International Journal of Molecular Sciences

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Open AccessEditorial

Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022

by Evgenii Gusev

Int. J. Mol. Sci. 2023, 24(22), 16073; https://doi.org/10.3390/ijms242216073 - 8 Nov 2023

Cited by 1 | Viewed by 974

Abstract

The aim of this Special Issue is to analyze the key patterns of the 2019 coronavirus disease pandemic (COVID-19), the biology of SARS-CoV-2 (severe-acute-respiratory-syndrome-related coronavirus 2, formerly 2019-nCoV), and the characteristics of the human body’s response to the invasion of this virus [...] [...] Read more.

The aim of this Special Issue is to analyze the key patterns of the 2019 coronavirus disease pandemic (COVID-19), the biology of SARS-CoV-2 (severe-acute-respiratory-syndrome-related coronavirus 2, formerly 2019-nCoV), and the characteristics of the human body’s response to the invasion of this virus [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

Research

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18 pages, 6188 KiB

Open AccessArticle

Meta-Analysis of the Mechanisms Underlying COVID-19 Modulation of Parkinson’s Disease

by Jonathan Zhang, Muhammed Bishir, Sharman Barbhuiya and Sulie L. Chang

Int. J. Mol. Sci. 2023, 24(17), 13554; https://doi.org/10.3390/ijms241713554 - 31 Aug 2023

Cited by 3 | Viewed by 1771

Abstract

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm”, and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), [...] Read more.

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm”, and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson’s disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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14 pages, 2797 KiB

Open AccessArticle

Cytokine Kinetics during Progression of COVID-19 in Rwanda Patients: Could IL-9/IFNγ Ratio Predict Disease Severity?

by Ella Larissa Ndoricyimpaye, Jacques Van Snick, Rutayisire Robert, Emmanuel Bikorimana, Onesphore Majyambere, Enatha Mukantwari, Thaddée Nshimiyimana, Valens Mbonigaba, Jean Paul Coutelier and Nadine Rujeni

Int. J. Mol. Sci. 2023, 24(15), 12272; https://doi.org/10.3390/ijms241512272 - 31 Jul 2023

Viewed by 1769

Abstract

For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the [...] Read more.

For effective treatments and preventive measures against severe COVID-19, it is essential to determine early markers of disease severity in different populations. We analysed the cytokine kinetics of 129 COVID-19 patients with mild symptoms, 68 severe cases, and 20 healthy controls for the first time in Rwanda. Pro-inflammatory (IFNγ, IL-6, TNFα), Treg (IL-10, TGFβ1, TGFβ3), Th9 (IL-9), Th17 (IL-17), and Th2 (IL-4, IL-13) cytokines, total IgM and IgG, as well as gene expressions of FoxP3, STAT5+, IFNγ-R1, and ROR alpha+, were measured at day 1, day 7, day 14, day 21, and day 28 post-infection. Severe cases showed a significantly stronger increase than mild patients in levels of all cytokines (except IL-9) and all gene expression on day 1 of infection. Some cytokine levels dropped to levels comparable to mild cases at later time points. Further analysis identified IFNγ as a marker of severity throughout the disease course, while TGFβ1, IL-6, and IL-17 were markers of severity only at an early phase. Importantly, this study revealed a striking low IL-9 level and high IFNγ/IL-9 ratio in the plasma of patients who later died compared to mild and severe cases who recovered, suggesting that this could be an important biomarker for predicting the severity of COVID-19 and post-COVID-19 syndrome. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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23 pages, 7074 KiB

Open AccessArticle

Low-Density Lipoprotein Receptor (LDLR) Is Involved in Internalization of Lentiviral Particles Pseudotyped with SARS-CoV-2 Spike Protein in Ocular Cells

by Sheetal Uppal, Olga Postnikova, Rafael Villasmil, Igor B. Rogozin, Alexander V. Bocharov, Thomas L. Eggerman, Eugenia Poliakov and T. Michael Redmond

Int. J. Mol. Sci. 2023, 24(14), 11860; https://doi.org/10.3390/ijms241411860 - 24 Jul 2023

Cited by 6 | Viewed by 2706

Abstract

Here, we present evidence that caveolae-mediated endocytosis using LDLR is the pathway for SARS-CoV-2 virus internalization in the ocular cell line ARPE-19. Firstly, we found that, while Angiotensin-converting enzyme 2 (ACE2) is expressed in these cells, blocking ACE2 by antibody treatment did not [...] Read more.

