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Coronavirus Disease (COVID-19): Pathophysiology 2.0
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Coronavirus Disease (COVID-19): Pathophysiology 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 58058

Special Issue Editors

Prof. Dr. Jacek Z. Kubiak

E-Mail Website
Guest Editor
Dynamics and Mechanics of Epithelia Group, Faculty of Medicine, Institute of Genetics and Development of Rennes, University of Rennes, CNRS, UMR 6290, 35043 Rennes, France
Interests: embryo development; cell cycle; gene regulation; cancer; stem cells; gonads; genetic diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Malgorzata Kloc

E-Mail Website
Guest Editor
Transplant Immunology, The Houston Methodist Research Institute, Houston, TX 77030, USA
Interests: macrophages; actin cytoskeleton; RhoA pathway; chronic rejection; transplantation; germ cells; stem cells; Xenopus laevis; development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The COVID-19 pandemic triggered an astounding wave of research on all aspects of this novel viral disease. The pace of research on this completely unprecedented situation has been remarkable, resulting in the explosion of scientific reports and extraordinary achievements in the areas of treatment and prevention. The number of novel and efficient vaccines created is the best example of this. The avalanche of research in just one year vastly increased our knowledge of SARS-CoV-2 and other coronaviruses. We uncovered and came to understand some of the hitherto unknown mechanisms involved in the immune response to SARS-CoV-2 infection. Scientific research delivered novel antiviral drugs and treatments to decrease the severity of disease and save human lives during the pandemic. Genetic research allows for the identification of continuously evolving novel variants of the virus, and epidemiological studies characterize and follow their propagation in various regions of the world. Unprecedented phenomena were discovered, such as enormous differences in the viral infectivity and course of the disease in children and adults or between different individuals. Although new observations and research continue to expand our knowledge about this disease, we still have many unanswered questions. Does COVID-19 provoke diabetes? Does it cause orchitis? Why are the majority of children so resistant to SARS-CoV-2 infection while some of them develop pediatric inflammatory multisystem syndrome (PIMS)? Why do some COVID-19 patients continue to experience symptoms after their initial recovery? These people suffer from so-called post-COVID-19 syndrome or "long COVID-19." What causes these long-term effects? Why do some patients, a long time after their purported recovery, suffer from nervous system and brain damage. Another area that is still not fully understood is the response of different types of immune cells to the initial infection and their role in both the halting and propagation of the virus within the patient’s body. Additionally, why in some, but not all, patients does the immune system go into overdrive, causing a cytokine storm?

In this Special Issue, entitled “Coronavirus Disease (COVID-19): Pathophysiology”, we aim to present research and theoretical papers addressing all of these questions and many others related to COVID-19. Thus, we invite colleagues working in any field related to COVID-19, from viral genetics to epidemiology and computer modeling, to submit their work for publication in this Special Issue. We believe that this Special Issue of the International Journal of Molecular Sciences will be not only very timely but also scientifically innovative and exciting.

Prof. Dr. Jacek Z. Kubiak
Prof. Dr. Malgorzata Kloc
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • COVID-19
  • SARS-CoV-2
  • coronavirus, pandemic
  • viral diseases
  • pediatrics
  • inflammation
  • immune cells, macrophages
  • pneumonia
  • vaccines
  • cytokines
  • cytokine storm
  • PIMS
  • immunity

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Published Papers (14 papers)

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Editorial

Jump to: Research, Review

4 pages, 202 KiB  
Editorial
Recent Progress in Research on COVID-19 Pathophysiology: Biomarkers, Repurposed Drugs, Viral Invasiveness, SARS-CoV-2 Genetic Diversity, the Crystal Structure of Viral Proteins, and the Molecular and Cellular Outcomes of COVID-19
by Jacek Z. Kubiak and Malgorzata Kloc
Int. J. Mol. Sci. 2022, 23(22), 14194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214194 - 17 Nov 2022
Cited by 2 | Viewed by 1133
Abstract
COVID-19 is a disease caused by a novel zoonotic germ known as SARS-CoV-2 coronavirus [...] Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)

