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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.

2.
Signal Transduct Target Ther ; 7(1): 124, 2022 04 18.
Article in English | MEDLINE | ID: covidwho-1795804

ABSTRACT

Variants of concern (VOCs) like Delta and Omicron, harbor a high number of mutations, which aid these viruses in escaping a majority of known SARS-CoV-2 neutralizing antibodies (NAbs). In this study, Rhesus macaques immunized with 2-dose inactivated vaccines (Coronavac) were boosted with an additional dose of homologous vaccine or an RBD-subunit vaccine, or a bivalent inactivated vaccine (Beta and Delta) to determine the effectiveness of sequential immunization. The booster vaccination significantly enhanced the duration and levels of neutralizing antibody titers against wild-type, Beta, Delta, and Omicron. Animals administered with an indicated booster dose and subsequently challenged with Delta or Omicron variants showed markedly reduced viral loads and improved histopathological profiles compared to control animals, indicating that sequential immunization could protect primates against Omicron. These results suggest that sequential immunization of inactivated vaccines or polyvalent vaccines could be a potentially effective countermeasure against newly emerging variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Macaca mulatta , SARS-CoV-2/genetics , Vaccination , Vaccines, Inactivated/genetics
3.
Animal Model Exp Med ; 5(1): 89-93, 2022 02.
Article in English | MEDLINE | ID: covidwho-1712020

ABSTRACT

BACKGROUND: The Omicron (B.1.1.529) SARS-COV-2 variant has raised serious concerns because of its unprecedented rapid rate of spreading and the fact that there are 36 mutations in the spike protein. Since the vaccine-induced neutralizing antibody targets are the spike protein, this may lead to the possibility of vaccine-induced humoral immunity escape. METHODS: We measured the neutralizing activity in vitro for Omicron and compared this with wild type (WH-09) and Delta variants in human and monkey sera from different types of immunity. The monkey sera samples were collected at 1 and 3 months post three-dose inactivated (PiCoVacc) and recombinant protein (ZF2001) vaccination. Human sera were collected from 1 month post three-dose inactivated vaccination. RESULTS: In inactivated vaccine sera, at 1/3 months post three-dose, geometric mean titers (GMTs) of neutralization antibody (NAb) against the Omicron variant were 4.9/5.2-fold lower than those of the wild type. In recombinant protein vaccine sera, GMTs of NAb against Omicron were 15.7/8.9-fold lower than those of the wild type. In human sera, at 1 month post three-dose inactivated vaccination, GMTs of NAb against Omicron were 3.1-fold lower than those of the wild type. CONCLUSION: This study demonstrated that despite a reduction in neutralization titers, cross-neutralizing activity against Omicron and Delta variants was still observed after three doses of inactivated and recombinant protein vaccination.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/administration & dosage , COVID-19 , Cross Reactions , SARS-CoV-2 , Animals , Antibodies, Neutralizing/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Haplorhini , Humans , Neutralization Tests , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics
4.
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
5.
Signal Transduct Target Ther ; 6(1): 200, 2021 05 20.
Article in English | MEDLINE | ID: covidwho-1237988

ABSTRACT

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.


Subject(s)
COVID-19 , Coinfection , Influenza A Virus, H1N1 Subtype/immunology , Orthomyxoviridae Infections , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Coinfection/immunology , Coinfection/pathology , Coinfection/virology , Disease Models, Animal , Ferrets , Humans , Male , Mice , Mice, Transgenic , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology
7.
Biochem Pharmacol ; 183: 114302, 2021 01.
Article in English | MEDLINE | ID: covidwho-893616

ABSTRACT

Baicalein is the main active compound of Scutellaria baicalensis Georgi, a medicinal herb with multiple pharmacological activities, including the broad anti-virus effects. In this paper, the preclinical study of baicalein on the treatment of COVID-19 was performed. Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 µM and above. The effective concentration could be reached after oral administration of 200 mg/kg crystal form ß of baicalein in rats. Furthermore, baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1ß and TNF-α in serum. In conclusion, oral administration of crystal form ß of baicalein could reach its effective concentration against SARS-CoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo. Therefore, baicalein might be a promising therapeutic drug for the treatment of COVID-19.


