International Journal of Molecular Sciences

Editorial

6 pages, 224 KiB

Open AccessEditorial

Coronavirus Disease Pathophysiology: Biomarkers, Potential New Remedies, Comorbidities, Long COVID-19, Post Pandemic Epidemiological Surveillance

by Jacek Z. Kubiak and Małgorzata Kloc

Int. J. Mol. Sci. 2023, 24(15), 12236; https://doi.org/10.3390/ijms241512236 - 31 Jul 2023

Cited by 3 | Viewed by 1403

Abstract

The toughest challenge modern biomedical research ever faced was the rapid understanding of the SARS-CoV-2 physiopathology [...] Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

Research

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16 pages, 5836 KiB

Open AccessArticle

Targeted Blood Plasma Proteomics and Hemostasis Assessment of Post COVID-19 Patients with Acute Myocardial Infarction

by Anna Kalinskaya, Daria Vorobyeva, George Rusakovich, Elena Maryukhnich, Alexandra Anisimova, Oleg Dukhin, Antonina Elizarova, Oxana Ivanova, Anna Bugrova, Alexander Brzhozovskiy, Alexey Kononikhin, Evgeny Nikolaev and Elena Vasilieva

Int. J. Mol. Sci. 2023, 24(7), 6523; https://doi.org/10.3390/ijms24076523 - 30 Mar 2023

Cited by 5 | Viewed by 2491

Abstract

The molecular mechanisms underlying cardiovascular complications after the SARS-CoV-2 infection remain unknown. The goal of our study was to analyze the features of blood coagulation, platelet aggregation, and plasma proteomics in COVID-19 convalescents with AMI. The study included 66 AMI patients and 58 [...] Read more.

The molecular mechanisms underlying cardiovascular complications after the SARS-CoV-2 infection remain unknown. The goal of our study was to analyze the features of blood coagulation, platelet aggregation, and plasma proteomics in COVID-19 convalescents with AMI. The study included 66 AMI patients and 58 healthy volunteers. The groups were divided according to the anti-N IgG levels (AMI post-COVID (n = 44), AMI control (n = 22), control post-COVID (n = 31), and control (n = 27)). All participants underwent rotational thromboelastometry, thrombodynamics, impedance aggregometry, and blood plasma proteomics analysis. Both AMI groups of patients demonstrated higher values of clot growth rates, thrombus size and density, as well as the elevated levels of components of the complement system, proteins modifying the state of endothelium, acute-phase and procoagulant proteins. In comparison with AMI control, AMI post-COVID patients demonstrated decreased levels of proteins connected to inflammation and hemostasis (lipopolysaccharide-binding protein, C4b-binding protein alpha-chain, plasma protease C1 inhibitor, fibrinogen beta-chain, vitamin K-dependent protein S), and altered correlations between inflammation and fibrinolysis. A new finding is that AMI post-COVID patients opposite the AMI control group, are characterized by a less noticeable growth of acute-phase proteins and hemostatic markers that could be explained by prolonged immune system alteration after COVID-19. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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20 pages, 3717 KiB

Open AccessArticle

Plasma Proteomics Unveil Novel Immune Signatures and Biomarkers upon SARS-CoV-2 Infection

by Víctor Urbiola-Salvador, Suiane Lima de Souza, Peter Grešner, Talha Qureshi and Zhi Chen

Int. J. Mol. Sci. 2023, 24(7), 6276; https://doi.org/10.3390/ijms24076276 - 27 Mar 2023

Cited by 6 | Viewed by 3118

Abstract

Several elements have an impact on COVID-19, including comorbidities, age and sex. To determine the protein profile changes in peripheral blood caused by a SARS-CoV-2 infection, a proximity extension assay was used to quantify 1387 proteins in plasma samples among 28 Finnish patients [...] Read more.

Several elements have an impact on COVID-19, including comorbidities, age and sex. To determine the protein profile changes in peripheral blood caused by a SARS-CoV-2 infection, a proximity extension assay was used to quantify 1387 proteins in plasma samples among 28 Finnish patients with COVID-19 with and without comorbidities and their controls. Key immune signatures, including CD4 and CD28, were changed in patients with comorbidities. Importantly, several unreported elevated proteins in patients with COVID-19, such as RBP2 and BST2, which show anti-microbial activity, along with proteins involved in extracellular matrix remodeling, including MATN2 and COL6A3, were identified. RNF41 was downregulated in patients compared to healthy controls. Our study demonstrates that SARS-CoV-2 infection causes distinct plasma protein changes in the presence of comorbidities despite the interpatient heterogeneity, and several novel potential biomarkers associated with a SARS-CoV-2 infection alone and in the presence of comorbidities were identified. Protein changes linked to the generation of SARS-CoV-2-specific antibodies, long-term effects and potential association with post-COVID-19 condition were revealed. Further study to characterize the identified plasma protein changes from larger cohorts with more diverse ethnicities of patients with COVID-19 combined with functional studies will facilitate the identification of novel diagnostic, prognostic biomarkers and potential therapeutic targets for patients with COVID-19. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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21 pages, 5470 KiB

Open AccessArticle

Direct Application of 3-Maleimido-PROXYL for Proving Hypoalbuminemia in Cases of SARS-CoV-2 Infection: The Potential Diagnostic Method of Determining Albumin Instability and Oxidized Protein Level in Severe COVID-19

by Ekaterina Georgieva, Vasil Atanasov, Rositsa Kostandieva, Vanya Tsoneva, Mitko Mitev, Georgi Arabadzhiev, Yovcho Yovchev, Yanka Karamalakova and Galina Nikolova

Int. J. Mol. Sci. 2023, 24(6), 5807; https://doi.org/10.3390/ijms24065807 - 18 Mar 2023

Cited by 4 | Viewed by 1783

Abstract

Oxidative stress and the albumin oxidized form can lead to hypoalbuminemia, which is a predisposing factor for reduced treatment effectiveness and an increased mortality rate in severe COVID-19 patients. The aim of the study is to evaluate the application of free radical 3-Maleimido-PROXYL [...] Read more.