Research

Jump to: Editorial, Review

24 pages, 3164 KiB  
Article
Combining Deep Phenotyping of Serum Proteomics and Clinical Data via Machine Learning for COVID-19 Biomarker Discovery
by Antonio Paolo Beltrami, Maria De Martino, Emiliano Dalla, Matilde Clarissa Malfatti, Federica Caponnetto, Marta Codrich, Daniele Stefanizzi, Martina Fabris, Emanuela Sozio, Federica D’Aurizio, Carlo E. M. Pucillo, Leonardo A. Sechi, Carlo Tascini, Francesco Curcio, Gian Luca Foresti, Claudio Piciarelli, Axel De Nardin, Gianluca Tell and Miriam Isola
Int. J. Mol. Sci. 2022, 23(16), 9161; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169161 - 15 Aug 2022
Cited by 6 | Viewed by 2956
Abstract
The persistence of long-term coronavirus-induced disease 2019 (COVID-19) sequelae demands better insights into its natural history. Therefore, it is crucial to discover the biomarkers of disease outcome to improve clinical practice. In this study, 160 COVID-19 patients were enrolled, of whom 80 had [...] Read more.
The persistence of long-term coronavirus-induced disease 2019 (COVID-19) sequelae demands better insights into its natural history. Therefore, it is crucial to discover the biomarkers of disease outcome to improve clinical practice. In this study, 160 COVID-19 patients were enrolled, of whom 80 had a “non-severe” and 80 had a “severe” outcome. Sera were analyzed by proximity extension assay (PEA) to assess 274 unique proteins associated with inflammation, cardiometabolic, and neurologic diseases. The main clinical and hematochemical data associated with disease outcome were grouped with serological data to form a dataset for the supervised machine learning techniques. We identified nine proteins (i.e., CD200R1, MCP1, MCP3, IL6, LTBP2, MATN3, TRANCE, α2-MRAP, and KIT) that contributed to the correct classification of COVID-19 disease severity when combined with relative neutrophil and lymphocyte counts. By analyzing PEA, clinical and hematochemical data with statistical methods that were able to handle many variables in the presence of a relatively small sample size, we identified nine potential serum biomarkers of a “severe” outcome. Most of these were confirmed by literature data. Importantly, we found three biomarkers associated with central nervous system pathologies and protective factors, which were downregulated in the most severe cases. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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10 pages, 1476 KiB  
Communication
A Systematic Study on the Optimal Nucleotide Analogue Concentration and Rate Limiting Nucleotide of the SARS-CoV-2 RNA-Dependent RNA Polymerase
by Hasan Vatandaslar
Int. J. Mol. Sci. 2022, 23(15), 8302; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158302 - 27 Jul 2022
Cited by 4 | Viewed by 1692
Abstract
The current COVID-19 pandemic has highlighted the necessity of more efficient antiviral compounds. The antiviral efficacy of adenosine-based analogs, the main repurposed drugs for SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibition, is mainly assessed through in vitro or cell-free polymerization assays, under arbitrary conditions [...] Read more.
The current COVID-19 pandemic has highlighted the necessity of more efficient antiviral compounds. The antiviral efficacy of adenosine-based analogs, the main repurposed drugs for SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibition, is mainly assessed through in vitro or cell-free polymerization assays, under arbitrary conditions that do not reflect the physiological environment. We show that SARS-CoV-2 RdRp inhibition efficiency of remdesivir and cordycepin, two common adenosine analogs, is influenced by endogenous adenosine level, and that the current clinically approved concentrations for COVID-19 treatment are suboptimal for effective RdRp inhibition. Furthermore, we identified GTP as the rate-limiting nucleotide of SARS-CoV-2 replication. Our results demonstrate that nucleotide sensitivity of the RdRp complex and competition of nucleoside analog drugs against endogenous concentrations of nucleotides are crucial elements to be considered when designing new SARS-CoV-2 antiviral compounds. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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18 pages, 5674 KiB  
Article
Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase
by Sakshi Piplani, Puneet Singh, David A. Winkler and Nikolai Petrovsky
Int. J. Mol. Sci. 2022, 23(14), 7704; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147704 - 12 Jul 2022
Cited by 7 | Viewed by 2155
Abstract
Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 [...] Read more.
Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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17 pages, 4940 KiB  
Article
Biodistribution and Cellular Internalization of Inactivated SARS-CoV-2 in Wild-Type Mice
by Anett Hudák, Gareth Morgan, Jaromir Bacovsky, Roland Patai, Tamás F. Polgár, Annamária Letoha, Aladar Pettko-Szandtner, Csaba Vizler, László Szilák and Tamás Letoha
Int. J. Mol. Sci. 2022, 23(14), 7609; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147609 - 09 Jul 2022
Cited by 3 | Viewed by 4408
Abstract
Despite the growing list of identified SARS-CoV-2 receptors, the human angiotensin-converting enzyme 2 (ACE2) is still viewed as the main cell entry receptor mediating SARS-CoV-2 internalization. It has been reported that wild-type mice, like other rodent species of the Muridae family, cannot be [...] Read more.