Here, we present evidence that caveolae-mediated endocytosis using LDLR is the pathway for SARS-CoV-2 virus internalization in the ocular cell line ARPE-19. Firstly, we found that, while Angiotensin-converting enzyme 2 (ACE2) is expressed in these cells, blocking ACE2 by antibody treatment did not prevent infection by SARS-CoV-2 spike pseudovirions, nor did antibody blockade of extracellular vimentin and other cholesterol-rich lipid raft proteins. Next, we implicated the role of cholesterol homeostasis in infection by showing that incubating cells with different cyclodextrins and oxysterol 25-hydroxycholesterol (25-HC) inhibits pseudovirion infection of ARPE-19. However, the effect of 25-HC is likely not via cholesterol biosynthesis, as incubation with lovastatin did not appreciably affect infection. Additionally, is it not likely to be an agonistic effect of 25-HC on LXR receptors, as the LXR agonist GW3965 had no significant effect on infection of ARPE-19 cells at up to 5 μM GW3965. We probed the role of endocytic pathways but determined that clathrin-dependent and flotillin-dependent rafts were not involved. Furthermore, 20 µM chlorpromazine, an inhibitor of clathrin-mediated endocytosis (CME), also had little effect. In contrast, anti-dynamin I/II antibodies blocked the entry of SARS-CoV-2 spike pseudovirions, as did dynasore, a noncompetitive inhibitor of dynamin GTPase activity. Additionally, anti-caveolin-1 antibodies significantly blocked spike pseudotyped lentiviral infection of ARPE-19. However, nystatin, a classic inhibitor of caveolae-dependent endocytosis, did not affect infection while indomethacin inhibited only at 10 µM at the 48 h time point. Finally, we found that anti-LDLR antibodies block pseudovirion infection to a similar degree as anti-caveolin-1 and anti-dynamin I/II antibodies, while transfection with LDLR-specific siRNA led to a decrease in spike pseudotyped lentiviral infection, compared to scrambled control siRNAs. Thus, we conclude that SARS-CoV-2 spike pseudovirion infection in ARPE-19 cells is a dynamin-dependent process that is primarily mediated by LDLR. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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20 pages, 3729 KiB

Open AccessArticle

Alterations in the CD56⁻ and CD56⁺ T Cell Subsets during COVID-19

by Julia D. Vavilova, Maria O. Ustiuzhanina, Anna A. Boyko, Maria A. Streltsova, Sofya A. Kust, Leonid M. Kanevskiy, Rustam N. Iskhakov, Alexander M. Sapozhnikov, Ekaterina O. Gubernatorova, Marina S. Drutskaya, Mikhail V. Bychinin, Oksana N. Novikova, Anna G. Sotnikova, Gaukhar M. Yusubalieva, Vladimir P. Baklaushev and Elena I. Kovalenko

Int. J. Mol. Sci. 2023, 24(10), 9047; https://doi.org/10.3390/ijms24109047 - 20 May 2023

Cited by 3 | Viewed by 2679

Abstract

The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied [...] Read more.

The effectiveness of the antiviral immune response largely depends on the activation of cytotoxic T cells. The heterogeneous group of functionally active T cells expressing the CD56 molecule (NKT-like cells), that combines the properties of T lymphocytes and NK cells, is poorly studied in COVID-19. This work aimed to analyze the activation and differentiation of both circulating NKT-like cells and CD56⁻ T cells during COVID-19 among intensive care unit (ICU) patients, moderate severity (MS) patients, and convalescents. A decreased proportion of CD56⁺ T cells was found in ICU patients with fatal outcome. Severe COVID-19 was accompanied by a decrease in the proportion of CD8⁺ T cells, mainly due to the CD56⁻ cell death, and a redistribution of the NKT-like cell subset composition with a predominance of more differentiated cytotoxic CD8⁺ T cells. The differentiation process was accompanied by an increase in the proportions of KIR2DL2/3⁺ and NKp30⁺ cells in the CD56⁺ T cell subset of COVID-19 patients and convalescents. Decreased percentages of NKG2D⁺ and NKG2A⁺ cells and increased PD-1 and HLA-DR expression levels were found in both CD56⁻ and CD56⁺ T cells, and can be considered as indicators of COVID-19 progression. In the CD56⁻ T cell fraction, increased CD16 levels were observed in MS patients and in ICU patients with lethal outcome, suggesting a negative role for CD56⁻CD16⁺ T cells in COVID-19. Overall, our findings suggest an antiviral role of CD56⁺ T cells in COVID-19. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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28 pages, 8145 KiB

Open AccessArticle

In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

by Martin Tobi, Martin H. Bluth, Noreen F. Rossi, Ereny Demian, Harvinder Talwar, Yosef Y. Tobi, Paula Sochacki, Edi Levi, Michael Lawson and Benita McVicker

Int. J. Mol. Sci. 2023, 24(8), 7536; https://doi.org/10.3390/ijms24087536 - 19 Apr 2023

Cited by 3 | Viewed by 1900

Abstract

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. [...] Read more.

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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16 pages, 2872 KiB

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Dissection of Antibody Responses of Gam-COVID-Vac-Vaccinated Subjects Suggests Involvement of Epitopes Outside RBD in SARS-CoV-2 Neutralization

by Maria Byazrova, Pia Gattinger, Ekaterina Astakhova, Gerhard Hofer, Musa Khaitov, Alexander Filatov and Rudolf Valenta

Int. J. Mol. Sci. 2023, 24(6), 5104; https://doi.org/10.3390/ijms24065104 - 7 Mar 2023

Cited by 2 | Viewed by 5504

Abstract

Millions of people have been vaccinated with Gam-COVID-Vac but fine specificities of induced antibodies have not been fully studied. Plasma from 12 naïve and 10 coronavirus disease 2019 (COVID-19) convalescent subjects was obtained before and after two immunizations with Gam-COVID-Vac. Antibody reactivity in [...] Read more.

