
Protein Cell ; 2022 Apr 04.
Article in English | MEDLINE | ID: covidwho-1773029

ABSTRACT

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

4.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331560

ABSTRACT

Since the outbreak of COVID-19 in 2019, the 2019-nCov coronavirus has appeared diverse mutational characteristics due to its own flexible conformation. One multiple-mutant strain (Omicron) with surprisingly infective activity outburst, and affected the biological activities of current drugs and vaccines, making the epidemic significantly difficult to prevent and control, and seriously threaten health around the world. Importunately exploration of mutant characteristics for novel coronavirus Omicron can supply strong theoretical guidance for learning binding mechanism of mutant viruses. What’s more, full acknowledgement of key mutated-residues on Omicron strain can provide new methodology of the novel pathogenic mechanism to human ACE2 receptor, as well as the subsequent vaccine development. In this research, 3D structures of 32 single-point mutations of 2019-nCov were firstly constructed, and 32-sites multiple-mutant Omicron were finally obtained based one the wild-type virus by homology modeling method. One total number of 33 2019-nCov/ACE2 complex systems were acquired by protein-protein docking, and optimized by using preliminary molecular dynamics simulations. Binding free energies between each 2019-nCov mutation system and human ACE2 receptor were calculated, and corresponding binding patterns especially the regions adjacent to mutation site were analyzed. The results indicated that one total number of 6 mutated sites on the Omicron strain played crucial role in improving binding capacities from 2019-nCov to ACE2 protein. Subsequently, we performed long-term molecular dynamic simulations and protein-protein binding energy analysis for the selected 6 mutations. 3 infected individuals, the mutants T478K, Q493R and G496S with lower binding energies − 66.36, -67.98 and − 67.09 kcal/mol also presents the high infectivity. These findings indicated that the 3 mutations T478K, Q493R and G496S play the crucial roles in enhancing binding affinity of Omicron to human ACE2 protein. All these results illuminate important theoretical guidance for future virus detection of the Omicron epidemic, drug research and vaccine development.

5.
Frontiers in medicine ; 8, 2021.
Article in English | EuropePMC | ID: covidwho-1728543

ABSTRACT

Background and Purpose To investigate the effect of prior ischemic stroke on the outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19), and to describe the incidence, clinical features, and risk factors of acute ischemic stroke (AIS) following COVID-19. Methods In this population-based retrospective study, we included all the hospitalized positive patients with COVID-19 at Wuhan City from December 29, 2019 to April 15, 2020. Clinical data were extracted from administrative datasets coordinated by the Wuhan Health Commission. The propensity score matching and multivariate logistic regression analyses were used to adjust the confounding factors. Results There are 36,358 patients in the final cohort, in which 1,160 (3.2%) had a prior stroke. After adjusting for available baseline characteristics, patients with prior stroke had a higher proportion of severe and critical illness and mortality. We found for the first time that the premorbid modified Rankin Scale (MRS) grouping (odds ratio [OR] = 1.796 [95% CI 1.334–2.435], p < 0.001) and older age (OR = 1.905 [95% CI 1.211–3.046], p = 0.006) imparted increased risk of death. AIS following COVID-19 occurred in 124 (0.34%) cases, and patients with prior stroke had a much higher incidence of AIS (3.4%). Logistic regression analyses confirmed an association between the severity of COVID-19 with the incidence of AIS. COVID-19 patients with AIS had a significantly higher mortality compared with COVID-19 patients without stroke and AIS patients without COVID-19. Conclusions Coronavirus disease 2019 patients with prior stroke, especially those with the higher premorbid MRS or aged, have worse clinical outcomes. Furthermore, COVID-19 increases the incidence of AIS, and the incidence is positively associated with the severity of COVID-19.

6.
Chin Med J (Engl) ; 133(9): 1015-1024, 2020 May 05.
Article in English | MEDLINE | ID: covidwho-1722617

ABSTRACT

BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. RESULTS: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown ß-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. CONCLUSION: A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.


