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1.
Cell Rep ; 40(5): 111160, 2022 Aug 02.
Article in English | MEDLINE | ID: covidwho-1936138

ABSTRACT

Although COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging on development of multispecies coronavirus vaccines. Here we develop prototype lipid nanoparticle (LNP)-mRNA vaccine candidates against SARS-CoV-2 Delta, SARS-CoV, and MERS-CoV, and we test how multiplexing LNP-mRNAs can induce effective immune responses in animal models. Triplex and duplex LNP-mRNA vaccinations induce antigen-specific antibody responses against SARS-CoV-2, SARS-CoV, and MERS-CoV. Single-cell RNA sequencing profiles the global systemic immune repertoires and respective transcriptome signatures of vaccinated animals, revealing a systemic increase in activated B cells and differential gene expression across major adaptive immune cells. Sequential vaccination shows potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrate the feasibility, antibody responses, and single-cell immune profiles of multispecies coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights into optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species.


Subject(s)
COVID-19 , Middle East Respiratory Syndrome Coronavirus , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Liposomes , Middle East Respiratory Syndrome Coronavirus/genetics , Nanoparticles , RNA, Messenger/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Vaccines, Synthetic , mRNA Vaccines
3.
Cell Rep Methods ; 2(7): 100252, 2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1894918

ABSTRACT

Efficient quantitative assays for measurement of viral replication and infectivity are indispensable for future endeavors to develop prophylactic or therapeutic antiviral drugs or vaccines against SARS-CoV-2. We developed a SARS-CoV-2 cell-cell transmission assay that provides a rapid and quantitative readout to assess SARS-CoV-2 spike hACE2 interaction in the absence of pseudotyped particles or live virus. We established two well-behaved stable cell lines, which demonstrated a remarkable correlation with standard cell-free viral pseudotyping for inhibition by convalescent sera, small-molecule drugs, and murine anti-spike monoclonal antibodies. The assay is rapid, reliable, and highly reproducible, without a requirement for any specialized research reagents or laboratory equipment and should be easy to adapt for use in most investigative and clinical settings. It can be effectively used or modified for high-throughput screening for compounds and biologics that interfere with virus-cell binding and entry to complement other neutralization assays currently in use.

4.
Nat Commun ; 13(1): 3250, 2022 06 06.
Article in English | MEDLINE | ID: covidwho-1878526

ABSTRACT

The Omicron variant of SARS-CoV-2 recently swept the globe and showed high level of immune evasion. Here, we generate an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and test its activity in animals, both alone and as a heterologous booster to WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicits strong antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA show a > 40-fold reduction in neutralization potency against Omicron than WT two weeks post boost, which further reduce to background level after 3 months. The WT or Omicron LNP-mRNA booster increases the waning antibody response of WT LNP-mRNA vaccinated mice against Omicron by 40 fold at two weeks post injection. Interestingly, the heterologous Omicron booster elicits neutralizing titers 10-20 fold higher than the homologous WT booster against Omicron variant, with comparable titers against Delta variant. All three types of vaccination, including Omicron alone, WT booster and Omicron booster, elicit broad binding antibody responses against SARS-CoV-2 WA-1, Beta, Delta variants and SARS-CoV. These data provide direct assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to WT mRNA vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Liposomes , Mice , Nanoparticles , RNA, Messenger/genetics , SARS-CoV-2/genetics , Vaccination , Vaccines, Synthetic , mRNA Vaccines
5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-336847

ABSTRACT

Although successful COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging for development of multi-species coronavirus vaccines. Here we developed prototype LNP-mRNA vaccine candidates against SARS-CoV-2 (Delta variant), SARS-CoV and MERS-CoV, and test how multiplexing of these LNP-mRNAs can induce effective immune responses in animal models. A triplex scheme of LNP-mRNA vaccination induced antigen-specific antibody responses against SARS-CoV-2, SARS-CoV and MERS-CoV, with a relatively weaker MERS-CoV response in this setting. Single cell RNA-seq profiled the global systemic immune repertoires and the respective transcriptome signatures of multiplexed vaccinated animals, which revealed a systemic increase in activated B cells, as well as differential gene expression signatures across major adaptive immune cells. Sequential vaccination showed potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrated the feasibility, antibody responses and single cell immune profiles of multi-species coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights on optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species. One sentence summary Multiplexed mRNA vaccination in simultaneous and sequential modes provide broad and potent immunity against pathogenic coronavirus species.