Millions of people have been vaccinated with Gam-COVID-Vac but fine specificities of induced antibodies have not been fully studied. Plasma from 12 naïve and 10 coronavirus disease 2019 (COVID-19) convalescent subjects was obtained before and after two immunizations with Gam-COVID-Vac. Antibody reactivity in the plasma samples (n = 44) was studied on a panel of micro-arrayed recombinant folded and unfolded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and 46 peptides spanning the spike protein (S) and by immunoglobulin G (IgG) subclass enzyme-linked immunosorbent assay (ELISA). The ability of Gam-COVID-Vac-induced antibodies to inhibit binding of the receptor-binding domain (RBD) to its receptor angiotensin converting enzyme 2 (ACE2) was investigated in a molecular interaction assay (MIA). The virus-neutralizing capacity of antibodies was studied by the pseudo-typed virus neutralization test (pVNT) for Wuhan-Hu-1 and Omicron. We found that Gam-COVID-Vac vaccination induced significant increases of IgG₁ but not of other IgG subclasses against folded S, spike protein subunit 1 (S1), spike protein subunit 2 (S2), and RBD in a comparable manner in naïve and convalescent subjects. Virus neutralization was highly correlated with vaccination-induced antibodies specific for folded RBD and a novel peptide (i.e., peptide 12). Peptide 12 was located close to RBD in the N-terminal part of S1 and may potentially be involved in the transition of the pre- to post-fusion conformation of the spike protein. In summary, Gam-COVID-Vac vaccination induced S-specific IgG₁ antibodies in naive and convalescent subjects in a comparable manner. Besides the antibodies specific for RBD, the antibodies induced against a peptide close to the N-terminus of RBD were also associated with virus-neutralization. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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25 pages, 4441 KiB

Open AccessArticle

Treatment of Acute Respiratory Distress Syndrome Caused by COVID-19 with Human Umbilical Cord Mesenchymal Stem Cells

by Tetiana Bukreieva, Hanna Svitina, Viktoriia Nikulina, Alyona Vega, Oleksii Chybisov, Iuliia Shablii, Alina Ustymenko, Petro Nemtinov, Galyna Lobyntseva, Inessa Skrypkina and Volodymyr Shablii

Int. J. Mol. Sci. 2023, 24(5), 4435; https://doi.org/10.3390/ijms24054435 - 23 Feb 2023

Cited by 4 | Viewed by 3895

Abstract

This study aimed to identify the impact of mesenchymal stem cell transplantation on the safety and clinical outcomes of patients with severe COVID-19. This research focused on how lung functional status, miRNA, and cytokine levels changed following mesenchymal stem cell transplantation in patients [...] Read more.

This study aimed to identify the impact of mesenchymal stem cell transplantation on the safety and clinical outcomes of patients with severe COVID-19. This research focused on how lung functional status, miRNA, and cytokine levels changed following mesenchymal stem cell transplantation in patients with severe COVID-19 pneumonia and their correlation with fibrotic changes in the lung. This study involved 15 patients following conventional anti-viral treatment (Control group) and 13 patients after three consecutive doses of combined treatment with MSC transplantation (MCS group). ELISA was used to measure cytokine levels, real-time qPCR for miRNA expression, and lung computed tomography (CT) imaging to grade fibrosis. Data were collected on the day of patient admission (day 0) and on the 7th, 14th, and 28th days of follow-up. A lung CT assay was performed on weeks 2, 8, 24, and 48 after the beginning of hospitalization. The relationship between levels of biomarkers in peripheral blood and lung function parameters was investigated using correlation analysis. We confirmed that triple MSC transplantation in individuals with severe COVID-19 was safe and did not cause severe adverse reactions. The total score of lung CT between patients from the Control and MSC groups did not differ significantly on weeks 2, 8, and 24 after the beginning of hospitalization. However, on week 48, the CT total score was 12 times lower in patients in the MSC group (p ≤ 0.05) compared to the Control group. In the MSC group, this parameter gradually decreased from week 2 to week 48 of observation, whereas in the Control group, a significant drop was observed up to week 24 and remained unchanged afterward. In our study, MSC therapy improved lymphocyte recovery. The percentage of banded neutrophils in the MSC group was significantly lower in comparison with control patients on day 14. Inflammatory markers such as ESR and CRP decreased more rapidly in the MSC group in comparison to the Control group. The plasma levels of surfactant D, a marker of alveocyte type II damage, decreased after MSC transplantation for four weeks in contrast to patients in the Control group, in whom slight elevations were observed. We first showed that MSC transplantation in severe COVID-19 patients led to the elevation of the plasma levels of IP-10, MIP-1α, G-CSF, and IL-10. However, the plasma levels of inflammatory markers such as IL-6, MCP-1, and RAGE did not differ between groups. MSC transplantation had no impact on the relative expression levels of miR-146a, miR-27a, miR-126, miR-221, miR-21, miR-133, miR-92a-3p, miR-124, and miR-424. In vitro, UC-MSC exhibited an immunomodulatory impact on PBMC, increasing neutrophil activation, phagocytosis, and leukocyte movement, activating early T cell markers, and decreasing effector and senescent effector T cell maturation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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16 pages, 4929 KiB