Subject(s)
Antioxidants/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Flavanones/therapeutic use , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Animals , Antioxidants/pharmacokinetics , COVID-19/metabolism , Chlorocebus aethiops , Dose-Response Relationship, Drug , Female , Flavanones/pharmacokinetics , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Random Allocation , Rats , Rats, Sprague-Dawley , Treatment Outcome , Vero Cells
8.
Animal Model Exp Med ; 3(1): 93-97, 2020 Mar.
Article in English | MEDLINE | ID: covidwho-847791

ABSTRACT

BACKGROUND: Since December 2019, an outbreak of the Corona Virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Wuhan, China, has become a public health emergency of international concern. The high fatality of aged cases caused by SARS-CoV-2 was a need to explore the possible age-related phenomena with non-human primate models. METHODS: Three 3-5 years old and two 15 years old rhesus macaques were intratracheally infected with SARS-CoV-2, and then analyzed by clinical signs, viral replication, chest X-ray, histopathological changes and immune response. RESULTS: Viral replication of nasopharyngeal swabs, anal swabs and lung in old monkeys was more active than that in young monkeys for 14 days after SARS-CoV-2 challenge. Monkeys developed typical interstitial pneumonia characterized by thickened alveolar septum accompanied with inflammation and edema, notably, old monkeys exhibited diffuse severe interstitial pneumonia. Viral antigens were detected mainly in alveolar epithelial cells and macrophages. CONCLUSION: SARS-CoV-2 caused more severe interstitial pneumonia in old monkeys than that in young monkeys. Rhesus macaque models infected with SARS-CoV-2 provided insight into the pathogenic mechanism and facilitated the development of vaccines and therapeutics against SARS-CoV-2 infection.

9.
Nature ; 586(7830): 572-577, 2020 10.
Article in English | MEDLINE | ID: covidwho-691301

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.


Subject(s)
Antibodies, Viral/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/immunology , Pneumonia, Viral/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Neutralizing/immunology , COVID-19 , COVID-19 Vaccines , Humans , Macaca mulatta/immunology , Macaca mulatta/virology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Animal , Models, Molecular , Protein Domains , SARS-CoV-2 , Serum/immunology , Spleen/cytology , Spleen/immunology , T-Lymphocytes/immunology , Vaccination
10.
Science ; 369(6505): 818-823, 2020 08 14.
Article in English | MEDLINE | ID: covidwho-631755

ABSTRACT

Coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. It is unclear whether convalescing patients have a risk of reinfection. We generated a rhesus macaque model of SARS-CoV-2 infection that was characterized by interstitial pneumonia and systemic viral dissemination mainly in the respiratory and gastrointestinal tracts. Rhesus macaques reinfected with the identical SARS-CoV-2 strain during the early recovery phase of the initial SARS-CoV-2 infection did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses. Our results suggest that primary SARS-CoV-2 exposure protects against subsequent reinfection in rhesus macaques.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Coronavirus Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Anal Canal/virology , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , B-Lymphocyte Subsets/immunology , Betacoronavirus/immunology , Betacoronavirus/isolation & purification , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Disease Models, Animal , Host Microbial Interactions , Immunity, Cellular , Immunity, Humoral , Lung/diagnostic imaging , Lung/immunology , Lung/pathology , Lung/virology , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/pathology , Lung Diseases, Interstitial/virology , Macaca mulatta , Nasopharynx/virology , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Recurrence , SARS-CoV-2 , T-Lymphocyte Subsets/immunology , Viral Load , Virus Replication
11.
Nature ; 583(7818): 830-833, 2020 07.
Article in English | MEDLINE | ID: covidwho-220333

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/virology , Lung/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Transgenes , Angiotensin-Converting Enzyme 2 , Animals , Antigens, Viral/immunology , Antigens, Viral/metabolism , Betacoronavirus/immunology , Betacoronavirus/metabolism , Bronchi/pathology , Bronchi/virology , COVID-19 , Coronavirus Infections/immunology , Disease Models, Animal , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Humans , Immunoglobulin G/immunology , Lung/immunology , Lung/virology , Lymphocytes/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Male , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/immunology , Receptors, Complement 3d/genetics , Receptors, Complement 3d/metabolism , SARS-CoV-2 , Virus Replication , Weight Loss
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