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1.
biorxiv; 2024.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2024.02.07.579394

ABSTRACT

HIV poses a significant threat to human health. Although some progress has been made in the development of an HIV vaccine, there is currently no reported success in achieving an effective and fully functional vaccine for HIV. This highlights the challenges involved in HIV vaccine development. Through mathematical modeling, we have conducted a systematic study on the impact of antibody-dependent cellular cytotoxicity (ADCC) on HIV-specific immune responses. Unlike other viral infections, the ADCC effect following HIV infection may cause significant damage to the follicular center Th cells, leading to apoptosis of follicular center cells and rapid death of effector Th cells. This impedes the generation of neutralizing antibodies and creates barriers to viral clearance, thereby contributing to long-term infection. Another challenge posed by this effect is the substantial reduction in vaccine effectiveness, as effective antigenic substances such as gp120 bind to Th cell surfaces, resulting in the apoptosis of follicular center Th cells due to ADCC, hindering antibody regeneration. To address this issue, we propose the concept of using bispecific antibodies. By genetically editing B cells to insert the bispecific antibody gene, which consists of two parts targeting the CD4 binding site of HIV, such as the broadly neutralizing antibody 3BNC117, and the other targeting antibodies against other viruses, such as the spike protein of SARS-CoV-2. We can simultaneously enhance the levels of two pathogen-specific antibodies through stimulation with non-HIV-antigens corresponding to the other part of the chimeric antibody, such as the spike protein. This study contributes to the elucidation of the pathophysiology of HIV, while also providing a theoretical framework for the successful development of an HIV vaccine.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , HIV Infections , Disease Models, Animal
2.
arxiv; 2024.
Preprint in English | PREPRINT-ARXIV | ID: ppzbmed-2401.14816v1

ABSTRACT

In the context of journalism, the COVID-19 pandemic brought unprecedented challenges, necessitating rapid adaptations in newsrooms. Data journalism emerged as a pivotal approach for effectively conveying complex information to the public. Here, we show the profound impact of COVID-19 on data journalism, revealing a surge in data-driven publications and heightened collaboration between data and science journalists. Employing a quantitative methodology, including negative binomial regression and Relational hyperevent models (RHEM), on byline data of articles co-authored by data journalists, we comprehensively analyze data journalism outputs, authorship trends, and collaboration networks to address five key research questions. The findings reveal a significant increase in data journalistic pieces during and after the pandemic, in particular with a rise in publications within scientific departments. Collaborative efforts among data and science journalists intensified, evident through increased authorship and co-authorship trends. Prior common authorship experiences somewhat influenced the likelihood of future co-authorships, underscoring the importance of building collaborative communities of practice. These quantitative insights provide an understanding of the transformational role of data journalism during COVID-19, contributing to the growing body of literature in computational communication science and journalism practice.


Subject(s)
COVID-19 , Disease Models, Animal
3.
preprints.org; 2023.
Preprint in English | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202307.0965.v1

ABSTRACT

A mathematical model is proposed to analyze the spreading dynamics of COVID-19. By using the parameters of the model, namely the basic reproduction number (R0) and the attenuation constant (k), the daily number of infections (DNI) and the cumulative number of infections (CNI) are deduced and shown to be in good agreement with experimental data. This model effectively addresses three key issues: explaining the waveform pattern of DNI, predicting the occurrence of the second wave of infection, and understanding the competitive spread of two viruses in a region. The findings demonstrate that these significant challenges can be comprehensively tackled using a simple mathematical framework. The theoretical insights derived from this model hold potential in guiding the estimation of the severity of an infection wave and formulating effective strategies for the control and mitigation of epidemic outbreaks.