Open AccessArticle

Transcriptional Insights of Oxidative Stress and Extracellular Traps in Lung Tissues of Fatal COVID-19 Cases

by Aref Hosseini, Darko Stojkov, Timothée Fettrelet, Rostyslav Bilyy, Shida Yousefi and Hans-Uwe Simon

Int. J. Mol. Sci. 2023, 24(3), 2646; https://doi.org/10.3390/ijms24032646 - 31 Jan 2023

Cited by 9 | Viewed by 2965

Abstract

Neutrophil extracellular traps (NETs) and oxidative stress are considered to be beneficial in the innate immune defense against pathogens. However, defective clearance of NETs in the lung of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients could lead to severe respiratory syndrome infection, the [...] Read more.

Neutrophil extracellular traps (NETs) and oxidative stress are considered to be beneficial in the innate immune defense against pathogens. However, defective clearance of NETs in the lung of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients could lead to severe respiratory syndrome infection, the so-called coronavirus disease 2019 (COVID-19). To elucidate the pathways that are related to NETs within the pathophysiology of COVID-19, we utilized RNA sequencing (RNA-seq) as well as immunofluorescence and immunohistochemistry methods. RNA-seq analysis provided evidence for increased oxidative stress and the activation of viral-related signaling pathways in post-mortem lungs of COVID-19 patients compared to control donors. Moreover, an excess of neutrophil infiltration and NET formation were detected in the patients’ lungs, where the extracellular DNA was oxidized and co-localized with neutrophil granule protein myeloperoxidase (MPO). Interestingly, staining of the lipid peroxidation marker 4-hydroxynonenal (4-HNE) depicted high colocalization with NETs and was correlated with the neutrophil infiltration of the lung tissues, suggesting that it could serve as a suitable marker for the identification of NETs and the severity of the disease. Moreover, local inhalation therapy to reduce the excess lipid oxidation and NETs in the lungs of severely infected patients might be useful to ameliorate their clinical conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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10 pages, 291 KiB

Open AccessArticle

Impact on the Clinical Evolution of Patients with COVID-19 Pneumonia and the Participation of the NFE2L2/KEAP1 Polymorphisms in Regulating SARS-CoV-2 Infection

by María Elena Soto, Giovanny Fuentevilla-Álvarez, Adrián Palacios-Chavarría, Rafael Ricardo Valdez Vázquez, Héctor Herrera-Bello, Lidia Moreno-Castañeda, Yazmín Estela Torres-Paz, Nadia Janet González-Moyotl, Idalia Pérez-Torres, Alfredo Aisa-Alvarez, Linaloe Manzano-Pech, Israel Pérez-Torres, Claudia Huesca-Gómez and Ricardo Gamboa

Int. J. Mol. Sci. 2023, 24(1), 415; https://doi.org/10.3390/ijms24010415 - 27 Dec 2022

Cited by 3 | Viewed by 2406

Abstract

In patients with severe pneumonia due to COVID-19, the deregulation of oxidative stress is present. Nuclear erythroid factor 2 (NRF2) is regulated by KEAP1, and NRF2 regulates the expression of genes such as NFE2L2-KEAP1, which are involved in cellular defense against oxidative [...] Read more.

In patients with severe pneumonia due to COVID-19, the deregulation of oxidative stress is present. Nuclear erythroid factor 2 (NRF2) is regulated by KEAP1, and NRF2 regulates the expression of genes such as NFE2L2-KEAP1, which are involved in cellular defense against oxidative stress. In this study, we analyzed the participation of the polymorphisms of NFE2L2 and KEAP1 genes in the mechanisms of damage in lung disease patients with SARS-CoV-2 infection. Patients with COVID-19 and a control group were included. Organ dysfunction was evaluated using SOFA. SARS-CoV-2 infection was confirmed and classified as moderate or severe by ventilatory status and by the Berlin criteria for acute respiratory distress syndrome. SNPs in the gene locus for NFE2L2, rs2364723C>G, and KEAP1, rs9676881A>G, and rs34197572C>T were determined by qPCR. We analyzed 110 individuals with SARS-CoV-2 infection: 51 with severe evolution and 59 with moderate evolution. We also analyzed 111 controls. Significant differences were found for rs2364723 allele G in severe cases vs. controls (p = 0.02); for the rs9676881 allele G in moderate cases vs. controls (p = 0.04); for the rs34197572 allele T in severe cases vs. controls (p = 0.001); and in severe vs. moderate cases (p = 0.004). Our results showed that NFE2L2 rs2364723C>G allele G had a protective effect against severe COVID-19, while KEAP1 rs9676881A>G allele G and rs34197572C>T minor allele T were associated with more aggressive stages of COVID-19. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

12 pages, 2871 KiB

Open AccessArticle

Long-Term Effectiveness of BNT162b2 Pfizer-BioNTech mRNA-Based Vaccine on B Cell Compartment: Efficient Recall of SARS-CoV-2-Specific Memory B Cells

by Rosalia Busà, Monica Miele, Maria Concetta Sorrentino, Giandomenico Amico, Francesca Timoneri, Vitale Miceli, Mariangela Di Bella, Giovanna Russelli, Alessia Gallo, Giovanni Zito, Gioacchin Iannolo, Pier Giulio Conaldi and Matteo Bulati

Int. J. Mol. Sci. 2022, 23(23), 15046; https://doi.org/10.3390/ijms232315046 - 30 Nov 2022

Cited by 2 | Viewed by 2679

Abstract

At present, there is a lack of clinical evidence about the impact and long-term durability of the immune response induced by the third dose of mRNA vaccines. In this study, we followed up the B cell compartment behavior in a cohort of immunocompetent [...] Read more.

