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1.
Mol Ther ; 31(2): 344-361, 2023 02 01.
Article in English | MEDLINE | ID: covidwho-2159943

ABSTRACT

Increasing evidence shows that SARS-CoV-2 can infect kidneys and cause acute kidney injury (AKI) in critically ill COVID-19 patients. However, mechanisms through which COVID-19 induces AKI are largely unknown, and treatment remains ineffective. Here, we report that kidney-specific overexpressing SARS-CoV-2 N gene can cause AKI, including tubular necrosis and elevated levels of serum creatinine and BUN in 8-week-old diabetic db/db mice, which become worse in those with older age (16 weeks) and underlying diabetic kidney disease (DKD). Treatment with quercetin, a purified product from traditional Chinese medicine (TCM) that shows effective treatment of COVID-19 patients, can significantly inhibit SARS-CoV-2 N protein-induced AKI in diabetic mice with or without underlying DKD. Mechanistically, quercetin can block the binding of SARS-CoV-2 N protein to Smad3, thereby inhibiting Smad3 signaling and Smad3-mediated cell death via the p16-dependent G1 cell-cycle arrest mechanism in vivo and in vitro. In conclusion, SARS-CoV-2 N protein is pathogenic and can cause severe AKI in diabetic mice, particularly in those with older age and pre-existing DKD, via the Smad3-dependent G1 cell-cycle arrest mechanism. Importantly, we identify that quercetin may be an effective TCM compound capable of inhibiting COVID-19 AKI by blocking SARS-CoV-2 N-Smad3-mediated cell death pathway.


Subject(s)
Acute Kidney Injury , COVID-19 , Diabetes Mellitus, Experimental , Mice , Animals , SARS-CoV-2 , COVID-19/complications , Quercetin/pharmacology , Diabetes Mellitus, Experimental/complications , Acute Kidney Injury/drug therapy , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Mice, Inbred Strains , Cell Cycle Checkpoints
2.
PLoS One ; 17(7): e0272019, 2022.
Article in English | MEDLINE | ID: covidwho-1963043

ABSTRACT

Coronavirus disease (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is currently spreading globally. To overcome the COVID-19 pandemic, preclinical evaluations of vaccines and therapeutics using K18-hACE2 and CAG-hACE2 transgenic mice are ongoing. However, a comparative study on SARS-CoV-2 infection between K18-hACE2 and CAG-hACE2 mice has not been published. In this study, we compared the susceptibility and resistance to SARS-CoV-2 infection between two strains of transgenic mice, which were generated in FVB background mice. K18-hACE2 mice exhibited severe weight loss with definitive lethality, but CAG-hACE2 mice survived; and differences were observed in the lung, spleen, cerebrum, cerebellum, and small intestine. A higher viral titer was detected in the lungs, cerebrums, and cerebellums of K18-hACE2 mice than in the lungs of CAG-hACE2 mice. Severe pneumonia was observed in histopathological findings in K18-hACE2, and mild pneumonia was observed in CAG-hACE2. Atrophy of the splenic white pulp and reduction of spleen weight was observed, and hyperplasia of goblet cells with villi atrophy of the small intestine was observed in K18-hACE2 mice compared to CAG-hACE2 mice. These results indicate that K18-hACE2 mice are relatively susceptible to SARS-CoV-2 and that CAG-hACE2 mice are resistant to SARS-CoV-2. Based on these lineage-specific sensitivities, we suggest that K18-hACE2 mouse is suitable for highly susceptible model of SARS-CoV-2, and CAG-hACE2 mouse is suitable for mild susceptible model of SARS-CoV-2 infection.


Subject(s)
COVID-19 , Pneumonia , Angiotensin-Converting Enzyme 2/genetics , Animals , Atrophy/pathology , Disease Models, Animal , Disease Susceptibility/pathology , Humans , Lung/pathology , Mice , Mice, Inbred Strains , Mice, Transgenic , Pandemics , Peptidyl-Dipeptidase A , Pneumonia/pathology , SARS-CoV-2
3.
Sci Immunol ; 5(44)2020 02 21.
Article in English | MEDLINE | ID: covidwho-1575907

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.