Oxidative stress and the albumin oxidized form can lead to hypoalbuminemia, which is a predisposing factor for reduced treatment effectiveness and an increased mortality rate in severe COVID-19 patients. The aim of the study is to evaluate the application of free radical 3-Maleimido-PROXYL and SDSL-EPR spectroscopy in the in vitro determination of ox/red HSA in serum samples from patients with SARS-CoV-2 infection. Venous blood was collected from patients intubated (pO₂ < 90%) with a positive PCR test for SARS-CoV-2 and controls. At the 120th minute after the incubation of the serum samples from both groups with the 3-Maleimido-PROXYL, the EPR measurement was started. The high levels of free radicals were determined through the nitroxide radical TEMPOL, which probably led to increased oxidation of HSA and hypoalbuminemia in severe COVID-19. The double-integrated spectra of 3-Maleimido-PROXYL radical showed a low degree of connectivity due to high levels of oxidized albumin in COVID-19 patients. The low concentrations of reduced albumin in serum samples partially inhibit spin-label rotation, with A_max values and ΔH₀ spectral parameters comparable to those of 3-Maleimido-PROXYL/DMSO. Based on the obtained results, we suggest that the stable nitroxide radical 3-Maleimido-PROXYL can be successfully used as a marker to study oxidized albumin levels in COVID-19. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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15 pages, 2100 KiB

Open AccessArticle

The SARS-CoV-2 Virus and the Cholinergic System: Spike Protein Interaction with Human Nicotinic Acetylcholine Receptors and the Nicotinic Agonist Varenicline

by Eric C. Carlson, Marian Macsai, Sonia Bertrand, Daniel Bertrand and Jeffrey Nau

Int. J. Mol. Sci. 2023, 24(6), 5597; https://doi.org/10.3390/ijms24065597 - 15 Mar 2023

Cited by 6 | Viewed by 2870

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with [...] Read more.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the worldwide coronavirus disease 2019 (COVID-19) pandemic. Although the pathophysiology of SARS-CoV-2 infection is still being elucidated, the nicotinic cholinergic system may play a role. To evaluate the interaction of the SARS-CoV-2 virus with human nicotinic acetylcholine receptors (nAChRs), we assessed the in vitro interaction of the spike protein of the SARS-CoV-2 virus with various subunits of nAChRs. Electrophysiology recordings were conducted at α4β2, α3β4, α3α5β4, α4α6β2, and α7 neuronal nAChRs expressed in Xenopus oocytes. In cells expressing the α4β2 or α4α6β2 nAChRs, exposure to the 1 µg/mL Spike-RBD protein caused a marked reduction of the current amplitude; effects at the α3α5β4 receptor were equivocal and effects at the α3β4 and α7 receptors were absent. Overall, the spike protein of the SARS-CoV-2 virus can interact with select nAChRs, namely the α4β2 and/or α4α6β2 subtypes, likely at an allosteric binding site. The nAChR agonist varenicline has the potential to interact with Spike-RBD and form a complex that may interfere with spike function, although this effect appears to have been lost with the omicron mutation. These results help understand nAChR’s involvement with acute and long-term sequelae associated with COVID-19, especially within the central nervous system. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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19 pages, 3147 KiB

Open AccessArticle

Secretory Phospholipase A2 and Interleukin-6 Levels as Predictive Markers of the Severity and Outcome of Patients with COVID-19 Infections

by Stanislav Urazov, Alexandr Chernov, Oleg Popov, Natalya Klenkova, Natalya Sushentseva, Irina Polkovnikova, Svetlana Apalko, Kseniya Kislyuk, Dragana Pavlovich, Andrey Ivanov and Sergey Shcherbak

Int. J. Mol. Sci. 2023, 24(6), 5540; https://doi.org/10.3390/ijms24065540 - 14 Mar 2023

Cited by 4 | Viewed by 2063

Abstract

Coronavirus disease (COVID-19) has become a global pandemic. COVID-19 patients need immediate diagnosis and rehabilitation, which makes it urgent to identify new protein markers for a prognosis of the severity and outcome of the disease. The aim of this study was to analyze [...] Read more.

Coronavirus disease (COVID-19) has become a global pandemic. COVID-19 patients need immediate diagnosis and rehabilitation, which makes it urgent to identify new protein markers for a prognosis of the severity and outcome of the disease. The aim of this study was to analyze the levels of interleukin-6 (IL-6) and secretory phospholipase (sPLA2) in the blood of patients regarding the severity and outcome of COVID-19 infection. The study included clinical and biochemical data obtained from 158 patients with COVID-19 treated at St. Petersburg City Hospital No. 40. A detailed clinical blood test was performed on all patients, as well as an assessment of IL-6, sPLA2, aspartate aminotransferase (AST), total protein, albumin, lactate dehydrogenase (LDH), APTT, fibrinogen, procalcitonin, D-dimer, C-reactive protein (CRB), ferritin, and glomerular filtration rate (GFR) levels. It was found that the levels of PLA2, IL-6, APTV, AST, CRP, LDH, IL-6, D-dimer, and ferritin, as well as the number of neutrophils, significantly increased in patients with mild to severe COVID-19 infections. The levels of IL-6 were positively correlated with APTT; the levels of AST, LDH, CRP, D-dimer, and ferritin; and the number of neutrophils. The increase in the level of sPLA2 was positively correlated with the levels of CRP, LDH, D-dimer, and ferritin, the number of neutrophils, and APTT, and negatively correlated with the levels of GFR and lymphocytes. High levels of IL-6 and PLA2 significantly increase the risk of a severe course by 13.7 and 2.24 times, and increase the risk of death from COVID-19 infection by 14.82 and 5.32 times, respectively. We have shown that the blood levels of sPLA2 and IL-6 increase in cases which eventually result in death and when patients are transferred to the ICU (as the severity of COVID-19 infection increases), showing that IL-6 and sPLA2 can be considered as early predictors of aggravation of COVID-19 infections. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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18 pages, 2718 KiB