At present, there is a lack of clinical evidence about the impact and long-term durability of the immune response induced by the third dose of mRNA vaccines. In this study, we followed up the B cell compartment behavior in a cohort of immunocompetent individuals three and six months after the third dose of vaccine. During this period, some subjects contracted the virus. In uninfected vaccinated subjects, we did not report any changes in serum spike-specific IgG levels, with a significant reduction in IgA. Instead, subjects recovered from natural infection showed a significant increase in both specific IgG and IgA. Moreover, we showed a time-related decrease in IgG neutralizing potential to all SARS-CoV-2 variants of concern (VOC) in uninfected compared to recovered subjects, who displayed an increased neutralizing ability, particularly against the omicron variant. Finally, we underlined the presence of a pool of SARS-CoV-2-specific B cells in both groups that are prone to respond to restimulation, as demonstrated by their ability to differentiate into plasma cells and to produce anti-SARS-CoV-2-specific immunoglobulins. These data lead us to assert the long-term effectiveness of the BNT162b2 vaccine in contrasting the severe form of the pathology and prevent COVID-19-associated hospitalization. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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13 pages, 1299 KiB

Open AccessArticle

Immune Response Gaps Linked to SARS-CoV-2 Infection: Cellular Exhaustion, Senescence, or Both?

by Leonardo Vinicius Barbosa, Daniele Margarita Marani Prá, Seigo Nagashima, Marcos Roberto Curcio Pereira, Rebecca Benicio Stocco, Francys de Luca Fernandes da Silva, Milena Rueda Cruz, Djessyka Dallagassa, Thiago João Stupak, George Willian Xavier da Rosa Götz, Georgia Garofani Nasimoto, Luiz Augusto Fanhani Cracco, Isabela Busto Silva, Karen Fernandes de Moura, Marina de Castro Deus, Ana Paula Camargo Martins, Beatriz Akemi Kondo Van Spitzenbergen, Andréa Novais Moreno Amaral, Caroline Busatta Vaz de Paula, Cleber Machado-Souza and Lucia de Noronha Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(22), 13734; https://doi.org/10.3390/ijms232213734 - 8 Nov 2022

Cited by 2 | Viewed by 2588

Abstract

The COVID-19 pandemic, promoted by the SARS-CoV-2 respiratory virus, has resulted in widespread global morbidity and mortality. The immune response against this pathogen has shown a thin line between protective effects and pathological reactions resulting from the massive release of cytokines and poor [...] Read more.

The COVID-19 pandemic, promoted by the SARS-CoV-2 respiratory virus, has resulted in widespread global morbidity and mortality. The immune response against this pathogen has shown a thin line between protective effects and pathological reactions resulting from the massive release of cytokines and poor viral clearance. The latter is possibly caused by exhaustion, senescence, or both of TCD8+ cells and reduced activity of natural killer (NK) cells. The imbalance between innate and adaptive responses during the early stages of infection caused by SARS-CoV-2 contributes to the ineffective control of viral spread. The present study evaluated the tissue immunoexpression of the tissue biomarkers (Arginase-1, CCR4, CD3, CD4, CD8, CD20, CD57, CD68, CD138, IL-4, INF-α, INF-γ, iNOS, PD-1, Perforin and Sphingosine-1) to understand the cellular immune response triggered in patients who died of COVID-19. We evaluated twenty-four paraffin-embedded lung tissue samples from patients who died of COVID-19 (COVID-19 group) and compared them with ten lung tissue samples from patients who died of H1N1pdm09 (H1N1 group) with the immunohistochemical markers mentioned above. In addition, polymorphisms in the Perforin gene were genotyped through Real-Time PCR. Significantly increased tissue immunoexpression of Arginase, CD4, CD68, CD138, Perforin, Sphingosine-1, and IL-4 markers were observed in the COVID-19 group. A significantly lower immunoexpression of CD8 and CD57 was also found in this group. It is suggested that patients who died from COVID-19 had a poor cellular response concerning viral clearance and adaptive response going through tissue repair. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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14 pages, 4437 KiB

Open AccessArticle

Target-Specific Machine Learning Scoring Function Improved Structure-Based Virtual Screening Performance for SARS-CoV-2 Drugs Development

by Muhammad Tahir ul Qamar, Xi-Tong Zhu, Ling-Ling Chen, Laila Alhussain, Maha A. Alshiekheid, Abdulrahman Theyab and Mohammad Algahtani

Int. J. Mol. Sci. 2022, 23(19), 11003; https://doi.org/10.3390/ijms231911003 - 20 Sep 2022

Cited by 17 | Viewed by 2526

Abstract

Leveraging machine learning has been shown to improve the accuracy of structure-based virtual screening. Furthermore, a tremendous amount of empirical data is publicly available, which further enhances the performance of the machine learning approach. In this proof-of-concept study, the 3CL^pro enzyme of [...] Read more.