Subject(s)
Breast Neoplasms/pathology , Myeloid-Derived Suppressor Cells/pathology , Single-Cell Analysis , Transcriptome , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Breast Neoplasms/immunology , Cell Differentiation/genetics , Female , Humans , Mice , Mice, Inbred Strains , Mice, Transgenic , Myeloid-Derived Suppressor Cells/immunology , RNA, Neoplasm/genetics , RNA, Neoplasm/immunology , Signaling Lymphocytic Activation Molecule Family/genetics , Signaling Lymphocytic Activation Molecule Family/immunology
4.
Theranostics ; 11(16): 8076-8091, 2021.
Article in English | MEDLINE | ID: covidwho-1337802

ABSTRACT

Rationale: Pulmonary vascular endotheliitis, perivascular inflammation, and immune activation are observed in COVID-19 patients. While the initial SARS-CoV-2 infection mainly infects lung epithelial cells, whether it also infects endothelial cells (ECs) and to what extent SARS-CoV-2-mediated pulmonary vascular endotheliitis is associated with immune activation remain to be determined. Methods: To address these questions, we studied SARS-CoV-2-infected K18-hACE2 (K18) mice, a severe COVID-19 mouse model, as well as lung samples from SARS-CoV-2-infected nonhuman primates (NHP) and patient deceased from COVID-19. We used immunostaining, RNAscope, and electron microscopy to analyze the organs collected from animals and patient. We conducted bulk and single cell (sc) RNA-seq analyses, and cytokine profiling of lungs or serum of the severe COVID-19 mice. Results: We show that SARS-CoV-2-infected K18 mice develop severe COVID-19, including progressive body weight loss and fatality at 7 days, severe lung interstitial inflammation, edema, hemorrhage, perivascular inflammation, systemic lymphocytopenia, and eosinopenia. Body weight loss in K18 mice correlated with the severity of pneumonia, but not with brain infection. We also observed endothelial activation and dysfunction in pulmonary vessels evidenced by the up-regulation of VCAM1 and ICAM1 and the downregulation of VE-cadherin. We detected SARS-CoV-2 in capillary ECs, activation and adhesion of platelets and immune cells to the vascular wall of the alveolar septa, and increased complement deposition in the lungs, in both COVID-19-murine and NHP models. We also revealed that pathways of coagulation, complement, K-ras signaling, and genes of ICAM1 and VCAM1 related to EC dysfunction and injury were upregulated, and were associated with massive immune activation in the lung and circulation. Conclusion: Together, our results indicate that SARS-CoV-2 causes endotheliitis via both infection and infection-mediated immune activation, which may contribute to the pathogenesis of severe COVID-19 disease.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Animals , COVID-19/metabolism , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/virology , Epithelial Cells/immunology , Epithelial Cells/virology , Lung/pathology , Mice , Mice, Inbred Strains , Mice, Transgenic , SARS-CoV-2/isolation & purification
5.
Sci Rep ; 11(1): 14917, 2021 07 21.
Article in English | MEDLINE | ID: covidwho-1320238