Despite the growing list of identified SARS-CoV-2 receptors, the human angiotensin-converting enzyme 2 (ACE2) is still viewed as the main cell entry receptor mediating SARS-CoV-2 internalization. It has been reported that wild-type mice, like other rodent species of the Muridae family, cannot be infected with SARS-CoV-2 due to differences in their ACE2 receptors. On the other hand, the consensus heparin-binding motif of SARS-CoV-2’s spike protein, PRRAR, enables the attachment to rodent heparan sulfate proteoglycans (HSPGs), including syndecans, a transmembrane HSPG family with a well-established role in clathrin- and caveolin-independent endocytosis. As mammalian syndecans possess a relatively conserved structure, we analyzed the cellular uptake of inactivated SARS-CoV-2 particles in in vitro and in vivo mice models. Cellular studies revealed efficient uptake into murine cell lines with established syndecan-4 expression. After intravenous administration, inactivated SARS-CoV-2 was taken up by several organs in vivo and could also be detected in the brain. Internalized by various tissues, inactivated SARS-CoV-2 raised tissue TNF-α levels, especially in the heart, reflecting the onset of inflammation. Our studies on in vitro and in vivo mice models thus shed light on unknown details of SARS-CoV-2 internalization and help broaden the understanding of the molecular interactions of SARS-CoV-2. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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17 pages, 1230 KiB  
Article
Effective Natural Killer Cell Degranulation Is an Essential Key in COVID-19 Evolution
by Sara Garcinuño, Francisco Javier Gil-Etayo, Esther Mancebo, Marta López-Nevado, Antonio Lalueza, Raquel Díaz-Simón, Daniel Enrique Pleguezuelo, Manuel Serrano, Oscar Cabrera-Marante, Luis M. Allende, Estela Paz-Artal and Antonio Serrano
Int. J. Mol. Sci. 2022, 23(12), 6577; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126577 - 13 Jun 2022
Cited by 3 | Viewed by 2131
Abstract
NK degranulation plays an important role in the cytotoxic activity of innate immunity in the clearance of intracellular infections and is an important factor in the outcome of the disease. This work has studied NK degranulation and innate immunological profiles and functionalities in [...] Read more.
NK degranulation plays an important role in the cytotoxic activity of innate immunity in the clearance of intracellular infections and is an important factor in the outcome of the disease. This work has studied NK degranulation and innate immunological profiles and functionalities in COVID-19 patients and its association with the severity of the disease. A prospective observational study with 99 COVID-19 patients was conducted. Patients were grouped according to hospital requirements and severity. Innate immune cell subpopulations and functionalities were analyzed. The profile and functionality of innate immune cells differ between healthy controls and severe patients; CD56dim NK cells increased and MAIT cells and NK degranulation rates decreased in the COVID-19 subjects. Higher degranulation rates were observed in the non-severe patients and in the healthy controls compared to the severe patients. Benign forms of the disease had a higher granzymeA/granzymeB ratio than complex forms. In a multivariate analysis, the degranulation capacity resulted in a protective factor against severe forms of the disease (OR: 0.86), whereas the permanent expression of NKG2D in NKT cells was an independent risk factor (OR: 3.81; AUC: 0.84). In conclusion, a prompt and efficient degranulation functionality in the early stages of infection could be used as a tool to identify patients who will have a better evolution. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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36 pages, 4680 KiB  
Article
Evolution of SARS-CoV-2 in Spain during the First Two Years of the Pandemic: Circulating Variants, Amino Acid Conservation, and Genetic Variability in Structural, Non-Structural, and Accessory Proteins
by Paloma Troyano-Hernáez, Roberto Reinosa and África Holguín
Int. J. Mol. Sci. 2022, 23(12), 6394; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126394 - 07 Jun 2022
Cited by 17 | Viewed by 3108
Abstract
Monitoring SARS-CoV-2’s genetic diversity and emerging mutations in this ongoing pandemic is crucial to understanding its evolution and ensuring the performance of COVID-19 diagnostic tests, vaccines, and therapies. Spain has been one of the main epicenters of COVID-19, reaching the highest number of [...] Read more.