Subject(s)
COVID-19 , Disease Models, Animal
5.
Proc Natl Acad Sci U S A ; 120(25): e2207210120, 2023 06 20.
Article in English | MEDLINE | ID: covidwho-20238795

ABSTRACT

The classical manifestation of COVID-19 is pulmonary infection. After host cell entry via human angiotensin-converting enzyme II (hACE2), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can infect pulmonary epithelial cells, especially the AT2 (alveolar type II) cells that are crucial for maintaining normal lung function. However, previous hACE2 transgenic models have failed to specifically and efficiently target the cell types that express hACE2 in humans, especially AT2 cells. In this study, we report an inducible, transgenic hACE2 mouse line and showcase three examples for specifically expressing hACE2 in three different lung epithelial cells, including AT2 cells, club cells, and ciliated cells. Moreover, all these mice models develop severe pneumonia after SARS-CoV-2 infection. This study demonstrates that the hACE2 model can be used to precisely study any cell type of interest with regard to COVID-19-related pathologies.


Subject(s)
COVID-19 , Humans , Animals , Mice , Mice, Transgenic , SARS-CoV-2 , Epithelial Cells , Alveolar Epithelial Cells , Disease Models, Animal
6.
J Med Virol ; 95(6): e28863, 2023 06.
Article in English | MEDLINE | ID: covidwho-20238042

ABSTRACT

The ongoing COVID-19 has not only caused millions of deaths worldwide, but it has also led to economic recession and the collapse of public health systems. The vaccines and antivirals developed in response to the pandemic have improved the situation markedly; however, the pandemic is still not under control with recurring surges. Thus, it is still necessary to develop therapeutic agents. In our previous studies, we designed and synthesized a series of novel 2-anilinoquinazolin-4(3H)-one derivatives, and demonstrated inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and MERS-CoV in vitro. We then conducted in vivo studies using modified compounds that are suitable for oral administration. These compounds demonstrated no toxicity in rats and inhibited viral entry. Here, we investigated the in vivo efficacy of these drug candidates against SARS-CoV-2. Three candidate drugs, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (1), N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-dichlorophenyl)acetamide (2), and N-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N-(3,5-difluorophenyl)acetamide (3) were administered orally to hACE2 transgenic mice at a dose of 100 mg/kg. All three drugs improved survival rate and reduced the viral load in the lungs. These results show that the derivatives possess in vivo antiviral efficacy similar to that of molnupiravir, which is currently being used to treat COVID-19. Overall, our data suggest that 2-anilinoquinazolin-4(3H)-one derivatives are promising as potential oral antiviral drug candidates against SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , SARS-CoV-2 , Animals , Humans , Mice , Rats , Acetamides , Angiotensin-Converting Enzyme 2/genetics , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/genetics , COVID-19/therapy , Disease Models, Animal , Mice, Transgenic , Quinazolines/pharmacology , Quinazolines/therapeutic use , SARS-CoV-2/genetics
7.
Int J Mol Sci ; 24(11)2023 May 31.
Article in English | MEDLINE | ID: covidwho-20237382

ABSTRACT

The ongoing COVID-19 pandemic highlights the urgent need for effective antiviral agents and vaccines. Drug repositioning, which involves modifying existing drugs, offers a promising approach for expediting the development of novel therapeutics. In this study, we developed a new drug, MDB-MDB-601a-NM, by modifying the existing drug nafamostat (NM) with the incorporation of glycyrrhizic acid (GA). We assessed the pharmacokinetic profiles of MDB-601a-NM and nafamostat in Sprague-Dawley rats, revealing rapid clearance of nafamostat and sustained drug concentration of MDB-601a-NM after subcutaneous administration. Single-dose toxicity studies showed potential toxicity and persistent swelling at the injection site with high-dose administration of MDB-601a-NM. Furthermore, we evaluated the efficacy of MDB-601a-NM in protecting against SARS-CoV-2 infection using the K18 hACE-2 transgenic mouse model. Mice treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM exhibited improved protectivity in terms of weight loss and survival rates compared to the nafamostat-treated group. Histopathological analysis revealed dose-dependent improvements in histopathological changes and enhanced inhibitory efficacy in MDB-601a-NM-treated groups. Notably, no viral replication was detected in the brain tissue when mice were treated with 60 mg/kg and 100 mg/kg of MDB-601a-NM. Our developed MDB-601a-NM, a modified Nafamostat with glycyrrhizic acid, shows improved protectivity against SARS-CoV-2 infection. Its sustained drug concentration after subcutaneous administration and dose-dependent improvements makes it a promising therapeutic option.