Leveraging machine learning has been shown to improve the accuracy of structure-based virtual screening. Furthermore, a tremendous amount of empirical data is publicly available, which further enhances the performance of the machine learning approach. In this proof-of-concept study, the 3CL^pro enzyme of SARS-CoV-2 was used. Structure-based virtual screening relies heavily on scoring functions. It is widely accepted that target-specific scoring functions may perform more effectively than universal scoring functions in real-world drug research and development processes. It would be beneficial to drug discovery to develop a method that can effectively build target-specific scoring functions. In the current study, the bindingDB database was used to retrieve experimental data. Smina was utilized to generate protein-ligand complexes for the extraction of InteractionFingerPrint (IFP) and SimpleInteractionFingerPrint SIFP fingerprints via the open drug discovery tool (oddt). The present study found that randomforestClassifier and randomforestRegressor performed well when used with the above fingerprints along the Molecular ACCess System (MACCS), Extended Connectivity Fingerprint (ECFP4), and ECFP6. It was found that the area under the precision-recall curve was 0.80, which is considered a satisfactory level of accuracy. In addition, our enrichment factor analysis indicated that our trained scoring function ranked molecules correctly compared to smina’s generic scoring function. Further molecular dynamics simulations indicated that the top-ranked molecules identified by our developed scoring function were highly stable in the active site, supporting the validity of our developed process. This research may provide a template for developing target-specific scoring functions against specific enzyme targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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20 pages, 12807 KiB

Open AccessArticle

Singularity and Commonality in Response to SARS-CoV-2 in Lung and Colon Cell Models

by Anastasia Meshcheryakova, Philip Zimmermann, Martina Salzmann, Peter Pietschmann and Diana Mechtcheriakova

Int. J. Mol. Sci. 2022, 23(18), 10451; https://doi.org/10.3390/ijms231810451 - 9 Sep 2022

Cited by 2 | Viewed by 5512

Abstract

The systemic nature of COVID-19 with multiple extrapulmonary manifestations of disease, largely due to the wide tissue expression of SARS-CoV-2 major entry factors, as well as the patient-specific features of COVID-19 pathobiology, determine important directions for basic and translational research. In the current [...] Read more.

The systemic nature of COVID-19 with multiple extrapulmonary manifestations of disease, largely due to the wide tissue expression of SARS-CoV-2 major entry factors, as well as the patient-specific features of COVID-19 pathobiology, determine important directions for basic and translational research. In the current study, we addressed the questions of singularities and commonalities in cellular responses to SARS-CoV-2 and related SARS-CoV on the basis of compendium-wide analysis of publicly available transcriptomic datasets as part of the herein implemented multi-modular UNCOVIDING approach. We focused on cellular models attributed to the epithelial cells of the respiratory system, the Calu-3 cell line, and epithelial cells of the gastrointestinal tract, the Caco-2 cell line, infected with either SARS-CoV-2 or SARS-CoV. Here, we report the outcome of a comparative analysis based on differentially expressed genes in terms of perturbations and diseases, Canonical pathways, and Upstream Regulators. We furthermore performed compendium-wide analysis across more than 19,000 mRNASeq datasets and dissected the condition-specific gene signatures. Information was gained with respect to common and unique cellular responses and molecular events. We identified that in cell lines of colon or lung origin, both viruses show similarities in cellular responses; by contrast, there are cell type-specific regulators that differed for Calu-3 and Caco-2 cells. Among the major findings is the impact of the interferon system for lung Calu-3 cells and novel links to the liver- and lipid-metabolism-associated responses for colon Caco-2 cells as part of the extrapulmonary pathomechanisms in the course of COVID-19. Among differently expressed genes, we specifically dissected the expression pattern of the APOBEC family members and propose APOBEC3G as a promising intrinsic antiviral factor of the host response to SARS-CoV-2. Overall, our study provides gene expression level evidence for the cellular responses attributed to pulmonary and gastrointestinal manifestations of COVID-19. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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20 pages, 4588 KiB

Open AccessArticle

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients

by Jorge Monserrat, Ana Gómez-Lahoz, Miguel A. Ortega, José Sanz, Benjamin Muñoz, Juan Arévalo-Serrano, José Miguel Rodríguez, Jose Maria Gasalla, Óscar Gasulla, Alberto Arranz, Jordi Fortuny-Profitós, Ferran A. Mazaira-Font, Miguel Teixidó Román, Carlos Martínez-A, Dimitri Balomenos, Angel Asunsolo, Melchor Álvarez-Mon and on behalf of the COVID-19 HUPA Group

Int. J. Mol. Sci. 2022, 23(18), 10344; https://doi.org/10.3390/ijms231810344 - 7 Sep 2022

Cited by 16 | Viewed by 3397

Abstract

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but [...] Read more.