Subject(s)
Betacoronavirus , Coronavirus Infections/virology , Pneumonia, Viral/virology , Adult , Aged , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/therapy , Female , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/therapy , SARS-CoV-2 , Tomography, X-Ray , Treatment Outcome
8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324533

ABSTRACT

SARS-CoV-2 infection causes complicated clinic manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various tissues/organs examined, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Neuronal receptor NRP1 expression showed a significant induction by SARS-CoV-2 in cerebral cortex, which might be responsible for a higher infectivity and consequent inflammatory response. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-323719

ABSTRACT

The SARS-CoV-2 has led to a worldwide health crisis. The ACE2 has been identified as the entry receptor in a species-specific manner. Classic laboratory mice were insusceptible since the virus cannot use murine ACE2 orthologue. Animal models rely on gene modification on the virus or the host. However, these mice were restricted in limited genetic backgrounds and did not support natural infection. Here we showed two wild-type inbred lines (CAST and FEW) from Genetic Diversity mice supported authentic SARS-CoV-2 infection, and developed mild to moderate interstitial pneumonia, along with infiltrating inflammatory cells. Particularly, FEW featured age-dependent damages, while CAST charactered by pulmonary fibrosis. Genome and transcriptome comparative analysis suggested the mutated ACE2 was not responsible for SARS-CoV-2 infection in CAST and FEW, and the differential gene expressions in immune response and immune cell may be risk factors for the infection. In summary, the GD mice, derived from the multi-parental panel, provided promising murine models for exploring sophisticated pathogenesis in SARS-CoV-2.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-319504

ABSTRACT

Background: In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan and rapidly spread throughout China. The immune response is likely to be highly involved in the pathological process of coronavirus disease 2019 (COVID-19). However, information on specific changes of immune response in COVID-19 are limited. Methods: Demographic and clinical data of all confirmed cases with COVID-19 on admission at Tongji Hospital from January 10 to February 12, 2020, were collected and analyzed. The expression of lymphocytes, lymphocyte subsets, infection related biomarkers and inflammatory cytokines were analyzed and compared between severe cases and non-severe patients. Findings: Of the 452 patients with COVID-19 recruited from January 10 to February 12, 2020, 286 were diagnosed as severe infection. The median age was 58 years and 235 were male. 201 patients had chronic diseases and a higher percentage in the severe cases. The most common symptoms were fever, shortness of breath, expectoration, and fatigue. Severe cases tend to have higher white blood cell and neutrophil lymphopenia ratio (NLR), as well as lower percentages of monocytes, eosinophils, and basophils. Most of severe cases demonstrated elevated levels of infection-related biomarkers, and inflammatory cytokines. The numbers of B cells, T cells and NK cells was significantly decreased in patients with COVID-19, and more severely decreased in the severe cases. T cells were shown to be most affected by SARS-CoV-2, and more hampered in severe cases. Both helper T cells and suppressor T cells in patients with COVID-19 were below normal levels. Helper T cells tend to be more affected in severe cases. The percentage of naïve helper T cells increased and memory helper T cells decreased in severe cases. Patients with COVID-19 have lower level of regulatory T cells, and more obviously damaged in severe cases. Interpretation: SARS-CoV-2 might mainly act on lymphocytes, especially T lymphocytes, and induce a cytokine storm in the body, generate a series of immune responses. Surveillance of NLR and lymphocyte subsets is helpful in the early screening of critical illness, diagnosis and treatment of COVID-19.Funding Statement: None.Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study was performed in accordance with Tongji Hospital Ethics Committee (IRB ID: TJ-C20200121). Written informed consent was waived by the Ethics Commission of the designated hospital for emerging infectious disease.

11.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-315287

ABSTRACT

Background: To develop and evaluate the prognostic machine-learning model for mortality in patients with coronavirus disease 2019 (COVID-19). Methods: Clinical data of confirmed COVID-19 were retrospectively collected from Wuhan between 18th January and 29th March 2020. Gradient Boosting Decision Tree (GBDT), logistic regression (LR) model, and simplified LR with selected 5 features (LR-5) model were built to predict the mortality of COVID-19. 5-fold area under curve (AUC), accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated and compared between models. Results: A total of 2,924 patients were included in the final analysis, 257(8.8%) of whom died during hospitalization and 2,667 (91.2%) survived. There were 21(0.7%) mild cases, 2,051(70.1%) moderate case, 779(26.6%) severe cases, and 73(2.5%) critically severe cases of COVID-19 on admission. The overall 5-fold AUC was observed highest in GBDT model (0.941), followed by LR (0.928) and LR-5 (0.913). The diagnostic accuracy were 0.889 in GBDT, 0.868 in LR and 0.887 in LR-5. GBDT model also showed the highest sensitivity (0.899) and speciality (0.889). The NPV of all three models exceeded 97%, while the PPV were relatively low in all models, 0.381 for LR, 0.402 for LR-5 and 0.432 for GBDT. In subgroups analysis with severe cases only, GBDT model also performed the best with a accuracy of 0.799 and 5-fold AUC (0.918). Conclusion: The finding revealed that mortality prediction performance of the GBDT was superior to the LR models in confirmed cases of COVID-19, regardless of disease severity.