Open AccessArticle

New Insights into the Identification of Metabolites and Cytokines Predictive of Outcome for Patients with Severe SARS-CoV-2 Infection Showed Similarity with Cancer

by Susan Costantini, Gabriele Madonna, Elena Di Gennaro, Francesca Capone, Palmina Bagnara, Mariaelena Capone, Silvia Sale, Carmine Nicastro, Lidia Atripaldi, Giuseppe Fiorentino, Roberto Parrella, Vincenzo Montesarchio, Luigi Atripaldi, Paolo A. Ascierto and Alfredo Budillon

Int. J. Mol. Sci. 2023, 24(5), 4922; https://doi.org/10.3390/ijms24054922 - 3 Mar 2023

Cited by 4 | Viewed by 2399

Abstract

SARS-CoV-2 infection is characterized by several clinical manifestations, ranging from the absence of symptoms to severe forms that necessitate intensive care treatment. It is known that the patients with the highest rate of mortality develop increased levels of proinflammatory cytokines, called the “cytokine [...] Read more.

SARS-CoV-2 infection is characterized by several clinical manifestations, ranging from the absence of symptoms to severe forms that necessitate intensive care treatment. It is known that the patients with the highest rate of mortality develop increased levels of proinflammatory cytokines, called the “cytokine storm”, which is similar to inflammatory processes that occur in cancer. Additionally, SARS-CoV-2 infection induces modifications in host metabolism leading to metabolic reprogramming, which is closely linked to metabolic changes in cancer. A better understanding of the correlation between perturbed metabolism and inflammatory responses is necessary. We evaluated untargeted plasma metabolomics and cytokine profiling via ¹H-NMR (proton nuclear magnetic resonance) and multiplex Luminex assay, respectively, in a training set of a limited number of patients with severe SARS-CoV-2 infection classified on the basis of their outcome. Univariate analysis and Kaplan–Meier curves related to hospitalization time showed that lower levels of several metabolites and cytokines/growth factors, correlated with a good outcome in these patients and these data were confirmed in a validation set of patients with similar characteristics. However, after the multivariate analysis, only the growth factor HGF, lactate and phenylalanine retained a significant prediction of survival. Finally, the combined analysis of lactate and phenylalanine levels correctly predicted the outcome of 83.3% of patients in both the training and the validation set. We highlighted that the cytokines and metabolites involved in COVID-19 patients’ poor outcomes are similar to those responsible for cancer development and progression, suggesting the possibility of targeting them by repurposing anticancer drugs as a therapeutic strategy against severe SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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12 pages, 1319 KiB

Open AccessArticle

Monitoring of SARS-CoV-2 Infection in Ragusa Area: Next Generation Sequencing and Serological Analysis

by Maria Denaro, Elisa Ferro, Giuseppe Barrano, Salvatore Meli, Mariangela Busacca, Damiano Corallo, Alessia Capici, Alessandra Zisa, Luana Cucuzza, Sandra Gradante, Marialuisa Occhipinti, Paola Santalucia, Raffaele Elia, Angelo Aliquò, Daniele Tibullo, Carmelo Fidone and Vincenzo Bramanti

Int. J. Mol. Sci. 2023, 24(5), 4742; https://doi.org/10.3390/ijms24054742 - 1 Mar 2023

Cited by 3 | Viewed by 1942

Abstract

The coronavirus disease 19 (COVID-19) post pandemic evolution is correlated to the development of new variants. Viral genomic and immune response monitoring are fundamental to the surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since 1 January to 31 July 2022, [...] Read more.

The coronavirus disease 19 (COVID-19) post pandemic evolution is correlated to the development of new variants. Viral genomic and immune response monitoring are fundamental to the surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Since 1 January to 31 July 2022, we monitored the SARS-CoV-2 variants trend in Ragusa area sequencing n.600 samples by next generation sequencing (NGS) technology: n.300 were healthcare workers (HCWs) of ASP Ragusa. The evaluation of anti-Nucleocapside (N), receptor-binding domain (RBD), the two subunit of S protein (S1 and S2) IgG levels in 300 exposed vs. 300 unexposed HCWs to SARS-CoV-2 was performed. Differences in immune response and clinical symptoms related to the different variants were investigated. The SARS-CoV-2 variants trend in Ragusa area and in Sicily region were comparable. BA.1 and BA.2 were the most representative variants, whereas the diffusion of BA.3 and BA.4 affected some places of the region. Although no correlation was found between variants and clinical manifestations, anti-N and anti-S2 levels were positively correlated with an increase in the symptoms number. SARS-CoV-2 infection induced a statistically significant enhancement in antibody titers compared to that produced by SARS-CoV-2 vaccine administration. In post-pandemic period, the evaluation of anti-N IgG could be used as an early marker to identify asymptomatic subjects. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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11 pages, 3893 KiB

Open AccessArticle

The Comparison of Retinal Microvascular Findings in Acute COVID-19 and 1-Year after Hospital Discharge Assessed with Multimodal Imaging—A Prospective Longitudinal Cohort Study

by Kristina Jevnikar, Andrej Meglič, Luka Lapajne, Mateja Logar, Nataša Vidovič Valentinčič, Mojca Globočnik Petrovič and Polona Jaki Mekjavić

Int. J. Mol. Sci. 2023, 24(4), 4032; https://doi.org/10.3390/ijms24044032 - 17 Feb 2023

Cited by 5 | Viewed by 1941

Abstract

This study aimed to quantify possible long-term impairment of the retinal microcirculation and microvasculature by reassessing a cohort of patients with acute COVID-19 without other known comorbidities one year after their discharge from the hospital. Thirty patients in the acute phase of COVID-19 [...] Read more.