Monitoring SARS-CoV-2’s genetic diversity and emerging mutations in this ongoing pandemic is crucial to understanding its evolution and ensuring the performance of COVID-19 diagnostic tests, vaccines, and therapies. Spain has been one of the main epicenters of COVID-19, reaching the highest number of cases and deaths per 100,000 population in Europe at the beginning of the pandemic. This study aims to investigate the epidemiology of SARS-CoV-2 in Spain and its 18 Autonomous Communities across the six epidemic waves established from February 2020 to January 2022. We report on the circulating SARS-CoV-2 variants in each epidemic wave and Spanish region and analyze the mutation frequency, amino acid (aa) conservation, and most frequent aa changes across each structural/non-structural/accessory viral protein among the Spanish sequences deposited in the GISAID database during the study period. The overall SARS-CoV-2 mutation frequency was 1.24 × 10−5. The aa conservation was >99% in the three types of protein, being non-structural the most conserved. Accessory proteins had more variable positions, while structural proteins presented more aa changes per sequence. Six main lineages spread successfully in Spain from 2020 to 2022. The presented data provide an insight into the SARS-CoV-2 circulation and genetic variability in Spain during the first two years of the pandemic. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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15 pages, 4976 KiB  
Article
A Structural Comparison of SARS-CoV-2 Main Protease and Animal Coronaviral Main Protease Reveals Species-Specific Ligand Binding and Dimerization Mechanism
by Chien-Yi Ho, Jia-Xin Yu, Yu-Chuan Wang, Yu-Chuan Lin, Yi-Fang Chiu, Jing-Yan Gao, Shu-Jung Lai, Ming-Jen Chen, Wei-Chien Huang, Ni Tien and Yeh Chen
Int. J. Mol. Sci. 2022, 23(10), 5669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105669 - 18 May 2022
Cited by 3 | Viewed by 1895
Abstract
Animal coronaviruses (CoVs) have been identified to be the origin of Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and probably SARS-CoV-2 that cause severe to fatal diseases in humans. Variations of zoonotic coronaviruses pose potential threats to global human beings. [...] Read more.
Animal coronaviruses (CoVs) have been identified to be the origin of Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and probably SARS-CoV-2 that cause severe to fatal diseases in humans. Variations of zoonotic coronaviruses pose potential threats to global human beings. To overcome this problem, we focused on the main protease (Mpro), which is an evolutionary conserved viral protein among different coronaviruses. The broad-spectrum anti-coronaviral drug, GC376, was repurposed to target canine coronavirus (CCoV), which causes gastrointestinal infections in dogs. We found that GC376 can efficiently block the protease activity of CCoV Mpro and can thermodynamically stabilize its folding. The structure of CCoV Mpro in complex with GC376 was subsequently determined at 2.75 Å. GC376 reacts with the catalytic residue C144 of CCoV Mpro and forms an (R)- or (S)-configuration of hemithioacetal. A structural comparison of CCoV Mpro and other animal CoV Mpros with SARS-CoV-2 Mpro revealed three important structural determinants in a substrate-binding pocket that dictate entry and release of substrates. As compared with the conserved A141 of the S1 site and P188 of the S4 site in animal coronaviral Mpros, SARS-CoV-2 Mpro contains N142 and Q189 at equivalent positions which are considered to be more catalytically compatible. Furthermore, the conserved loop with residues 46–49 in animal coronaviral Mpros has been replaced by a stable α-helix in SARS-CoV-2 Mpro. In addition, the species-specific dimerization interface also influences the catalytic efficiency of CoV Mpros. Conclusively, the structural information of this study provides mechanistic insights into the ligand binding and dimerization of CoV Mpros among different species. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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20 pages, 32233 KiB  
Article
SARS-CoV-2 Infection Dysregulates Cilia and Basal Cell Homeostasis in the Respiratory Epithelium of Hamsters
by Tom Schreiner, Lisa Allnoch, Georg Beythien, Katarzyna Marek, Kathrin Becker, Dirk Schaudien, Stephanie Stanelle-Bertram, Berfin Schaumburg, Nancy Mounogou Kouassi, Sebastian Beck, Martin Zickler, Gülsah Gabriel, Wolfgang Baumgärtner, Federico Armando and Malgorzata Ciurkiewicz
Int. J. Mol. Sci. 2022, 23(9), 5124; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095124 - 04 May 2022
Cited by 14 | Viewed by 3864
Abstract
Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent [...] Read more.
Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent regeneration is crucial to assess the possible long-term consequences of COVID-19. The aim of this study was to characterize the sequence of histological and ultrastructural changes observed in the ciliated epithelium during and after SARS-CoV-2 infection in the golden Syrian hamster model. We show that acute infection induces a severe, transient loss of cilia, which is, at least in part, caused by cilia internalization. Internalized cilia colocalize with membrane invaginations, facilitating virus entry into the cell. Infection also results in a progressive decline in cells expressing the regulator of ciliogenesis FOXJ1, which persists beyond virus clearance and the termination of inflammatory changes. Ciliary loss triggers the mobilization of p73+ and CK14+ basal cells, which ceases after regeneration of the cilia. Although ciliation is restored after two weeks despite the lack of FOXJ1, an increased frequency of cilia with ultrastructural alterations indicative of secondary ciliary dyskinesia is observed. In summary, the work provides new insights into SARS-CoV-2 pathogenesis and expands our understanding of virally induced damage to defense mechanisms in the conducting airways. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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Review