Subject(s)
COVID-19 , SARS-CoV-2 , Rats , Humans , Animals , Mice , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Pandemics , Disease Models, Animal , Rats, Sprague-Dawley
8.
Nat Commun ; 14(1): 3026, 2023 05 25.
Article in English | MEDLINE | ID: covidwho-20242082

ABSTRACT

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-2. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing a role for an accessory protein in this context.


Subject(s)
COVID-19 , SARS-CoV-2 , Cricetinae , Animals , Humans , Mice , SARS-CoV-2/genetics , Animals, Newborn , Ferrets , Disease Models, Animal , Mesocricetus
10.
Pharmacol Res Perspect ; 11(3): e01071, 2023 06.
Article in English | MEDLINE | ID: covidwho-2314090

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting Coronavirus disease 2019 emerged in late 2019 and is responsible for significant morbidity and mortality worldwide. A hallmark of severe COVID-19 is exaggerated systemic inflammation, regarded as a "cytokine storm," which contributes to the damage of various organs, primarily the lungs. The inflammation associated with some viral illnesses is known to alter the expression of drug-metabolizing enzymes and transporters. These alterations can lead to modifications in drug exposure and the processing of various endogenous compounds. Here, we provide evidence to support changes in the mitochondrial ribonucleic acid expression of a subset of drug transporters (84 transporters) in the liver, kidneys, and lungs and metabolizing enzymes (84 enzymes) in the liver in a humanized angiotensin-converting enzyme 2 receptor mouse model. Specifically, three drug transporters (Abca3, Slc7a8, Tap1) and the pro-inflammatory cytokine IL-6 were upregulated in the lungs of SARS-CoV-2 infected mice. We also found significant downregulation of drug transporters responsible for the movement of xenobiotics in the liver and kidney. Additionally, expression of cytochrome P-450 2f2 which is known to metabolize some pulmonary toxicants, was significantly decreased in the liver of infected mice. The significance of these findings requires further exploration. Our results suggest that further research should emphasize altered drug disposition when investigating therapeutic compounds, whether re-purposed or new chemical entities, in other animal models and ultimately in individuals infected with SARS-CoV-2. Moreover, the influence and impact of these changes on the processing of endogenous compounds also require further investigation.


Subject(s)
COVID-19 , Mice , Animals , SARS-CoV-2 , Disease Models, Animal , Peptidyl-Dipeptidase A/metabolism , Inflammation
11.
Am J Pathol ; 193(6): 690-701, 2023 06.
Article in English | MEDLINE | ID: covidwho-2312845

ABSTRACT

Clinical evidence of vascular dysfunction and hypercoagulability as well as pulmonary vascular damage and microthrombosis are frequently reported in severe cases of human coronavirus disease 2019 (COVID-19). Syrian golden hamsters recapitulate histopathologic pulmonary vascular lesions reported in patients with COVID-19. Herein, special staining techniques and transmission electron microscopy further define vascular pathologies in a Syrian golden hamster model of human COVID-19. The results show that regions of active pulmonary inflammation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by ultrastructural evidence of endothelial damage with platelet marginalization and both perivascular and subendothelial macrophage infiltration. SARS-CoV-2 antigen/RNA was not detectable within affected blood vessels. Taken together, these findings suggest that the prominent microscopic vascular lesions in SARS-CoV-2-inoculated hamsters likely occur due to endothelial damage followed by platelet and macrophage infiltration.


Subject(s)
COVID-19 , Vascular Diseases , Cricetinae , Animals , Humans , Mesocricetus , SARS-CoV-2 , COVID-19/pathology , Lung/pathology , Vascular Diseases/pathology , Disease Models, Animal
12.
Am J Pathol ; 193(7): 866-882, 2023 Jul.
Article in English | MEDLINE | ID: covidwho-2309498