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system—IL-1α, IL-1α, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNFα, TGFα, IL-10, sRAGE, sTNF-RI and sTNF-RII—for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFNγ, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNFβ, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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18 pages, 2433 KiB

Open AccessArticle

Cytokine Storm Signature in Patients with Moderate and Severe COVID-19

by Olga Kalinina, Alexey Golovkin, Ekaterina Zaikova, Arthur Aquino, Vadim Bezrukikh, Olesya Melnik, Elena Vasilieva, Tatiana Karonova, Igor Kudryavtsev and Evgeny Shlyakhto

Int. J. Mol. Sci. 2022, 23(16), 8879; https://doi.org/10.3390/ijms23168879 - 10 Aug 2022

Cited by 46 | Viewed by 3169

Abstract

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. [...] Read more.

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1β, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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Review

Jump to: Editorial, Research

34 pages, 4713 KiB

Open AccessReview

COVID-19 Therapeutic Potential of Natural Products

by Zhaoxuan Low, Rafidah Lani, Vunjia Tiong, Chitlaa Poh, Sazaly AbuBakar and Pouya Hassandarvish

Int. J. Mol. Sci. 2023, 24(11), 9589; https://doi.org/10.3390/ijms24119589 - 31 May 2023

Cited by 16 | Viewed by 3589

Abstract

Despite the fact that coronavirus disease 2019 (COVID-19) treatment and management are now considerably regulated, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still one of the leading causes of death in 2022. The availability of COVID-19 vaccines, FDA-approved antivirals, and monoclonal antibodies [...] Read more.

Despite the fact that coronavirus disease 2019 (COVID-19) treatment and management are now considerably regulated, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still one of the leading causes of death in 2022. The availability of COVID-19 vaccines, FDA-approved antivirals, and monoclonal antibodies in low-income countries still poses an issue to be addressed. Natural products, particularly traditional Chinese medicines (TCMs) and medicinal plant extracts (or their active component), have challenged the dominance of drug repurposing and synthetic compound libraries in COVID-19 therapeutics. Their abundant resources and excellent antiviral performance make natural products a relatively cheap and readily available alternative for COVID-19 therapeutics. Here, we deliberately review the anti-SARS-CoV-2 mechanisms of the natural products, their potency (pharmacological profiles), and application strategies for COVID-19 intervention. In light of their advantages, this review is intended to acknowledge the potential of natural products as COVID-19 therapeutic candidates. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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24 pages, 1299 KiB

Open AccessReview

Importance, Applications and Features of Assays Measuring SARS-CoV-2 Neutralizing Antibodies

by Pia Gattinger, Anna Ohradanova-Repic and Rudolf Valenta

Int. J. Mol. Sci. 2023, 24(6), 5352; https://doi.org/10.3390/ijms24065352 - 10 Mar 2023

Cited by 14 | Viewed by 4429

Abstract

More than three years ago, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused the unforeseen COVID-19 pandemic with millions of deaths. In the meantime, SARS-CoV-2 has become endemic and is now part of the repertoire of viruses causing seasonal severe respiratory infections. [...] Read more.

More than three years ago, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused the unforeseen COVID-19 pandemic with millions of deaths. In the meantime, SARS-CoV-2 has become endemic and is now part of the repertoire of viruses causing seasonal severe respiratory infections. Due to several factors, among them the development of SARS-CoV-2 immunity through natural infection, vaccination and the current dominance of seemingly less pathogenic strains belonging to the omicron lineage, the COVID-19 situation has stabilized. However, several challenges remain and the possible new occurrence of highly pathogenic variants remains a threat. Here we review the development, features and importance of assays measuring SARS-CoV-2 neutralizing antibodies (NAbs). In particular we focus on in vitro infection assays and molecular interaction assays studying the binding of the receptor binding domain (RBD) with its cognate cellular receptor ACE2. These assays, but not the measurement of SARS-CoV-2-specific antibodies per se, can inform us of whether antibodies produced by convalescent or vaccinated subjects may protect against the infection and thus have the potential to predict the risk of becoming newly infected. This information is extremely important given the fact that a considerable number of subjects, in particular vulnerable persons, respond poorly to the vaccination with the production of neutralizing antibodies. Furthermore, these assays allow to determine and evaluate the virus-neutralizing capacity of antibodies induced by vaccines and administration of plasma-, immunoglobulin preparations, monoclonal antibodies, ACE2 variants or synthetic compounds to be used for therapy of COVID-19 and assist in the preclinical evaluation of vaccines. Both types of assays can be relatively quickly adapted to newly emerging virus variants to inform us about the magnitude of cross-neutralization, which may even allow us to estimate the risk of becoming infected by newly appearing virus variants. Given the paramount importance of the infection and interaction assays we discuss their specific features, possible advantages and disadvantages, technical aspects and not yet fully resolved issues, such as cut-off levels predicting the degree of in vivo protection. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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18 pages, 614 KiB

Open AccessReview

COVID-19 Heart Lesions in Children: Clinical, Diagnostic and Immunological Changes

by Elena Vasichkina, Daria Alekseeva, Igor Kudryavtsev, Anzhela Glushkova, Anastasia Y. Starshinova, Anna Malkova, Dmitry Kudlay and Anna Starshinova

Int. J. Mol. Sci. 2023, 24(2), 1147; https://doi.org/10.3390/ijms24021147 - 6 Jan 2023

Cited by 17 | Viewed by 7990

Abstract

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of [...] Read more.