This study aimed to quantify possible long-term impairment of the retinal microcirculation and microvasculature by reassessing a cohort of patients with acute COVID-19 without other known comorbidities one year after their discharge from the hospital. Thirty patients in the acute phase of COVID-19 without known systemic comorbidities were enrolled in this prospective longitudinal cohort study. Fundus photography, SS-OCT, and SS-OCTA using swept-source OCT (SS-OCT, Topcon DRI OCT Triton; Topcon Corp., Tokyo, Japan) were performed in the COVID-19 unit and 1-year after hospital discharge. The cohort’s median age was 60 years (range 28–65) and 18 (60%) were male. Mean vein diameter (MVD) significantly decreased over time, from 134.8 μm in the acute phase to 112.4 μm at a 1-year follow-up (p < 0.001). A significantly reduced retinal nerve fiber layer (RNFL) thickness was observed at follow-up in the inferior quadrant of the inner ring (mean diff. 0.80 95% CI 0.01–1.60, p = 0.047) and inferior (mean diff. 1.56 95% CI 0.50–2.61, p < 0.001), nasal (mean diff. 2.21 95% CI 1.16–3.27, p < 0.001), and superior (mean diff. 1.69 95% CI 0.63–2.74, p < 0.001) quadrants of the outer ring. There were no statistically significant differences between the groups regarding vessel density of the superior and deep capillary plexuses. The transient dilatation of the retinal vessels in the acute phase of COVID-19, as well as RNFL thickness changes, could become a biomarker of angiopathy in patients with severe COVID-19. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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16 pages, 2475 KiB

Open AccessArticle

Recognition of Differentially Expressed Molecular Signatures and Pathways Associated with COVID-19 Poor Prognosis in Glioblastoma Patients

by Faisal A. Alzahrani, Mohd Faheem Khan and Varish Ahmad

Int. J. Mol. Sci. 2023, 24(4), 3562; https://doi.org/10.3390/ijms24043562 - 10 Feb 2023

Cited by 6 | Viewed by 2369

Abstract

Glioblastoma (GBM) is a type of brain cancer that is typically very aggressive and difficult to treat. Glioblastoma cases have been reported to have increased during COVID-19. The mechanisms underlying this comorbidity, including genomic interactions, tumor differentiation, immune responses, and host defense, are [...] Read more.

Glioblastoma (GBM) is a type of brain cancer that is typically very aggressive and difficult to treat. Glioblastoma cases have been reported to have increased during COVID-19. The mechanisms underlying this comorbidity, including genomic interactions, tumor differentiation, immune responses, and host defense, are not completely explained. Therefore, we intended to investigate the differentially expressed shared genes and therapeutic agents which are significant for these conditions by using in silico approaches. Gene expression datasets of GSE68848, GSE169158, and GSE4290 studies were collected and analyzed to identify the DEGs between the diseased and the control samples. Then, the ontology of the genes and the metabolic pathway enrichment analysis were carried out for the classified samples based on expression values. Protein–protein interactions (PPI) map were performed by STRING and fine-tuned by Cytoscape to screen the enriched gene module. In addition, the connectivity map was used for the prediction of potential drugs. As a result, 154 overexpressed and 234 under-expressed genes were identified as common DEGs. These genes were found to be significantly enriched in the pathways involved in viral diseases, NOD-like receptor signaling pathway, the cGMP-PKG signaling pathway, growth hormone synthesis, secretion, and action, the immune system, interferon signaling, and the neuronal system. STAT1, CXCL10, and SAMDL were screened out as the top 03 out of the top 10 most critical genes among the DEGs from the PPI network. AZD-8055, methotrexate, and ruxolitinib were predicted to be the possible agents for the treatment. The current study identified significant key genes, common metabolic signaling networks, and therapeutic agents to improve our perception of the common mechanisms of GBM–COVID-19. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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23 pages, 7528 KiB

Open AccessArticle

Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2

by Orsolya Dömötör and Éva A. Enyedy

Int. J. Mol. Sci. 2023, 24(3), 2849; https://doi.org/10.3390/ijms24032849 - 2 Feb 2023

Cited by 11 | Viewed by 3027

Abstract

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and [...] Read more.

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pK_a values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK′ = 5.8–6.0), while its binding to HSA is much weaker (logK′ ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and ‘acute-phase’ conditions as well. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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14 pages, 2268 KiB

Open AccessArticle

Hemodialysis-Associated Immune Dysregulation in SARS-CoV-2-Infected End-Stage Renal Disease Patients

by Cecilia González-Cuadrado, Paula Jara Caro-Espada, Marta Chivite-Lacaba, Alberto Utrero-Rico, Claudia Lozano-Yuste, Elena Gutierrez-Solis, Enrique Morales, Justo Sandino-Pérez, Francisco Javier Gil-Etayo, Luis Allende-Martínez, Rocio Laguna-Goya and Estela Paz-Artal

Int. J. Mol. Sci. 2023, 24(2), 1712; https://doi.org/10.3390/ijms24021712 - 15 Jan 2023

Cited by 6 | Viewed by 2129

Abstract

Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed [...] Read more.

Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1β and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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12 pages, 9076 KiB

Open AccessArticle

COVID-19 Plasma Extracellular Vesicles Increase the Density of Lipid Rafts in Human Small Airway Epithelial Cells

by Sara Darwish, Lauren P. Liu, Tanya O. Robinson, Spurthi Tarugu, Anna H. Owings, Sarah C. Glover and Abdel A. Alli

Int. J. Mol. Sci. 2023, 24(2), 1654; https://doi.org/10.3390/ijms24021654 - 14 Jan 2023