ABSTRACT

The disease severity of coronavirus disease 2019 (COVID-19) varies considerably from asymptomatic to serious, with fatal complications associated with dysregulation of innate and adaptive immunity. Lymphoid depletion in lymphoid tissues and lymphocytopenia have both been associated with poor disease outcomes in patients with COVID-19, but the mechanisms involved remain elusive. In this study, human angiotensin-converting enzyme 2 (hACE2) transgenic mouse models susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were used to investigate the characteristics and determinants of lethality associated with the lymphoid depletion observed in SARS-CoV-2 infection. The lethality of Wuhan SARS-CoV-2 infection in K18-hACE2 mice was characterized by severe lymphoid depletion and apoptosis in lymphoid tissues related to fatal neuroinvasion. The lymphoid depletion was associated with a decreased number of antigen-presenting cells (APCs) and their suppressed functionality below basal levels. Lymphoid depletion with reduced APC function was a specific feature observed in SARS-CoV-2 infection but not in influenza A infection and had the greatest prognostic value for disease severity in murine COVID-19. Comparison of transgenic mouse models resistant and susceptible to SARS-CoV-2 infection revealed that suppressed APC function could be determined by the hACE2 expression pattern and interferon-related signaling. Thus, we demonstrated that lymphoid depletion associated with suppressed APC function characterizes the lethality of COVID-19 mouse models. Our data also suggest a potential therapeutic approach to prevent the severe progression of COVID-19 by enhancing APC functionality.


Subject(s)
COVID-19 , Mice , Humans , Animals , SARS-CoV-2/metabolism , Peptidyl-Dipeptidase A/metabolism , Mice, Transgenic , Disease Susceptibility , Antigen-Presenting Cells , Disease Models, Animal , Lung/metabolism
13.
Front Immunol ; 14: 1030879, 2023.
Article in English | MEDLINE | ID: covidwho-2309368

ABSTRACT

Introduction: There is an unmet medical need for effective anti-inflammatory agents for the treatment of acute and post-acute lung inflammation caused by respiratory viruses. The semi-synthetic polysaccharide, Pentosan polysulfate sodium (PPS), an inhibitor of NF-kB activation, was investigated for its systemic and local anti-inflammatory effects in a mouse model of influenza virus A/PR8/1934 (PR8 strain) mediated infection. Methods: Immunocompetent C57BL/6J mice were infected intranasally with a sublethal dose of PR8 and treated subcutaneously with 3 or 6 mg/kg PPS or vehicle. Disease was monitored and tissues were collected at the acute (8 days post-infection; dpi) or post-acute (21 dpi) phase of disease to assess the effect of PPS on PR8-induced pathology. Results: In the acute phase of PR8 infection, PPS treatment was associated with a reduction in weight loss and improvement in oxygen saturation when compared to vehicle-treated mice. Associated with these clinical improvements, PPS treatment showed a significant retention in the numbers of protective SiglecF+ resident alveolar macrophages, despite uneventful changes in pulmonary leukocyte infiltrates assessed by flow cytometry. PPS treatment in PR8- infected mice showed significant reductions systemically but not locally of the inflammatory molecules, IL-6, IFN-g, TNF-a, IL-12p70 and CCL2. In the post-acute phase of infection, PPS demonstrated a reduction in the pulmonary fibrotic biomarkers, sICAM-1 and complement factor C5b9. Discussion: The systemic and local anti-inflammatory actions of PPS may regulate acute and post-acute pulmonary inflammation and tissue remodeling mediated by PR8 infection, which warrants further investigation.


Subject(s)
Influenzavirus A , Pneumonia , Mice , Animals , Pentosan Sulfuric Polyester/pharmacology , Pentosan Sulfuric Polyester/therapeutic use , Mice, Inbred C57BL , Pneumonia/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Disease Models, Animal
14.
mBio ; 14(2): e0033923, 2023 04 25.
Article in English | MEDLINE | ID: covidwho-2308144