6.
Cell Rep Med ; 3(5): 100634, 2022 05 17.
Article in English | MEDLINE | ID: covidwho-1805326

ABSTRACT

Lipid nanoparticle (LNP)-mRNA vaccines offer protection against COVID-19; however, multiple variant lineages caused widespread breakthrough infections. Here, we generate LNP-mRNAs specifically encoding wild-type (WT), B.1.351, and B.1.617 SARS-CoV-2 spikes, and systematically study their immune responses. All three LNP-mRNAs induced potent antibody and T cell responses in animal models; however, differences in neutralization activity have been observed between variants. All three vaccines offer potent protection against in vivo challenges of authentic viruses of WA-1, Beta, and Delta variants. Single-cell transcriptomics of WT- and variant-specific LNP-mRNA-vaccinated animals reveal a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induces a systemic increase of reactive CD8 T cells and altered gene expression programs in B and T lymphocytes. BCR-seq and TCR-seq unveil repertoire diversity and clonal expansions in vaccinated animals. These data provide assessment of efficacy and direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Neutralizing , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Immunity , Liposomes , Nanoparticles , RNA, Messenger/genetics , Vaccination
7.
Nat Commun ; 13(1): 1638, 2022 03 28.
Article in English | MEDLINE | ID: covidwho-1764180

ABSTRACT

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.


Subject(s)
Antibodies, Monoclonal, Humanized/immunology , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2 , Animals , Antibodies, Bispecific/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins
8.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-331004

ABSTRACT

The Omicron variant (B.1.1.529) of SARS-CoV-2 rapidly becomes dominant globally. Its extensive mutations confer severe efficacy reduction to most of existing antibodies or vaccines. Here, we developed RAMIHM, a highly efficient strategy to generate fully human monoclonal antibodies (mAbs), directly applied it with Omicron-mRNA immunization, and isolated three potent and specific clones against Omicron. Rapid mRNA immunization elicited strong anti-Omicron antibody response in humanized mice, along with broader anti-coronavirus activity. Customized single cell BCR sequencing mapped the clonal repertoires. Top-ranked clones collectively from peripheral blood, plasma B and memory B cell populations showed high rate of Omicron-specificity (93.3%) from RAMIHM-scBCRseq. Clone-screening identified three highly potent neutralizing antibodies that have low nanomolar affinity for Omicron RBD, and low ng/mL level IC50 in neutralization, more potent than majority of currently approved or authorized clinical RBD-targeting mAbs. These lead mAbs are fully human and ready for downstream IND-enabling and/or translational studies.

9.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330824

ABSTRACT

The Omicron sub-lineage BA.2 of SARS-CoV-2 has recently become dominant across many areas in the world in the on-going waves of COVID-19. Compared to the ancestral/wild-type (WT) virus, Omicron lineage variants, both BA.1 and BA.2, contain high number of mutations, especially in the spike protein, causing significant immune escape that leads to substantial reduction of vaccine and antibody efficacy. Because of this antigenic drift, BA.2 exhibited differential resistance profile to monoclonal antibodies than BA.1. Thus, it is important to understand whether the immunity elicited by currently available vaccines are effective against the BA.2 subvariant. We directly tested the heterotypic vaccination responses against Omicron BA.2, using vaccinated serum from animals receiving WT- and variant-specific mRNA vaccine in lipid nanoparticle (LNP) formulations. Omicron BA.1 and BA.2 antigen showed similar reactivity to serum antibodies elicited by two doses of WT, B.1.351 and B.1.617 LNP-mRNAs. Neutralizing antibody titers of B.1.351 and B.1.617 LNP-mRNA were ~2-fold higher than that of WT LNP-mRNA. Both homologous boosting with WT LNP-mRNA and heterologous boosting with BA.1 LNP-mRNA substantially increased waning immunity of WT vaccinated mice against both BA.1 and BA.2 subvariants. The BA.1 LNP-mRNA booster was ~3-fold more efficient than WT LNP-mRNA at elevating neutralizing antibody titers of BA.2. Together, these data provided a direct preclinical evaluation of WT and variant-specific LNP-mRNAs in standard two-dose and as boosters against BA.1 and BA.2 subvariants.