Cited by 4 | Viewed by 2482

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is the causative agent of the COVID-19 disease. COVID-19 viral infection can affect many cell types, including epithelial cells of the lungs and airways. Extracellular vesicles (EVs) are released by virtually all cell types, and [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is the causative agent of the COVID-19 disease. COVID-19 viral infection can affect many cell types, including epithelial cells of the lungs and airways. Extracellular vesicles (EVs) are released by virtually all cell types, and their packaged cargo allows for intercellular communication, cell differentiation, and signal transduction. Cargo from virus-infected cells may include virally derived metabolites, miRNAs, nucleic acids, and proteins. We hypothesized that COVID-19 plasma EVs can induce the formation of signaling platforms known as lipid rafts after uptake by normal human small airway epithelial cells (SAECs). Circulating EVs from patients with or without COVID-19 were characterized by nanoparticle tracking analysis, Western blotting using specific antibodies, and transmission electron microscopy. Primary cultures of normal human small airway epithelial cells were challenged with EVs from the two patient groups, and lipid raft formation was measured by fluorescence microscopy and assessed by sucrose density gradient analysis. Collectively, our data suggest that circulating EVs from COVID-19-infected patients can induce the formation of lipid rafts in normal human small airway epithelial cells. These results suggest the need for future studies aimed at investigating whether the increased density of lipid rafts in these cells promotes viral entry and alteration of specific signaling pathways in the recipient cells. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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26 pages, 3970 KiB

Open AccessArticle

Urokinase System in Pathogenesis of Pulmonary Fibrosis: A Hidden Threat of COVID-19

by Anna A. Shmakova, Vladimir S. Popov, Iliya P. Romanov, Nikita R. Khabibullin, Nailya R. Sabitova, Anna A. Karpukhina, Yana A. Kozhevnikova, Ella V. Kurilina, Zoya I. Tsokolaeva, Polina S. Klimovich, Kseniya A. Rubina, Yegor S. Vassetzky and Ekaterina V. Semina

Int. J. Mol. Sci. 2023, 24(2), 1382; https://doi.org/10.3390/ijms24021382 - 10 Jan 2023

Cited by 8 | Viewed by 2801

Abstract

Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung [...] Read more.

Pulmonary fibrosis is a common and threatening post-COVID-19 complication with poorly resolved molecular mechanisms and no established treatment. The plasminogen activator system, including urokinase (uPA) and urokinase receptor (uPAR), is involved in the pathogenesis of COVID-19 and contributes to the development of lung injury and post-COVID-19 pulmonary fibrosis, although their cellular and molecular underpinnings still remain obscure. The aim of the current study was to assess the role of uPA and uPAR in the pathogenesis of pulmonary fibrosis. We analyzed uPA and uPAR expression in human lung tissues from COVID-19 patients with pulmonary fibrosis using single-cell RNA-seq and immunohistochemistry. We modeled lung fibrosis in Plau-/- and Plaur-/- mice upon bleomycin instillation and explored the effect of uPAR downregulation in A549 and BEAS-2B lung epithelial cells. We found that uPAR expression drastically decreased in the epithelial airway basal cells and monocyte/macrophage cells, whereas uPA accumulation significantly increased in tissue samples of COVID-19 patients. Lung injury and fibrosis in Plaur-/- vs. WT mice upon bleomycin instillation revealed that uPAR deficiency resulted in pro-fibrogenic uPA accumulation, IL-6 and ACE2 upregulation in lung tissues and was associated with severe fibrosis, weight loss and poor survival. uPAR downregulation in A549 and BEAS-2B was linked to an increased N-cadherin expression, indicating the onset of epithelial–mesenchymal transition and potentially contributing to pulmonary fibrosis. Here for the first time, we demonstrate that plasminogen treatment reversed lung fibrosis in Plaur-/- mice: the intravenous injection of 1 mg of plasminogen on the 21st day of bleomycin-induced fibrosis resulted in a more than a two-fold decrease in the area of lung fibrosis as compared to non-treated mice as evaluated by the 42nd day. The expression and function of the plasminogen activator system are dysregulated upon COVID-19 infection, leading to excessive pulmonary fibrosis and worsening the prognosis. The potential of plasminogen as a life-saving treatment for non-resolving post-COVID-19 pulmonary fibrosis warrants further investigation. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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21 pages, 2208 KiB

Open AccessArticle

Iron Dyshomeostasis in COVID-19: Biomarkers Reveal a Functional Link to 5-Lipoxygenase Activation

by Beatrice Dufrusine, Silvia Valentinuzzi, Sandra Bibbò, Verena Damiani, Paola Lanuti, Damiana Pieragostino, Piero Del Boccio, Ersilia D’Alessandro, Alberto Rabottini, Alessandro Berghella, Nerino Allocati, Katia Falasca, Claudio Ucciferri, Francesco Mucedola, Marco Di Perna, Laura Martino, Jacopo Vecchiet, Vincenzo De Laurenzi and Enrico Dainese

Int. J. Mol. Sci. 2023, 24(1), 15; https://doi.org/10.3390/ijms24010015 - 20 Dec 2022

Cited by 8 | Viewed by 4509

Abstract

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and [...] Read more.

Coronavirus disease 2019 (COVID-19) is characterized by a broad spectrum of clinical symptoms. After acute infection, some subjects develop a post-COVID-19 syndrome known as long-COVID. This study aims to recognize the molecular and functional mechanisms that occur in COVID-19 and long-COVID patients and identify useful biomarkers for the management of patients with COVID-19 and long-COVID. Here, we profiled the response to COVID-19 by performing a proteomic analysis of lymphocytes isolated from patients. We identified significant changes in proteins involved in iron metabolism using different biochemical analyses, considering ceruloplasmin (Cp), transferrin (Tf), hemopexin (HPX), lipocalin 2 (LCN2), and superoxide dismutase 1 (SOD1). Moreover, our results show an activation of 5-lipoxygenase (5-LOX) in COVID-19 and in long-COVID possibly through an iron-dependent post-translational mechanism. Furthermore, this work defines leukotriene B4 (LTB4) and lipocalin 2 (LCN2) as possible markers of COVID-19 and long-COVID and suggests novel opportunities for prevention and treatment. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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9 pages, 281 KiB

Open AccessArticle

Shrunken Pore Syndrome Is Frequently Occurring in Severe COVID-19

by Anders O. Larsson, Michael Hultström, Robert Frithiof, Miklos Lipcsey and Mats B. Eriksson

Int. J. Mol. Sci. 2022, 23(24), 15687; https://doi.org/10.3390/ijms232415687 - 10 Dec 2022

Cited by 3 | Viewed by 2179

Abstract

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of [...] Read more.