ABSTRACT

Invasive fungal infections are a leading cause of death in immunocompromised patients. Current therapies have several limitations, and innovative antifungal agents are critically needed. Previously, we identified the fungus-specific enzyme sterylglucosidase as essential for pathogenesis and virulence of Cryptococcus neoformans and Aspergillus fumigatus (Af) in murine models of mycoses. Here, we developed Af sterylglucosidase A (SglA) as a therapeutic target. We identified two selective inhibitors of SglA with distinct chemical scaffolds that bind in the active site of SglA. Both inhibitors induce sterylglucoside accumulation and delay filamentation in Af and increase survival in a murine model of pulmonary aspergillosis. Structure-activity relationship (SAR) studies identified a more potent derivative that enhances both in vitro phenotypes and in vivo survival. These findings support sterylglucosidase inhibition as a promising antifungal approach with broad-spectrum potential. IMPORTANCE Invasive fungal infections are a leading cause of death in immunocompromised patients. Aspergillus fumigatus is a fungus ubiquitously found in the environment that, upon inhalation, causes both acute and chronic illnesses in at-risk individuals. A. fumigatus is recognized as one of the critical fungal pathogens for which a substantive treatment breakthrough is urgently needed. Here, we studied a fungus-specific enzyme, sterylglucosidase A (SglA), as a therapeutic target. We identified selective inhibitors of SglA that induce accumulation of sterylglucosides and delay filamentation in A. fumigatus and increase survival in a murine model of pulmonary aspergillosis. We determined the structure of SglA, predicted the binding poses of these inhibitors through docking analysis, and identified a more efficacious derivative with a limited SAR study. These results open several exciting avenues for the research and development of a new class of antifungal agents targeting sterylglucosidases.


Subject(s)
Aspergillosis , Invasive Fungal Infections , Pulmonary Aspergillosis , Animals , Mice , Aspergillus fumigatus/genetics , Antifungal Agents/pharmacology , Disease Models, Animal , Aspergillosis/drug therapy , Aspergillosis/microbiology , Pulmonary Aspergillosis/drug therapy
15.
J Allergy Clin Immunol ; 150(5): 1154-1167, 2022 11.
Article in English | MEDLINE | ID: covidwho-2311241

ABSTRACT

BACKGROUND: Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state. OBJECTIVE: We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation. METHODS: A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18-mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models. RESULTS: Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell-recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18-mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models. CONCLUSION: Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.


Subject(s)
Interleukin-10 , Interleukin-18 , Lymphohistiocytosis, Hemophagocytic , Myelopoiesis , Animals , Mice , Disease Models, Animal , Lymphohistiocytosis, Hemophagocytic/pathology
16.
Front Immunol ; 13: 1055811, 2022.
Article in English | MEDLINE | ID: covidwho-2309285

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has been a global health concern since 2019. The viral spike protein infects the host by binding to angiotensin-converting enzyme 2 (ACE2) expressed on the cell surface, which is then processed by type II transmembrane serine protease. However, ACE2 does not react to SARS-CoV-2 in inbred wild-type mice, which poses a challenge for preclinical research with animal models, necessitating a human ACE2 (hACE2)-expressing transgenic mouse model. Cytokeratin 18 (K18) promoter-derived hACE2 transgenic mice [B6.Cg-Tg(K18-ACE2)2Prlmn/J] are widely used for research on SARS-CoV-1, MERS-CoV, and SARS-CoV-2. However, SARS-CoV-2 infection is lethal at ≥105 PFU and SARS-CoV-2 target cells are limited to type-1 alveolar pneumocytes in K18-hACE2 mice, making this model incompatible with infections in the human lung. Hence, we developed lung-specific SARS-CoV-2 infection mouse models with surfactant protein B (SFTPB) and secretoglobin family 1a member 1 (Scgb1a1) promoters. After inoculation of 105 PFU of SARS-CoV-2 to the K18-hACE2, SFTPB-hACE2, and SCGB1A1-hACE2 models, the peak viral titer was detected at 2 days post-infection and then gradually decreased. In K18-hACE2 mice, the body temperature decreased by approximately 10°C, body weight decreased by over 20%, and the survival rate was reduced. However, SFTPB-hACE2 and SCGB1A1-hACE2 mice showed minimal clinical signs after infection. The virus targeted type I pneumocytes in K18-hACE2 mice; type II pneumocytes in SFTPB-hACE2 mice; and club, goblet, and ciliated cells in SCGB1A1-hACE2 mice. A time-dependent increase in severe lung lesions was detected in K18-hACE2 mice, whereas mild lesions developed in SFTPB-hACE2 and SCGB1A1-hACE2 mice. Spleen, small intestine, and brain lesions developed in K18-hACE2 mice but not in SFTPB-hACE2 and SCGB1A1-hACE2 mice. These newly developed SFTPB-hACE2 and SCGB1A1-hACE2 mice should prove useful to expand research on hACE2-mediated respiratory viruses.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Animals , Humans , Mice , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/genetics , Disease Models, Animal , Mice, Transgenic , SARS-CoV-2
17.
Viruses ; 15(4)2023 04 19.
Article in English | MEDLINE | ID: covidwho-2293805