10.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327678

ABSTRACT

The Omicron variant of SARS-CoV-2 has high transmissibility and recently been sweeping the globe, dominating new infection cases in the US and many regions in the world. Due to its extensive number of mutations, this variant has high level of immune evasion, which drastically reduced the efficacy of existing antibodies and vaccines. Thus, it is important to develop an Omicron-specific vaccine and test if it can induce immune responses against Omicron and broadly against other variants. Here, we generated an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and tested its potency of antibody induction in animals, both alone and as a booster to existing mRNA vaccine designed against the ancestral reference virus (WA-1). This Omicron-specific LNP-mRNA vaccine elicited strong and specific antibody response in vaccination-naïve mice. Consistent with recent reports, mice that received two-dose WA-1 LNP-mRNA, the one mimicking the commonly used Pfizer/Moderna mRNA vaccine administered in the general population, showed a 41-fold reduction in neutralization potency against Omicron variant as compared to WA-1 two weeks post second dose, which further reduced to background level 3.5 months post second dose. As a booster for WA-1 mRNA vaccination, a single dose Omicron LNP-mRNA induced potent antibody response against the Omicron variant, with over 1,000-fold increase at two weeks post injection as compared to the blood samples right before booster. The Omicron-specific antibody level of the Omicron-boosted samples is numerically similar to WA-1 vaccine against WA-1 variant. This boost also elicited broader antibody responses against WA-1 and Delta variants, restoring these activities of the WA-1 vaccinated animals that also dropped over time. A consecutive second dose of Omicron LNP-mRNA 2 weeks following the first dose did not significantly increased the level of antibodies. These in vivo animal data provided a timely proof-of-concept for Omicron-specific mRNA vaccination, alone and as a booster to the existing widely-used mRNA vaccine form.

11.
Sci Immunol ; 7(68): eabl5652, 2022 Feb 04.
Article in English | MEDLINE | ID: covidwho-1673340

ABSTRACT

T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)­based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell­B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , T Follicular Helper Cells/immunology , Amino Acid Sequence , Animals , Antibody Formation/immunology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/immunology , Humans , Lymphocyte Activation/immunology , Mice , T-Lymphocytes, Helper-Inducer
12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295709

ABSTRACT

Lipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP-mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617;and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.

13.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293615

ABSTRACT

Lipid-nanoparticle(LNP)-mRNA vaccines offer protection against COVID-19. However, multiple variant lineages caused widespread breakthrough infections. There is no report on variant-specific vaccines to date. Here, we generated LNP-mRNAs specifically encoding wildtype, B.1.351 and B.1.617 SARS-CoV-2 spikes, and systematically studied their immune responses in animal models. All three LNP-mRNAs induced potent antibody responses in mice. However, WT-LNP-mRNA vaccination showed reduced neutralization against B.1.351 and B.1.617;and B.1.617-specific vaccination showed differential neutralization. All three vaccine candidates elicited antigen-specific CD8 and CD4 T cell responses. Single cell transcriptomics of B.1.351-LNP-mRNA and B.1.617-LNP-mRNA vaccinated animals revealed a systematic landscape of immune cell populations and global gene expression. Variant-specific vaccination induced a systemic increase in reactive CD8 T cell population, with a strong signature of transcriptional and translational machineries in lymphocytes. BCR-seq and TCR-seq unveiled repertoire diversity and clonal expansions in vaccinated animals. These data provide direct systems immune profiling of variant-specific LNP-mRNA vaccination in vivo.

14.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293402

ABSTRACT

T cell receptor (TCR) repertoires are critical for antiviral immunity. Determining the TCR repertoires composition, diversity, and dynamics and how they change during viral infection can inform the molecular specificity of viral infection such as SARS-CoV-2. To determine signatures associated with COVID-19 disease severity, here we performed a large-scale analysis of over 4.7 billion sequences across 2,130 TCR repertoires from COVID-19 patients and healthy donors. TCR repertoire analyses from these data identified and characterized convergent COVID-19 associated CDR3 gene usages, specificity groups, and sequence patterns. T cell clonal expansion was found to be associated with upregulation of T cell effector function, TCR signaling, NF-kB signaling, and Interferon-gamma signaling pathways. Machine learning approaches accurately predicted disease severity for patients based on TCR sequence features, with certain high-power models reaching near-perfect AUROC scores across various predictor permutations. These analyses provided an integrative, systems immunology view of T cell adaptive immune responses to COVID-19.