A selective decrease in the renal filtration of larger molecules is attributed to the shrinkage of glomerular pores, a condition termed Shrunken Pore Syndrome (SPS). SPS is associated with poor long-term prognosis. We studied SPS as a risk marker in a cohort of patients with COVID-19 treated in an intensive care unit. SPS was defined as a ratio < 0.7 when the estimated glomerular filtration rate (eGFR), determined by cystatin C, calculated by the Cystatin C Caucasian-Asian-Pediatric-Adult equation (CAPA), was divided by the eGFR determined by creatinine, calculated by the revised Lund–Malmö creatinine equation (LMR). Clinical data were prospectively collected. In total, SPS was present in 86 (24%) of 352 patients with COVID-19 on ICU admission. Patients with SPS had a higher BMI, Simplified Physiology Score (SAPS3), and had diabetes and/or hypertension more frequently than patients without SPS. Ninety-nine patients in the total cohort were women, 50 of whom had SPS. In dexamethasone-naïve patients, C-reactive protein (CRP ), TNF-alpha, and interleukin-6 did not differ between SPS and non-SPS patients. Demographic factors (gender, BMI) and illness severity (SAPS3) were independent predictors of SPS. Age and dexamethasone treatment did not affect the frequency of SPS after adjustments for age, sex, BMI, and acute severity. SPS is frequent in severely ill COVID-19 patients. Female gender was associated with a higher proportion of SPS. Demographic factors and illness severity were independent predictors of SPS. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

15 pages, 2492 KiB

Open AccessArticle

SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects

by Celine Boschi, David E. Scheim, Audrey Bancod, Muriel Militello, Marion Le Bideau, Philippe Colson, Jacques Fantini and Bernard La Scola

Int. J. Mol. Sci. 2022, 23(24), 15480; https://doi.org/10.3390/ijms232415480 - 7 Dec 2022

Cited by 24 | Viewed by 62700

Abstract

Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19. To [...] Read more.

Experimental findings for SARS-CoV-2 related to the glycan biochemistry of coronaviruses indicate that attachments from spike protein to glycoconjugates on the surfaces of red blood cells (RBCs), other blood cells and endothelial cells are key to the infectivity and morbidity of COVID-19. To provide further insight into these glycan attachments and their potential clinical relevance, the classic hemagglutination (HA) assay was applied using spike protein from the Wuhan, Alpha, Delta and Omicron B.1.1.529 lineages of SARS-CoV-2 mixed with human RBCs. The electrostatic potential of the central region of spike protein from these four lineages was studied through molecular modeling simulations. Inhibition of spike protein-induced HA was tested using the macrocyclic lactone ivermectin (IVM), which is indicated to bind strongly to SARS-CoV-2 spike protein glycan sites. The results of these experiments were, first, that spike protein from these four lineages of SARS-CoV-2 induced HA. Omicron induced HA at a significantly lower threshold concentration of spike protein than the three prior lineages and was much more electropositive on its central spike protein region. IVM blocked HA when added to RBCs prior to spike protein and reversed HA when added afterward. These results validate and extend prior findings on the role of glycan bindings of viral spike protein in COVID-19. They furthermore suggest therapeutic options using competitive glycan-binding agents such as IVM and may help elucidate rare serious adverse effects (AEs) associated with COVID-19 mRNA vaccines, which use spike protein as the generated antigen. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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10 pages, 689 KiB

Open AccessCommunication

Weak Point of SARS-CoV-2: Human and Viral Ion Channels under External Physical Fields

by Andrzej Fuliński

Int. J. Mol. Sci. 2022, 23(23), 15185; https://doi.org/10.3390/ijms232315185 - 2 Dec 2022

Cited by 2 | Viewed by 1427

Abstract

The ionic E-nanochannel (viroporin) is the weak point of SARS-CoV-2, the virus responsible for the (still threatening) COVID-19 since it is vital to the virus’s budding and propagation. Therefore, targeting it to disable its functions ought to incapacitate, or at least weaken, the [...] Read more.

The ionic E-nanochannel (viroporin) is the weak point of SARS-CoV-2, the virus responsible for the (still threatening) COVID-19 since it is vital to the virus’s budding and propagation. Therefore, targeting it to disable its functions ought to incapacitate, or at least weaken, the virus. The ionic currents inside this channel could be affected and disturbed by direct physical attack via the actions of external fields. The paper presents the first step towards the application of such methods in the fight against the current pandemic, numerical simulations of external fields’ impact on ionic currents through viral channels. These simulations—based on the actual, detailed physical nanostructure of ionic channels, measured experimentally and reported in the literature—show that external physical fields can diminish the channel’s currents and that the lower the channel’s selectivity, the stronger the effect. Simulations suggest that SARS-CoV-2 E-viroporin is almost non-selective, which means that the whole virus ought to be highly vulnerable to the actions of external physical fields, much more vulnerable than the much more selective human cell ionic channels. If corroborated by experiment, this observation may result in an innovative method of dealing with the recent pandemic caused by SARS-CoV-2 and other similar viruses. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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18 pages, 2996 KiB

Open AccessArticle

Alterations in the Kynurenine–Tryptophan Pathway and Lipid Dysregulation Are Preserved Features of COVID-19 in Hemodialysis

by Max Schuller, Monika Oberhuber, Barbara Prietl, Elmar Zügner, Eva-Maria Prugger, Christoph Magnes, Alexander H. Kirsch, Sabine Schmaldienst, Thomas Pieber, Marianne Brodmann, Alexander R. Rosenkranz, Philipp Eller and Kathrin Eller

Int. J. Mol. Sci. 2022, 23(22), 14089; https://doi.org/10.3390/ijms232214089 - 15 Nov 2022

Cited by 3 | Viewed by 1965

Abstract

Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential [...] Read more.

Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in end-stage kidney disease (CKD G5), we analyzed the plasma metabolites in different COVID-19 stages in patients with or without HD. We recruited 18 and 9 asymptomatic and mild, 11 and 11 moderate, 2 and 13 severely affected, and 10 and 6 uninfected HD and non-HD patients, respectively. Plasma samples were taken at the time of diagnosis and/or upon admission to the hospital and analyzed by targeted metabolomics and cytokine/chemokine profiling. Targeted metabolomics confirmed stage-dependent alterations of the metabolome in non-HD patients with COVID-19, which were less pronounced in HD patients. Elevated kynurenine levels and lipid dysregulation, shown by an increase in circulating free fatty acids and a decrease in lysophospholipids, could distinguish patients with moderate COVID-19 from non-infected individuals in both groups. Kynurenine and lipid alterations were also associated with ICAM-1 and IL-15 levels in HD and non-HD patients. Our findings support the kynurenine pathway and plasma lipids as universal biomarkers of moderate and severe COVID-19 independent of kidney function. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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13 pages, 3591 KiB

Open AccessArticle

Lung Inflammasome Activation in SARS-CoV-2 Post-Mortem Biopsies

by Lucas Baena Carstens, Raissa Campos D’amico, Karen Fernandes de Moura, Eduardo Morais de Castro, Flávia Centenaro, Giovanna Silva Barbosa, Guilherme Vieira Cavalcante da Silva, Isadora Brenny, Júlio César Honório D’Agostini, Elisa Carolina Hlatchuk, Sabrina Pissette de Lima, Ana Paula Camargo Martins, Marina De Castro Deus, Carolline Konzen Klein, Ana Paula Kubaski Benevides, Seigo Nagashima, Cleber Machado-Souza, Ricardo A Pinho, Cristina Pellegrino Baena and Lúcia de Noronha

Int. J. Mol. Sci. 2022, 23(21), 13033; https://doi.org/10.3390/ijms232113033 - 27 Oct 2022

Cited by 10 | Viewed by 2730

Abstract

The inflammasome complex is a key part of chronic diseases and acute infections, being responsible for cytokine release and cell death mechanism regulation. The SARS-CoV-2 infection is characterized by a dysregulated cytokine release. In this context, the inflammasome complex analysis within SARS-CoV-2 infection [...] Read more.

The inflammasome complex is a key part of chronic diseases and acute infections, being responsible for cytokine release and cell death mechanism regulation. The SARS-CoV-2 infection is characterized by a dysregulated cytokine release. In this context, the inflammasome complex analysis within SARS-CoV-2 infection may prove beneficial to understand the disease’s mechanisms. Post-mortem minimally invasive autopsies were performed in patients who died from COVID-19 (n = 24), and lung samples were compared to a patient control group (n = 11) and an Influenza A virus H1N1 subtype group from the 2009 pandemics (n = 10). Histological analysis was performed using hematoxylin-eosin staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: ACE2, TLR4, NF-κB, NLRP-3 (or NALP), IL-1β, IL-18, ASC, CASP1, CASP9, GSDMD, NOX4, TNF-α. Data obtained from digital analysis underwent appropriate statistical tests. IHC analysis showed biomarkers that indicate inflammasome activation (ACE2; NF-κB; NOX4; ASC) were significantly increased in the COVID-19 group (p < 0.05 for all) and biomarkers that indicate cell pyroptosis and inflammasome derived cytokines such as IL-18 (p < 0.005) and CASP1 were greatly increased (p < 0.0001) even when compared to the H1N1 group. We propose that the SARS-CoV-2 pathogenesis is connected to the inflammasome complex activation. Further studies are still warranted to elucidate the pathophysiology of the disease. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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13 pages, 1402 KiB

Open AccessArticle

Dynamic Evaluation of Natural Killer Cells Subpopulations in COVID-19 Patients

by Adina Huțanu, Doina Manu, Manuela Rozalia Gabor, Anca Meda Văsieșiu, Akos Vince Andrejkovits and Minodora Dobreanu

Int. J. Mol. Sci. 2022, 23(19), 11875; https://doi.org/10.3390/ijms231911875 - 6 Oct 2022

Cited by 4 | Viewed by 1931

Abstract

The aim of the study was to evaluate the dynamic changes of the total Natural Killer (NK) cells and different NK subpopulations according to their differentiated expression of CD16/CD56 in COVID-19 patients. Blood samples with EDTA were analyzed on day 1 (admission moment), [...] Read more.

The aim of the study was to evaluate the dynamic changes of the total Natural Killer (NK) cells and different NK subpopulations according to their differentiated expression of CD16/CD56 in COVID-19 patients. Blood samples with EDTA were analyzed on day 1 (admission moment), day 5, and day 10 for the NK subtypes. At least 30,000 singlets were collected for each sample and white blood cells were gated in CD45/SSC and CD16/CD56 dot plots of fresh human blood. From the lymphocyte singlets, the NK cells subpopulations were analyzed based on the differentiated expression of surface markers and classified as follows: CD16^-CD56^+/++/CD16⁺CD56⁺⁺/CD16⁺CD56⁺/CD16⁺⁺CD56⁻. By examining the CD56 versus CD16 flow cytometry dot plots, we found four distinct NK sub-populations. These NK subtypes correspond to different NK phenotypes from secretory to cytolytic ones. There was no difference between total NK percentage of different disease forms. However, the total numbers decreased significantly both in survivors and non-survivors. Additionally, for the CD16^-CD56^+/++ phenotype, we observed different patterns, gradually decreasing in survivors and gradually increasing in those with fatal outcomes. Despite no difference in the proportion of the CD16⁻CD56⁺⁺ NK cells in survivors vs. non–survivors, the main cytokine producers gradually decline during the study period in the survival group, underling the importance of adequate IFN production during the early stage of SARS-CoV-2 infection. Persistency in the circulation of CD56⁺⁺ NK cells may have prognostic value in patients, with a fatal outcome. Total NK cells and the CD16⁺CD56⁺ NK subtypes exhibit significant decreasing trends across the moments for both survivors and non-survivors. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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14 pages, 2594 KiB