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23 pages, 2728 KiB  
Review
COVID-19 Vaccines, Effectiveness, and Immune Responses
by Haneen Imad Abufares, Leen Oyoun Alsoud, Mohammad A. Y. Alqudah, Mohd Shara, Nelson C. Soares, Karem H. Alzoubi, Waseem El-Huneidi, Yasser Bustanji, Sameh S. M. Soliman and Mohammad H. Semreen
Int. J. Mol. Sci. 2022, 23(23), 15415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315415 - 06 Dec 2022
Cited by 9 | Viewed by 4972
Abstract
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has captivated the globe’s attention since its emergence in 2019. This highly infectious, spreadable, and dangerous pathogen has caused health, social, and economic crises. Therefore, a worldwide collaborative effort was [...] Read more.
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has captivated the globe’s attention since its emergence in 2019. This highly infectious, spreadable, and dangerous pathogen has caused health, social, and economic crises. Therefore, a worldwide collaborative effort was made to find an efficient strategy to overcome and develop vaccines. The new vaccines provide an effective immune response that safeguards the community from the virus’ severity. WHO has approved nine vaccines for emergency use based on safety and efficacy data collected from various conducted clinical trials. Herein, we review the safety and effectiveness of the WHO-approved COVID-19 vaccines and associated immune responses, and their impact on improving the public’s health. Several immunological studies have demonstrated that vaccination dramatically enhances the immune response and reduces the likelihood of future infections in previously infected individuals. However, the type of vaccination and individual health status can significantly affect immune responses. Exposure of healthy individuals to adenovirus vectors or mRNA vaccines causes the early production of antibodies from B and T cells. On the other hand, unhealthy individuals were more likely to experience harmful events due to relapses in their existing conditions. Taken together, aligning with the proper vaccination to a patient’s case can result in better outcomes. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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14 pages, 836 KiB  
Review
Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives
by Rodrigo P. Silva-Aguiar, Douglas E. Teixeira, Rodrigo A. S. Peres, Diogo B. Peruchetti, Carlos P. Gomes, Alvin H. Schmaier, Patricia R. M. Rocco, Ana Acacia S. Pinheiro and Celso Caruso-Neves
Int. J. Mol. Sci. 2022, 23(22), 14193; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214193 - 17 Nov 2022
Cited by 5 | Viewed by 2052
Abstract
Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [...] Read more.
Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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14 pages, 2021 KiB  
Review
How to Restore Oxidative Balance That Was Disrupted by SARS-CoV-2 Infection
by Kajetan Kiełbowski, Mariola Herian and Andrzej Pawlik
Int. J. Mol. Sci. 2022, 23(12), 6377; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126377 - 07 Jun 2022
Cited by 6 | Viewed by 2904
Abstract
Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a [...] Read more.
Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a dysregulated immunological response known as cytokine storm. Many scientists have demonstrated that SARS-CoV-2 impacts oxidative homeostasis and stimulates the production of reactive oxygen species (ROS). In addition, the virus inhibits glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (NRF2)—a major antioxidant which induces expression of protective proteins and prevents ROS damage. Furthermore, the virus stimulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes which play a significant role in inducing a cytokine storm. A variety of agents with antioxidant properties have shown beneficial effects in experimental and clinical studies of COVID-19. This review aims to present mechanisms of oxidative stress induced by SARS-CoV-2 and to discuss whether antioxidative drugs can counteract detrimental outcomes of a cytokine storm. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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12 pages, 1027 KiB  
Review