ABSTRACT

Since December 2019, the world has been experiencing the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and we now face the emergence of several variants. We aimed to assess the differences between the wild-type (Wt) (Wuhan) strain and the P.1 (Gamma) and Delta variants using infected K18-hACE2 mice. The clinical manifestations, behavior, virus load, pulmonary capacity, and histopathological alterations were analyzed. The P.1-infected mice showed weight loss and more severe clinical manifestations of COVID-19 than the Wt and Delta-infected mice. The respiratory capacity was reduced in the P.1-infected mice compared to the other groups. Pulmonary histological findings demonstrated that a more aggressive disease was generated by the P.1 and Delta variants compared to the Wt strain of the virus. The quantification of the SARS-CoV-2 viral copies varied greatly among the infected mice although it was higher in P.1-infected mice on the day of death. Our data revealed that K18-hACE2 mice infected with the P.1 variant develop a more severe infectious disease than those infected with the other variants, despite the significant heterogeneity among the mice.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Humans , Mice , Disease Models, Animal , Mice, Transgenic , Pandemics , SARS-CoV-2/genetics , Virulence
18.
Front Immunol ; 14: 1147953, 2023.
Article in English | MEDLINE | ID: covidwho-2292455

ABSTRACT

Several COVID-19 vaccine strategies utilizing new formulations for the induction of neutralizing antibodies (nAbs) and T cell immunity are still under evaluation in preclinical and clinical studies. Here we used Simian Immunodeficiency Virus (SIV)-based integrase defective lentiviral vector (IDLV) delivering different conformations of membrane-tethered Spike protein in the mouse immunogenicity model, with the aim of inducing persistent nAbs against multiple SARS-CoV-2 variants of concern (VoC). Spike modifications included prefusion-stabilizing double proline (2P) substitutions, mutations at the furin cleavage site (FCS), D614G mutation and truncation of the cytoplasmic tail (delta21) of ancestral and Beta (B.1.351) Spike, the latter mutation to markedly improve IDLV membrane-tethering. BALB/c mice were injected once with IDLV delivering the different forms of Spike or the recombinant trimeric Spike protein with 2P substitutions and FCS mutations in association with a squalene-based adjuvant. Anti-receptor binding domain (RBD) binding Abs, nAbs and T cell responses were detected up to six months from a single immunization with escalating doses of vaccines in all mice, but with different levels and kinetics. Results indicated that IDLV delivering the Spike protein with all the combined modifications, outperformed the other candidates in terms of T cell immunity and level of both binding Abs and nAbs soon after the single immunization and persistence over time, showing the best capacity to neutralize all formerly circulating VoC Alpha, Beta, Gamma and Delta. Although present, the lowest response was detected against Omicron variants (BA.1, BA.2 and BA.4/5), suggesting that the magnitude of immune evasion may be related to the higher genetic distance of Omicron as indicated by increased number of amino acid substitutions in Spike acquired during virus evolution.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Humans , Mice , Spike Glycoprotein, Coronavirus/genetics , Integrases , COVID-19 Vaccines , SARS-CoV-2/genetics , Antibodies, Neutralizing , Disease Models, Animal , Mice, Inbred BALB C , Immunity
19.
Vaccine ; 41(20): 3233-3246, 2023 05 11.
Article in English | MEDLINE | ID: covidwho-2295171