12.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-311706

ABSTRACT

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Accumulating evidences suggest that SARS-CoV-2 infection causes dysregulation of immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced by SARS-CoV-2 in animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could reduce inflammatory response and rescue the pneumonia with substantial reduction of viral titers in SASR-CoV-2 infected animals. Remarkably, Paquinimod treatment resulted in 100% survival of mice in a lethal model of mouse coronavirus (MHV) infection. A novel group of neutrophils that contributed to the uncontrolled inflammation and onset of COVID-19 were dramatically induced by coronavirus infections. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and noncanonical neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.Funding: This work was supported by the National Natural Science Foundation of China (31570891;31872736), the National Key Research and Development Program of China (2016YFA0500302;2020YFA0707800), the National Key Research and Development Program (2020YFA0707500) and the Strategic Priority Research Program (XDB29010000). Xiangxi Wang was supported by Ten Thousand Talent Program and the NSFS Innovative Research Group (81921005). We thank National Mega projects of China for Major Infectious Diseases (2017ZX10304402), CAMS initiative for Innovative Medicine of China (2016-12M-2-006) and The National Natural Science Foundation of China (82041008) for the support on the animal model study. Conflict of Interest: The authors have no conflicts of interest to declare.Ethical Approval: All experiments with live SARS-CoV-2 viruses were carried out in the enhanced biosafety level 3 (P3+) facilities in the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) approved by the National Health Commission of the People’s Republic of China. All animals care and use were in accordance with the Guide for the Care and Use of Laboratory Animals of the Chinese Association for Laboratory Animal Science. All procedures of animal handling were approved by the Animal Care Committee of Peking University Health Science Center.

13.
Vet Pathol ; : 3009858211071016, 2022 Jan 29.
Article in English | MEDLINE | ID: covidwho-1662392

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes severe viral pneumonia and is associated with a high fatality rate. A substantial proportion of patients infected by SARS-CoV-2 suffer from mild hyposmia to complete loss of olfactory function, resulting in anosmia. However, the pathogenesis of the olfactory dysfunction and comparative pathology of upper respiratory infections with SARS-CoV-2 are unknown. We describe the histopathological, immunohistochemical, and in situ hybridization findings from rodent models of SARS-CoV-2 infection. The main histopathological findings in the olfactory epithelia of K8-hACE2 Tg mice, hACE2 Tg mice, and hamsters were varying degrees of inflammatory lesions, including disordered arrangement, necrosis, exfoliation, and macrophage infiltration of the olfactory epithelia, and inflammatory exudation. On the basis of these observations, the nasal epithelia of these rodent models appeared to develop moderate, mild, and severe rhinitis, respectively. Correspondingly, SARS-CoV-2 viral RNA and antigen were mainly identified in the olfactory epithelia and lamina propria. Moreover, viral RNA was abundant in the cerebrum of K18-hACE2 Tg mice, including the olfactory bulb. The K8-hACE2 Tg mouse, hACE2 Tg mouse, and hamster models could be used to investigate the pathology of SARS-CoV-2 infection in the upper respiratory tract and central nervous system. These models could help to provide a better understanding of the pathogenic process of this virus and to develop effective medications and prophylactic treatments.

14.
Nature ; 603(7903): 919-925, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1655591

ABSTRACT

Omicron (B.1.1.529), the most heavily mutated SARS-CoV-2 variant so far, is highly resistant to neutralizing antibodies, raising concerns about the effectiveness of antibody therapies and vaccines1,2. Here we examined whether sera from individuals who received two or three doses of inactivated SARS-CoV-2 vaccine could neutralize authentic Omicron. The seroconversion rates of neutralizing antibodies were 3.3% (2 out of 60) and 95% (57 out of 60) for individuals who had received 2 and 3 doses of vaccine, respectively. For recipients of three vaccine doses, the geometric mean neutralization antibody titre for Omicron was 16.5-fold lower than for the ancestral virus (254). We isolated 323 human monoclonal antibodies derived from memory B cells in triple vaccinees, half of which recognized the receptor-binding domain, and showed that a subset (24 out of 163) potently neutralized all SARS-CoV-2 variants of concern, including Omicron. Therapeutic treatments with representative broadly neutralizing monoclonal antibodies were highly protective against infection of mice with SARS-CoV-2 Beta (B.1.351) and Omicron. Atomic structures of the Omicron spike protein in complex with three classes of antibodies that were active against all five variants of concern defined the binding and neutralizing determinants and revealed a key antibody escape site, G446S, that confers greater resistance to a class of antibodies that bind on the right shoulder of the receptor-binding domain by altering local conformation at the binding interface. Our results rationalize the use of three-dose immunization regimens and suggest that the fundamental epitopes revealed by these broadly ultrapotent antibodies are rational targets for a universal sarbecovirus vaccine.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mice , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus
15.
Signal Transduct Target Ther ; 7(1): 29, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1655546

