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Special Issue "Coronavirus Disease (COVID-19): Pathophysiology 4.0"

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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: 31 January 2024 | Viewed by 4140

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Prof. Dr. Malgorzata Kloc

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Transplant Immunology, The Houston Methodist Research Institute, Houston, TX 77030, USA
Interests: macrophages; actin cytoskeleton; RhoA pathway; chronic rejection; transplantation; germ cells; Xenopus laevis; development
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Prof. Dr. Jacek Z. Kubiak

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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

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 the 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 as well as 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 responses 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 in addition to 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. Malgorzata Kloc
Prof. Dr. Jacek Z. Kubiak
Guest Editors

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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.

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Keywords

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

Related Special Issues

Coronavirus Disease (COVID-19): Pathophysiology in International Journal of Molecular Sciences (15 articles)
Coronavirus Disease (COVID-19): Pathophysiology 2.0 in International Journal of Molecular Sciences (14 articles)
Coronavirus Disease (COVID-19): Pathophysiology 3.0 in International Journal of Molecular Sciences (24 articles)

Published Papers (7 papers)

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Research

Open AccessArticle

The Effect of Potassium Canrenoate (Mineralocorticoid Receptor Antagonist) on the Markers of Inflammation in the Treatment of COVID-19 Pneumonia and Fibrosis—A Secondary Analysis of Randomized Placebo-Controlled Clinical Trial

Igor Karolak

Rafał Hrynkiewicz

Paulina Niedźwiedzka-Rystwej

and

Int. J. Mol. Sci. 2023, 24(18), 14247; https://doi.org/10.3390/ijms241814247 - 18 Sep 2023

Viewed by 208

Abstract

In March 2020, the World Health Organization (WHO) announced a global pandemic of coronavirus disease 2019 (COVID-19) that presented mainly as an acute infection of the lower respiratory tract (pneumonia), with multiple long-term consequences, including lung fibrosis. The aim of this study was to evaluate the influence of potassium canrenoate on inflammatory markers in the treatment of COVID-19 pneumonia. A randomized clinical trial (RCT) of intravenous potassium canrenoate vs. placebo was performed between December 2020 and November 2021. This study is a secondary analysis of that RCT. In the final analysis, a total of 49 hospitalized patients were included (24 allocated to the potassium canrenoate group and 25 to the placebo group). Patients were assessed by serum testing and blood cell cytometry on day 1 and day 7 of the intervention. Age, sex, and body mass index were not significantly different between the placebo group and intervention group. Although there was a significantly higher rate of ischemic heart disease in the placebo group, rates of other preexisting comorbidities were not significantly different. There were no significant differences in the inflammatory parameters between the potassium canrenoate and placebo groups on day 1 and day 7. However, the intragroup comparisons using Wilcoxon’s test showed significant differences between day 1 and day 7. The CD3% for potassium canrenoate increased significantly between day 1 and day 7 (12.85 ± 9.46; 11.55 vs. 20.50 ± 14.40; 17.80; p = 0.022), while the change in the placebo group was not significant (15.66 ± 11.39; 12.65 vs. 21.16 ± 15.37; 16.40; p = 0.181). The IL-1ß total count [%] increased over time for both potassium canrenoate (0.68 ± 0.58; 0.45 vs. 1.27 ± 0.83; 1.20; p = 0.004) and placebo (0.61 ± 0.59; 0.40 vs. 1.16 ± 0.91; 1.00; p = 0.016). The TNF-α total count (%) decreased significantly between day 1 and day 7 for potassium canrenoate (0.54 ± 0.45; 0.40 vs. 0.25 ± 0.23; 0.10; p = 0.031), but not for placebo (0.53 ± 0.47; 0.35 vs. 0.26 ± 0.31; 0.20; p = 0.056). Interleukin-6 (pg/mL) showed a significant decrease between day 1 and day 7 for potassium canrenoate (64.97 ± 72.52; 41.00 vs. 24.20 ± 69.38; 5.30; p = 0.006), but not the placebo group. This RCT has shown that the administration of potassium canrenoate to patients with COVID-19-induced pneumonia may be associated with significant changes in certain inflammatory markers (interleukin-6, CD3%, TNF-α), potentially related to pulmonary fibrosis. Although some positive trends were observed in the potassium canrenoate group, none of these observations reached statistical significance. Any possible benefits from the use of potassium canrenoate as an anti-inflammatory or antifibrotic drug in COVID-19 patients require further investigation. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