15.
Patterns (N Y) ; 3(2): 100407, 2022 Feb 11.
Article in English | MEDLINE | ID: covidwho-1521457

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has become a major threat across the globe. Here, we developed machine learning approaches to identify key pathogenic regions in coronavirus genomes. We trained and evaluated 7,562,625 models on 3,665 genomes including SARS-CoV-2, MERS-CoV, SARS-CoV, and other coronaviruses of human and animal origins to return quantitative and biologically interpretable signatures at nucleotide and amino acid resolutions. We identified hotspots across the SARS-CoV-2 genome, including previously unappreciated features in spike, RdRp, and other proteins. Finally, we integrated pathogenicity genomic profiles with B cell and T cell epitope predictions for enrichment of sequence targets to help guide vaccine development. These results provide a systematic map of predicted pathogenicity in SARS-CoV-2 that incorporates sequence, structural, and immunologic features, providing an unbiased collection of genetic elements for functional studies. This metavirome-based framework can also be applied for rapid characterization of new coronavirus strains or emerging pathogenic viruses.

16.
PLoS Biol ; 19(3): e3001143, 2021 03.
Article in English | MEDLINE | ID: covidwho-1138557

ABSTRACT

There are currently limited Food and Drug Administration (FDA)-approved drugs and vaccines for the treatment or prevention of Coronavirus Disease 2019 (COVID-19). Enhanced understanding of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and pathogenesis is critical for the development of therapeutics. To provide insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2, we performed single-cell (sc) RNA sequencing (RNA-seq) of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface (ALI) cultures over a time course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as a major target at the onset of infection, which we confirmed by electron and immunofluorescence microscopy. Over the course of infection, the cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell-intrinsic expression of type I and type III interferons (IFNs) and interleukin (IL)-6 but not IL-1. This results in expression of interferon-stimulated genes (ISGs) in both infected and bystander cells. This provides a detailed characterization of genes, cell types, and cell state changes associated with SARS-CoV-2 infection in the human airway.


Subject(s)
Bronchi/pathology , COVID-19/diagnosis , Gene Expression , SARS-CoV-2/isolation & purification , Single-Cell Analysis/methods , Adult , Bronchi/virology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cells, Cultured , Epithelium/pathology , Epithelium/virology , Humans , Immunity, Innate , Longitudinal Studies , SARS-CoV-2/genetics , Transcriptome , Viral Tropism
17.
Mol Cell ; 80(6): 1055-1066.e6, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-1009762

ABSTRACT

The causative virus of the COVID-19 pandemic, SARS-CoV-2, uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. Our cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional because of the incorrect position of the mRNA 3' region. Our results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advance understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Protein Biosynthesis , RNA, Messenger/metabolism , RNA, Viral/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Viral Nonstructural Proteins/metabolism , Animals , COVID-19/genetics , COVID-19/pathology , Chlorocebus aethiops , Cryoelectron Microscopy , Humans , RNA, Messenger/genetics , RNA, Viral/genetics , Ribosome Subunits, Small, Eukaryotic/genetics , Ribosome Subunits, Small, Eukaryotic/metabolism , Ribosome Subunits, Small, Eukaryotic/ultrastructure , Ribosome Subunits, Small, Eukaryotic/virology , SARS-CoV-2/genetics , SARS-CoV-2/ultrastructure , Vero Cells , Viral Nonstructural Proteins/genetics
18.
Nat Commun ; 12(1): 4, 2021 01 04.
Article in English | MEDLINE | ID: covidwho-1007630

ABSTRACT

Age is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21+ dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.


Subject(s)
Aging/genetics , COVID-19/genetics , Lung/physiology , A549 Cells , Adult , Aged , Aging/metabolism , Aging/pathology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Endothelial Cells/pathology , Female , Fibroblasts/pathology , Gene Expression , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Pericytes/pathology , RNA-Seq , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
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