ABSTRACT

We have developed a COVID-19 vaccine, hAd5 S-Fusion + N-ETSD, that expresses SARS-CoV-2 spike (S) and nucleocapsid (N) proteins with modifications to increase immune responses delivered using a human adenovirus serotype 5 (hAd5) platform. Here, we demonstrate subcutaneous (SC) prime and SC boost vaccination of CD-1 mice with this dual-antigen vaccine elicits T-helper cell 1 (Th1) biased T-cell and humoral responses to both S and N that are greater than those seen with hAd5 S wild type delivering only unmodified S. We then compared SC to intranasal (IN) prime vaccination with SC or IN boosts and show that an IN prime with an IN boost is as effective at generating Th1 biased humoral responses as the other combinations tested, but an SC prime with an IN or SC boost elicits greater T cell responses. Finally, we used a combined SC plus IN (SC + IN) prime with or without a boost and found the SC + IN prime alone to be as effective in generating humoral and T-cell responses as the SC + IN prime with a boost. The finding that SC + IN prime-only delivery has the potential to provide broad immunity-including mucosal immunity-against SARS-CoV-2 supports further testing of this vaccine and delivery approach in animal models of viral challenge.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Adenoviridae/genetics , Administration, Intranasal , Animals , Antibodies, Neutralizing , Antibodies, Viral/biosynthesis , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , Female , Genetic Vectors , Hypodermoclysis , Immunity, Cellular/immunology , Immunity, Mucosal/immunology , Immunization, Secondary , Mice , Mice, Inbred Strains , Vaccination/methods
6.
Zool Res ; 42(3): 335-338, 2021 May 18.
Article in English | MEDLINE | ID: covidwho-1231642

ABSTRACT

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 150 700 000 infections and 3 279 000 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.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/chemically induced , COVID-19/immunology , Particulate Matter/adverse effects , SARS-CoV-2 , Adsorption/drug effects , Animals , Disease Susceptibility/chemically induced , Disease Susceptibility/immunology , Epithelial Cells/metabolism , Mice , Mice, Inbred Strains , Particulate Matter/chemistry , RNA, Viral/analysis , SARS-CoV-2/genetics , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
7.
Drug Des Devel Ther ; 15: 2059-2089, 2021.
Article in English | MEDLINE | ID: covidwho-1231276

ABSTRACT

PURPOSE: One of the most common types of male infertility is recognized as oligoasthenozoospermia (OA), characterized by low sperm count and quality in males. As a traditional Chinese medicine (TCM), Cuscutae Semen-Mori Fructus coupled-herbs (CSMFCH) has been known to act a curative effect on OA for thousands of years. Nevertheless, the substantial basis and molecular mechanism of CSMFCH in treating OA remain elusive. METHODS: Herein, an integrated approach, including network pharmacology, molecular docking, and experiment validation, was utilized to reveal the new candidate active component and mechanism of CSMFCH in treating OA. RESULTS: The results show that kaempferol is the most significant bioactive component of CSMFCH on OA. The mechanism and targets of CSMFCH against OA are relevant to hormone regulation, oxidant stress, and reproductive promotion. In order to validate network pharmacology results, molecular docking and experiment validation were conducted. In detail, molecular docking was employed to verify the strong binding interactions between kaempferol and the core targets. UHPLC-Q-Orbitrap-MS was used to identify kaempferol in the CSMFCH extract. In vitro and in vivo experiments further proved CSMFCH and kaempferol could enhance the mouse Leydig (TM3) and mouse Sertoli (TM4) cell viability, improve the male reproductive organ weights, sperm quality, and decrease testis tissue damage in the OA mouse model induced by CP. CONCLUSION: Our results not only identify the new candidate active component of CSMFCH in treating OA but also provide new insights into the mechanisms of CSMFCH against OA.


Subject(s)
Asthenozoospermia/drug therapy , Drugs, Chinese Herbal/therapeutic use , Molecular Docking Simulation , Plant Extracts/therapeutic use , Animals , Cell Proliferation/drug effects , Cells, Cultured , Chromatography, High Pressure Liquid , Disease Models, Animal , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/isolation & purification , Fruit/chemistry , Male , Mass Spectrometry , Medicine, Chinese Traditional , Mice , Mice, Inbred Strains , Plant Extracts/chemistry , Plant Extracts/isolation & purification
8.
Physiol Behav ; 234: 113389, 2021 05 15.
Article in English | MEDLINE | ID: covidwho-1135542