Serum Pentraxin 3 as Promising Biomarker for the Long-Lasting Inflammatory Response of COVID-19

and

Int. J. Mol. Sci. 2023, 24(18), 14195; https://doi.org/10.3390/ijms241814195 - 17 Sep 2023

Viewed by 343

Abstract

Currently, biological markers for COVID-19 disease severity still constitute the main goal of enhancing an efficient treatment to reduce critical consequences such as an abnormal systemic inflammatory response. In this regard, the latest research has shown that Pentraxin 3 (PTX3), a highly conserved innate immunity protein, may serve as a valuable biochemical marker. Based on this evidence, we conducted a case–control study to compare the PTX3 serum levels and several immune-inflammatory mediators of 80 healthcare workers who were subdivided into subjects who were previously infected with SARS-CoV-2 (n = 40) and individuals who were never infected (n = 40). Using a commercially available Enzyme-Linked Immunosorbent Assay (ELISA), PTX3 and various immune-inflammatory protein levels were assessed in serum samples, while also considering possible variables (e.g., gender-related differences). We have shown elevated levels of PTX3 and other inflammatory proteins in previously infected COVID-19-positive subjects (p < 0.001). Moreover, the obtained data also indicate a degree of severity influenced by gender, as shown by the subgroup analysis, in which PTX3 expression was more pronounced in previously COVID-19-positive males (p < 0.001) than in females (p < 0.05) compared to the respective controls. In addition, our data further validate, through a direct comparison of previously COVID-19-positive subjects, greater pro-inflammatory levels in males than in females. Overall, our results may support the validity of PTX3 as a systemic biomarker in prolonged systemic inflammatory responses in the context of COVID-19. Thus, PTX3 modulation could constitute an effective therapeutic strategy for improving the recovery from COVID-19 and its systemic long-term consequences. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

Exploring the Syndecan-Mediated Cellular Internalization of the SARS-CoV-2 Omicron Variant

Annamária Letoha

Anett Hudák

and

Tamás Letoha

Int. J. Mol. Sci. 2023, 24(18), 14140; https://doi.org/10.3390/ijms241814140 - 15 Sep 2023

Viewed by 427

Abstract

SARS-CoV-2 variants evolve to rely more on heparan sulfate (HS) for viral attachment and subsequent infection. In our earlier work, we demonstrated that the Delta variant’s spike protein binds more strongly to HS compared to WT SARS-CoV-2, leading to enhanced cell internalization via syndecans (SDCs), a family of transmembrane HS proteoglycans (HSPGs) facilitating the cellular entry of the original strain. Using our previously established ACE2- or SDC-overexpressing cellular models, we now compare the ACE2- and SDC-dependent cellular uptake of heat-inactivated WT SARS-CoV-2 with the Delta and Omicron variants. Internalization studies with inactivated virus particles showed that ACE2 overexpression could not compensate for the loss of HS in Omicron’s internalization, suggesting that this variant primarily uses HSPGs to enter cells. Although SDCs increased the internalization of all three viruses, subtle differences could be detected between their SDC isoform preferences. The Delta variant particularly benefitted from SDC1, 2, and 4 overexpression for cellular entry, while SDC4 had the most prominent effect on Omicron internalization. The SDC4 knockdown (KD) in Calu-3 cells reduced the cellular uptake of all three viruses, but the inhibition was the most pronounced for Omicron. The polyanionic heparin also hindered the cellular internalization of all three viruses with a dominant inhibitory effect on Omicron. Omicron’s predominant HSPG affinity, combined with its preference for the universally expressed SDC4, might account for its efficient transmission yet reduced pathogenicity. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

Endothelial Damage, Neutrophil Extracellular Traps and Platelet Activation in COVID-19 vs. Community-Acquired Pneumonia: A Case–Control Study

Paula González-Jiménez

and

Int. J. Mol. Sci. 2023, 24(17), 13194; https://doi.org/10.3390/ijms241713194 - 25 Aug 2023