ABSTRACT

The ongoing SARS-CoV-2 pandemic is controlled but not halted by public health measures and mass vaccination strategies which have exclusively relied on intramuscular vaccines. Intranasal vaccines can prime or recruit to the respiratory epithelium mucosal immune cells capable of preventing infection. Here we report a comprehensive series of studies on this concept using various mouse models, including HLA class II-humanized transgenic strains. We found that a single intranasal (i.n.) dose of serotype-5 adenoviral vectors expressing either the receptor binding domain (Ad5-RBD) or the complete ectodomain (Ad5-S) of the SARS-CoV-2 spike protein was effective in inducing i) serum and bronchoalveolar lavage (BAL) anti-spike IgA and IgG, ii) robust SARS-CoV-2-neutralizing activity in the serum and BAL, iii) rigorous spike-directed T helper 1 cell/cytotoxic T cell immunity, and iv) protection of mice from a challenge with the SARS-CoV-2 beta variant. Intramuscular (i.m.) Ad5-RBD or Ad5-S administration did not induce serum or BAL IgA, and resulted in lower neutralizing titers in the serum. Moreover, prior immunity induced by an intramuscular mRNA vaccine could be potently enhanced and modulated towards a mucosal IgA response by an i.n. Ad5-S booster. Notably, Ad5 DNA was found in the liver or spleen after i.m. but not i.n. administration, indicating a lack of systemic spread of the vaccine vector, which has been associated with a risk of thrombotic thrombocytopenia. Unlike in otherwise genetically identical HLA-DQ6 mice, in HLA-DQ8 mice Ad5-RBD vaccine was inferior to Ad5-S, suggesting that the RBD fragment does not contain a sufficient collection of helper-T cell epitopes to constitute an optimal vaccine antigen. Our data add to previous promising preclinical results on intranasal SARS-CoV-2 vaccination and support the potential of this approach to elicit mucosal immunity for preventing transmission of SARS-CoV-2.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Animals , Mice , Spike Glycoprotein, Coronavirus/genetics , COVID-19 Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , SARS-CoV-2 , Administration, Intranasal , Disease Models, Animal , Immunoglobulin A
20.
Virol J ; 20(1): 75, 2023 04 20.
Article in English | MEDLINE | ID: covidwho-2302137

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes non-symptomatic infection, mild influenza-like symptoms to pneumonia, severe acute respiratory distress syndrome, and even death, reflecting different clinical symptoms of viral infection. However, the mechanism of its pathogenicity remains unclear. Host-specific traits have a breakthrough significance for studying the pathogenicity of SARS-CoV-2. We previously reported SARS-CoV-2/BMA8, a mouse-adapted strain, was lethal to aged BALB/c mice but not to aged C57BL/6N mice. Here, we further investigate the differences in pathogenicity of BMA8 strain against wild-type aged C57BL/6N and BALB/c mice. METHODS: Whole blood and tissues were collected from mice before and after BMA8 strain infection. Viral replication and infectivity were assessed by detection of viral RNA copies and viral titers; the degree of inflammation in mice was tested by whole blood cell count, ELISA and RT-qPCR assays; the pathogenicity of SARS-CoV-2/BMA8 in mice was measured by Histopathology and Immunohistochemistry; and the immune level of mice was evaluated by flow cytometry to detect the number of CD8+ T cells. RESULTS: Our results suggest that SARS-CoV-2/BMA8 strain caused lower pathogenicity and inflammation level in C57BL/6N mice than in BALB/c mice. Interestingly, BALB/c mice whose MHC class I haplotype is H-2Kd showed more severe pathogenicity after infection with BMA8 strain, while blockade of H-2Kb in C57BL/6N mice was also able to cause this phenomenon. Furthermore, H-2Kb inhibition increased the expression of cytokines/chemokines and accelerated the decrease of CD8+ T cells caused by SARS-CoV-2/BMA8 infection. CONCLUSIONS: Taken together, our work shows that host MHC molecules play a crucial role in the pathogenicity differences of SARS-CoV-2/BMA8 infection. This provides a more profound insight into the pathogenesis of SARS-CoV-2, and contributes enlightenment and guidance for controlling the virus spread.


Subject(s)
COVID-19 , SARS-CoV-2 , Mice , Animals , CD8-Positive T-Lymphocytes , Virulence , COVID-19/pathology , Mice, Inbred C57BL , Mice, Inbred BALB C , Inflammation , Lung/pathology , Disease Models, Animal
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