In the beginning of COVID-19, the proportion of confirmed cases in the pediatric population was relatively small and there was an opinion that children often had a mild or asymptomatic course of infection. Our understanding of the immune response, diagnosis and treatment of COVID-19 is highly oriented towards the adult population. At the same time, despite the fact that COVID-19 in children usually occurs in a mild form, there is an incomplete understanding of the course as an acute infection and its subsequent manifestations such as Long-COVID-19 or Post-COVID-19, PASC in the pediatric population, correlations with comorbidities and immunological changes. In mild COVID-19 in childhood, some authors explain the absence of population decreasing T and B lymphocytes. Regardless of the patient’s condition, they can have the second phase, related to the exacerbation of inflammation in the heart tissue even if the viral infection was completely eliminated—post infectious myocarditis. Mechanism of myocardial dysfunction development in MIS-C are not fully understood. It is known that various immunocompetent cells, including both resident inflammatory cells of peripheral tissues (for example macrophages, dendritic cells, resident memory T-lymphocytes and so on) and also circulating in the peripheral blood immune cells play an important role in the immunopathogenesis of myocarditis. It is expected that hyperproduction of interferons and the enhanced cytokine response of T cells 1 and 2 types contribute to dysfunction of the myocardium. However, the role of Th1 in the pathogenesis of myocarditis remains highly controversial. At the same time, the clinical manifestations and mechanisms of damage, including the heart, both against the background and after COVID-19, in children differ from adults. Further studies are needed to evaluate whether transient or persistent cardiac complications are associated with long-term adverse cardiac events. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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13 pages, 643 KiB

Open AccessReview

3D Lung Tissue Models for Studies on SARS-CoV-2 Pathophysiology and Therapeutics

by Roberto Plebani, Haiqing Bai, Longlong Si, Jing Li, Chunhe Zhang and Mario Romano

Int. J. Mol. Sci. 2022, 23(17), 10071; https://doi.org/10.3390/ijms231710071 - 3 Sep 2022

Cited by 12 | Viewed by 3712

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has provoked more than six million deaths worldwide and continues to pose a major threat to global health. Enormous efforts have been made by researchers around the world to elucidate [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has provoked more than six million deaths worldwide and continues to pose a major threat to global health. Enormous efforts have been made by researchers around the world to elucidate COVID-19 pathophysiology, design efficacious therapy and develop new vaccines to control the pandemic. To this end, experimental models are essential. While animal models and conventional cell cultures have been widely utilized during these research endeavors, they often do not adequately reflect the human responses to SARS-CoV-2 infection. Therefore, models that emulate with high fidelity the SARS-CoV-2 infection in human organs are needed for discovering new antiviral drugs and vaccines against COVID-19. Three-dimensional (3D) cell cultures, such as lung organoids and bioengineered organs-on-chips, are emerging as crucial tools for research on respiratory diseases. The lung airway, small airway and alveolus organ chips have been successfully used for studies on lung response to infection by various pathogens, including corona and influenza A viruses. In this review, we provide an overview of these new tools and their use in studies on COVID-19 pathogenesis and drug testing. We also discuss the limitations of the existing models and indicate some improvements for their use in research against COVID-19 as well as future emerging epidemics. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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20 pages, 1089 KiB

Open AccessReview

COVID-19 and the Immune Response: A Multi-Phasic Approach to the Treatment of COVID-19

by Tzuriel Sapir, Zaelig Averch, Brian Lerman, Abraham Bodzin, Yeshaya Fishman and Radhashree Maitra

Int. J. Mol. Sci. 2022, 23(15), 8606; https://doi.org/10.3390/ijms23158606 - 3 Aug 2022

Cited by 12 | Viewed by 3739

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral agent that causes Coronavirus disease 2019 (COVID-19), a disease that causes flu-like symptoms that, when exacerbated, can have life-threatening consequences. COVID-19 has been linked to persistent symptoms, sequelae, and medical complications that can [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral agent that causes Coronavirus disease 2019 (COVID-19), a disease that causes flu-like symptoms that, when exacerbated, can have life-threatening consequences. COVID-19 has been linked to persistent symptoms, sequelae, and medical complications that can last months after the initial infection. This systematic review aims to elucidate the innate and adaptive immune mechanisms involved and identify potential characteristics of COVID-19 pathology that may increase symptom duration. We also describe he three different stages of COVID-19—viral replication, immune hyperactivation, and post-acute sequelae—as well as each phase’s corresponding immune response. Finally, we use this multiphasic approach to describe different treatment approaches for each of the three stages—antivirals, immunosuppressants and monoclonal antibodies, and continued immunosuppressants—to fully curate the treatment to the stage of disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022)

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