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Metabolome , Mink/virology , SARS-CoV-2/metabolism , Amino Acids/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/pathology , Disease Models, Animal , Female , Humans , Lung/pathology , Lung/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/virology , Melatonin/metabolism , Metabolic Networks and Pathways/genetics , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sterols/metabolism , Virulence , Virus Replication/genetics
16.
Hum Vaccin Immunother ; 18(1): 2016201, 2022 Dec 31.
Article in English | MEDLINE | ID: covidwho-1642249

ABSTRACT

Genetic optimization of Nucleic Acid immunogens is important for potentially improving their immune potency. A COVID-19 DNA vaccine is in phase III clinical trial which is based on a promising highly developable technology platform. Here, we show optimization in mice generating a pGX-9501 DNA vaccine encoding full-length spike protein, which results in induction of potent humoral and cellular immune responses, including neutralizing antibodies, that block hACE2-RBD binding of live CoV2 virus in vitro. Optimization resulted in improved induction of cellular immunity by pGX-9501 as demonstrated by increased IFN-γ expression in both CD8+ and CD4 + T cells and this was associated with more robust antiviral CTL responses compared to unoptimized constructs. Vaccination with pGX-9501 induced subsequent protection against virus challenge in a rigorous hACE2 transgenic mouse model. Overall, pGX-9501 is a promising optimized COVID-19 DNA vaccine candidate inducing humoral and cellular immunity contributing to the vaccine's protective effects.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Base Sequence , COVID-19/prevention & control , Mice , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
17.
Cell Res ; 32(3): 269-287, 2022 03.
Article in English | MEDLINE | ID: covidwho-1634806

ABSTRACT

The emergence of SARS-CoV-2 variants and potentially other highly pathogenic sarbecoviruses in the future highlights the need for pan-sarbecovirus vaccines. Here, we discovered a new STING agonist, CF501, and found that CF501-adjuvanted RBD-Fc vaccine (CF501/RBD-Fc) elicited significantly stronger neutralizing antibody (nAb) and T cell responses than Alum- and cGAMP-adjuvanted RBD-Fc in mice. Vaccination of rabbits and rhesus macaques (nonhuman primates, NHPs) with CF501/RBD-Fc elicited exceptionally potent nAb responses against SARS-CoV-2 and its nine variants and 41 S-mutants, SARS-CoV and bat SARSr-CoVs. CF501/RBD-Fc-immunized hACE2-transgenic mice were almost completely protected against SARS-CoV-2 challenge, even 6 months after the initial immunization. NHPs immunized with a single dose of CF501/RBD-Fc produced high titers of nAbs. The immunized macaques also exhibited durable humoral and cellular immune responses and showed remarkably reduced viral load in the upper and lower airways upon SARS-CoV-2 challenge even at 108 days post the final immunization. Thus, CF501/RBD-Fc can be further developed as a novel pan-sarbecovirus vaccine to combat current and future outbreaks of sarbecovirus diseases.


Subject(s)
COVID-19 , Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Macaca mulatta , Mice , Rabbits , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes
18.
Cell Mol Immunol ; 19(2): 210-221, 2022 02.
Article in English | MEDLINE | ID: covidwho-1608557

ABSTRACT

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.


Subject(s)
Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , Cell-Derived Microparticles/metabolism , Cholesterol/metabolism , Endosomes/chemistry , Macrophages, Alveolar/metabolism , SARS-CoV-2/metabolism , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Female , Humans , Hydrogen-Ion Concentration , Lysosomes/chemistry , Mice , Mice, Inbred ICR , Mice, Transgenic , Oxidation-Reduction , RAW 264.7 Cells , Treatment Outcome , Vero Cells
19.
J Cardiovasc Transl Res ; 15(1): 38-48, 2022 02.
Article in English | MEDLINE | ID: covidwho-1594479

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.


Subject(s)
COVID-19 , Hypertension , Animals , Humans , Hypertension/complications , Hypertension/drug therapy , Inpatients , Mice , Mice, Transgenic , Renin-Angiotensin System , SARS-CoV-2 , Virulence
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