ABSTRACT

Exercise behavior is under partial genetic control, but it is also affected by numerous environmental factors, potentially including early-life experiences whose effects persist into adulthood. We studied genetic and early-life environmental effects on wheel-running behavior in a mouse model that includes four replicate high runner (HR) lines selectively bred for increased voluntary wheel running as young adults and four non-selected control (C) lines. In a full factorial design, mice from each line were granted wheel access or not and administered either standard or Western diet (WD) from weaning (3 weeks old) to 6 weeks of age (sexual maturity). In addition to acute effects, after a washout period of 8 weeks (∼6 human years) in which all mice had standard diet and no wheel access, we found both beneficial and detrimental effects of these early-life exposures. During the first week of treatments, WD increased distance run by 29% in C mice and 48% in HR mice (significant Diet × Linetype interaction), but diet effects disappeared by the third week. Across the three weeks of juvenile treatment, WD significantly increased fat mass (with lean mass as a covariate). Tested as adults, early-life exercise increased wheel running of C mice but not HR mice in the first week. Early-life exercise also reduced adult anxiety-like behavior and increased adult fasted blood glucose levels, triceps surae mass, subdermal fat pad mass, and brain mass, but decreased heart ventricle mass. Using fat mass as a covariate, early-life exercise treatment increased adult leptin concentration. In contrast, early-life WD increased adult wheel running of HR mice but not C mice. Early-life WD also increased adult lean mass and adult preference for Western diet in all groups. Surprisingly, early-life treatment had no significant effect on adult body fat or maximal aerobic capacity (VO2max). No previous study has tested for combined or interactive effects of early-life WD and exercise. Our results demonstrate that both factors can have long-lasting effects on adult voluntary exercise and related phenotypes, and that these effects are modulated by genetic background. Overall, the long-lasting effects of early-life exercise were more pervasive than those of WD, suggesting critical opportunities for health intervention in childhood habits, as well as possible threats from modern challenges. These results may be relevant for understanding potential effects of activity reductions and dietary changes associated with the obesity epidemic and COVID-19 pandemic.


Subject(s)
Diet, Western , Motor Activity , Adiposity , Animals , Diet, Western/adverse effects , Mice , Mice, Inbred Strains , Phenotype
9.
Vet Res Commun ; 44(3-4): 101-110, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-639440

ABSTRACT

The outbreak of the SARS-CoV-2 in mainland China with subsequent human to human transmission worldwide had taken up the shape of a devastating pandemic. The ability of the virus to infect multiple species other than humans has currently been reported in experimental conditions. Non-human primates, felines, ferrets, rodents and host of other animals could previously be infected in experimental conditions with SARS-CoV and recently with SARS-CoV-2, both virus using Angiotensin-converting-enzyme 2 receptor for cellular entry. The variations in sequence homology of ACE2 receptor across species is identified as one of the factors determining virulence and pathogenicity in animals. The infection in experimental animals with SARS-CoV or SARS-CoV-2 on most occasions are asymptomatic, however, the virus could multiply within the respiratory tract and extra-pulmonary organs in most of the species. Here, we discuss about the pathogenicity, transmission, variations in angiotensin-converting-enzyme 2 receptor-binding across species and host pathogen interactions of SARS and SARS-CoV-2 in laboratory animals used in research.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/veterinary , Host-Pathogen Interactions , Pandemics/veterinary , Pneumonia, Viral/veterinary , Severe Acute Respiratory Syndrome/veterinary , Severe acute respiratory syndrome-related coronavirus/pathogenicity , Animals , COVID-19 , Callithrix/virology , Cats/virology , Chickens/virology , Chiroptera/virology , Chlorocebus aethiops/virology , Coronavirus Infections/transmission , Coronavirus Infections/virology , Cricetinae/virology , Ferrets/virology , Macaca fascicularis/virology , Macaca mulatta/virology , Mice , Mice, Inbred Strains/virology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , Rodentia/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/transmission , Severe Acute Respiratory Syndrome/virology , Swine/virology
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