The Role of Nuclear Factor Kappa B (NF-κB) in Development and Treatment of COVID-19: Review
by Monika Gudowska-Sawczuk and Barbara Mroczko
Int. J. Mol. Sci. 2022, 23(9), 5283; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095283 - 09 May 2022
Cited by 20 | Viewed by 3704
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 19 (COVID-19), a disease that has affected more than 500 million people worldwide since the end of 2019. Due to its high complications and death rates, there is still a need to find the best therapy for SARS-CoV-2 infection. The dysregulation of the inflammatory response in COVID-19 plays a very important role in disease progression. It has been observed that abnormal activity of Nuclear Factor kappa B (NF-κB) is directly associated with, inter alia, increased synthesis of proinflammatory factors. Therefore, this review paper focuses on the functions of NF-κB in the development of SARS-CoV-2 infection and potential application of NF-κB inhibitors in COVID-19 immunotherapy. A comprehensive literature search was performed using the MEDLINE/PubMed database. In the current review, it is highlighted that NF-κB plays important functions in the modulation of an adaptive inflammatory response, including inducing the expression of proinflammatory genes. Increased activation of NF-κB in SARS-CoV-2 infection was observed. The association between NF-κB activation and the expression of SARS-CoV-2 structural and non-structural proteins were also reported. It was observed that modulation of NF-κB using, e.g., traditional Chinese medicine or glucocorticosteroids resulted in decreased synthesis of proinflammatory factors caused by SARS-CoV-2 infection. This review summarizes the role of NF-κB in COVID-19 and describes its potential immunotherapeutic target in treatment of SARS-CoV-2 infection. However, indisputably more studies involving patients with a severe course of COVID-19 are sorely needed. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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Review
COVID-19: Are We Facing Secondary Pellagra Which Cannot Simply Be Cured by Vitamin B3?
by Renata Novak Kujundžić
Int. J. Mol. Sci. 2022, 23(8), 4309; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084309 - 13 Apr 2022
Cited by 4 | Viewed by 18691
Abstract
Immune response to SARS-CoV-2 and ensuing inflammation pose a huge challenge to the host’s nicotinamide adenine dinucleotide (NAD+) metabolism. Humans depend on vitamin B3 for biosynthesis of NAD+, indispensable for many metabolic and NAD+-consuming signaling reactions. The [...] Read more.
Immune response to SARS-CoV-2 and ensuing inflammation pose a huge challenge to the host’s nicotinamide adenine dinucleotide (NAD+) metabolism. Humans depend on vitamin B3 for biosynthesis of NAD+, indispensable for many metabolic and NAD+-consuming signaling reactions. The balance between its utilization and resynthesis is vitally important. Many extra-pulmonary symptoms of COVID-19 strikingly resemble those of pellagra, vitamin B3 deficiency (e.g., diarrhoea, dermatitis, oral cavity and tongue manifestations, loss of smell and taste, mental confusion). In most developed countries, pellagra is successfully eradicated by vitamin B3 fortification programs. Thus, conceivably, it has not been suspected as a cause of COVID-19 symptoms. Here, the deregulation of the NAD+ metabolism in response to the SARS-CoV-2 infection is reviewed, with special emphasis on the differences in the NAD+ biosynthetic pathway’s efficiency in conditions predisposing for the development of serious COVID-19. SARS-CoV-2 infection-induced NAD+ depletion and the elevated levels of its metabolites contribute to the development of a systemic disease. Acute liberation of nicotinamide (NAM) in antiviral NAD+-consuming reactions potentiates “NAM drain”, cooperatively mediated by nicotinamide N-methyltransferase and aldehyde oxidase. “NAM drain” compromises the NAD+ salvage pathway’s fail-safe function. The robustness of the host’s NAD+ salvage pathway, prior to the SARS-CoV-2 infection, is an important determinant of COVID-19 severity and persistence of certain symptoms upon resolution of infection. Full article
(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 2.0)
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