Open AccessArticle

Direct Interaction of Coronavirus Nonstructural Protein 3 with Melanoma Differentiation-Associated Gene 5 Modulates Type I Interferon Response during Coronavirus Infection

by Xinxin Sun, Li Quan, Ruiai Chen and Dingxiang Liu

Int. J. Mol. Sci. 2022, 23(19), 11692; https://doi.org/10.3390/ijms231911692 - 2 Oct 2022

Cited by 7 | Viewed by 1945

Abstract

Coronavirus nonstructural protein 3 (nsp3) is a multi-functional protein, playing a critical role in viral replication and in regulating host antiviral innate immunity. In this study, we demonstrate that nsp3 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and avian coronavirus infectious bronchitis [...] Read more.

Coronavirus nonstructural protein 3 (nsp3) is a multi-functional protein, playing a critical role in viral replication and in regulating host antiviral innate immunity. In this study, we demonstrate that nsp3 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and avian coronavirus infectious bronchitis virus (IBV) directly interacts with melanoma differentiation-associated gene 5 (MDA5), rendering an inhibitory effect on the MDA5-mediated type I interferon (IFN) response. By the co-expression of MDA5 with wild-type and truncated nsp3 constructs, at least three interacting regions mapped to the papain-like protease (PLpro) domain and two other domains located at the N- and C-terminal regions were identified in SARS-CoV-2 nsp3. Furthermore, by introducing point mutations to the catalytic triad, the deubiquitylation activity of the PLpro domain from both SARS-CoV-2 and IBV nsp3 was shown to be responsible for the suppression of the MDA5-mediated type I IFN response. It was also demonstrated that both MDA5 and nsp3 were able to interact with ubiquitin and ubiquitinated proteins, contributing to the interaction between the two proteins. This study confirms the antagonistic role of nsp3 in the MDA5-mediated type I IFN signaling, highlighting the complex interaction between a multi-functional viral protein and the innate immune response. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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8 pages, 252 KiB

Open AccessArticle

Evaluation of Free Light Chains (FLCs) Synthesis in Response to Exposure to SARS-CoV-2

by Monika Gudowska-Sawczuk, Anna Moniuszko-Malinowska, Sara Pączek, Katarzyna Guziejko, Monika Chorąży and Barbara Mroczko

Int. J. Mol. Sci. 2022, 23(19), 11589; https://doi.org/10.3390/ijms231911589 - 30 Sep 2022

Cited by 4 | Viewed by 1615

Abstract

The aim of this study is to assess the synthesis of kappa (κ) and lambda (λ) free light chains (FLCs) in the serum of patients with COVID-19. All the 120 serum samples were collected from patients with COVID-19 and from healthy controls (vaccinated [...] Read more.

The aim of this study is to assess the synthesis of kappa (κ) and lambda (λ) free light chains (FLCs) in the serum of patients with COVID-19. All the 120 serum samples were collected from patients with COVID-19 and from healthy controls (vaccinated and non-vaccinated against SARS-CoV-2). FLCs, IgG total, IgG4, IgG anti-Nucleocapsid (N), anti-spike S1 receptor binding domain (S-RBD) antibodies and IL-6 were measured according to the manufacturers’ instructions. The concentrations of anti-N IgG, IgG total, IgG4 and IL-6 were elevated in the COVID-19 group in comparison to the vaccinated and non-vaccinated controls. The levels of anti-S-RBD IgG and κFLC were increased in COVID-19 and healthy vaccinated patients when compared to non-vaccinated controls. λFLC concentration was higher in the COVID-19 group than in the non-vaccinated group. The κ:λ ratio was lower in both COVID-19 and non-vaccinated groups in comparison to vaccinated controls. κFLC correlated with all tested parameters (anti-S-RBD IgG, anti-N IgG, λFLC, κ:λ ratio, IgG total, IgG4 and IL-6) except CRP, whereas λFLC correlated with all examined parameters except IgG4. Elevated levels of FLCs in COVID-19 and healthy vaccinated against SARS-CoV-2 patients, as well as the correlation between free light chains with specific anti-SARS-CoV-2 antibodies and IL-6, reflect hyperactivation of the immune system after contact with coronavirus. Furthermore, it seems that serum levels of FLCs might be used as predictive markers of COVID-19. Our findings suggest that free light chains are involved in SARS-CoV-2 infection. However, understanding the exact mechanism requires further investigation. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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14 pages, 572 KiB

Open AccessReview

Trained Immunity, BCG and SARS-CoV-2 General Outline and Possible Management in COVID-19

by Paweł Zapolnik, Wojciech Kmiecik, Artur Mazur and Hanna Czajka

Int. J. Mol. Sci. 2023, 24(4), 3218; https://doi.org/10.3390/ijms24043218 - 6 Feb 2023

Cited by 3 | Viewed by 2096

Abstract

The Bacillus Calmette–Guérin (BCG) vaccine has been in use for over 100 years. It protects against severe, blood-borne forms of tuberculosis. Observations indicate that it also increases immunity against other diseases. The mechanism responsible for this is trained immunity, an increased response of [...] Read more.

The Bacillus Calmette–Guérin (BCG) vaccine has been in use for over 100 years. It protects against severe, blood-borne forms of tuberculosis. Observations indicate that it also increases immunity against other diseases. The mechanism responsible for this is trained immunity, an increased response of non-specific immune cells in repeated contact with a pathogen, not necessarily of the same species. In the following review, we present the current state of knowledge on the molecular mechanisms responsible for this process. We also seek to identify the challenges facing science in this area and consider the application of this phenomenon in managing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 3.0)

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