Viewed by 396

Abstract

COVID-19 has been a diagnostic and therapeutic challenge. It has marked a paradigm shift when considering other types of pneumonia etiology. We analyzed the biomarkers related to endothelial damage and immunothrombosis in COVID-19 in comparison to community-acquired pneumonia (CAP) through a case–control study of 358 patients with pneumonia (179 hospitalized with COVID-19 vs. 179 matched hospitalized with CAP). Endothelial damage markers (endothelin and proadrenomedullin), neutrophil extracellular traps (NETs) (citrullinated-3 histone, cell-free DNA), and platelet activation (soluble P-selectin) were measured. In-hospital and 1-year follow-up outcomes were evaluated. Endothelial damage, platelet activation, and NET biomarkers are significantly higher in CAP compared to COVID-19. In-hospital mortality in COVID-19 was higher compared to CAP whereas 1-year mortality and cardiovascular complications were higher in CAP. In the univariate analysis (OR 95% CIs), proADM and endothelin were associated with in-hospital mortality (proADM: CAP 3.210 [1.698–6.070], COVID-19 8.977 [3.413–23.609]; endothelin: CAP 1.014 [1.006–1.022], COVID-19 1.024 [1.014–1.034]), in-hospital CVE (proADM: CAP 1.623 [1.080–2.439], COVID-19 2.146 [1.186–3.882]; endothelin: CAP 1.005 [1.000–1.010], COVID-19 1.010 [1.003–1.018]), and 1-year mortality (proADM: CAP 2.590 [1.644–4.080], COVID-19 13.562 [4.872–37.751]; endothelin: CAP 1.008 [1.003–1.013], COVID-19 1.026 [1.016–1.037]). In conclusion, COVID-19 and CAP showed different expressions of endothelial damage and NETs. ProADM and endothelin are associated with short- and long-term mortality. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

Identification of Host PDZ-Based Interactions with the SARS-CoV-2 E Protein in Human Monocytes

Antonia Ávila-Flores

Juan José Sánchez-Cabezón

Ane Ochoa-Echeverría

Ana I. Checa

Jorge Rosas-García

Mariana Téllez-Araiza

Sara Casado

Rosa Liébana

Teresa Santos-Mendoza

and

Isabel Mérida

Int. J. Mol. Sci. 2023, 24(16), 12793; https://doi.org/10.3390/ijms241612793 - 14 Aug 2023

Viewed by 483

Abstract

Proteins containing PDZ (post-synaptic density, PSD-95/disc large, Dlg/zonula occludens, ZO-1) domains assemble signaling complexes that orchestrate cell responses. Viral pathogens target host PDZ proteins by coding proteins containing a PDZ-binding motif (PBM). The presence of a PBM in the SARS-CoV-2 E protein contributes to the virus’s pathogenicity. SARS-CoV-2 infects epithelia, but also cells from the innate immune response, including monocytes and alveolar macrophages. This process is critical for alterations of the immune response that are related to the deaths caused by SARS-CoV-2. Identification of E-protein targets in immune cells might offer clues to understanding how SARS-CoV-2 alters the immune response. We analyzed the interactome of the SARS-CoV-2 E protein in human monocytes. The E protein was expressed fused to a GFP tag at the amino terminal in THP-1 monocytes, and associated proteins were identified using a proteomic approach. The E-protein interactome provided 372 partners; only 8 of these harbored PDZ domains, including the cell polarity protein ZO-2, the chemoattractant IL-16, and syntenin. We addressed the expression and localization of the identified PDZ proteins along the differentiation of primary and THP-1 monocytes towards macrophages and dendritic cells. Our data highlight the importance of identifying the functions of PDZ proteins in the maintenance of immune fitness and the viral alteration of inflammatory response. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

No Evidence for Myocarditis or Other Organ Affection by Induction of an Immune Response against Critical SARS-CoV-2 Protein Epitopes in a Mouse Model Susceptible for Autoimmunity

Rebecca Maria Ignatz

Vanessa Antje Zirkenbach

and

Int. J. Mol. Sci. 2023, 24(12), 9873; https://doi.org/10.3390/ijms24129873 - 08 Jun 2023

Viewed by 716

Abstract

After Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) developed into a global pandemic, not only the infection itself but also several immune-mediated side effects led to additional consequences. Immune reactions such as epitope spreading and cross-reactivity may also play a role in the development of long-COVID, although the exact pathomechanisms have not yet been elucidated. Infection with SARS-CoV-2 can not only cause direct damage to the lungs but can also lead to secondary indirect organ damage (e.g., myocardial involvement), which is often associated with high mortality. To investigate whether an immune reaction against the viral peptides can lead to organ affection, a mouse strain known to be susceptible to the development of autoimmune diseases, such as experimental autoimmune myocarditis (EAM), was used. First, the mice were immunized with single or pooled peptide sequences of the virus’s spike (SP), membrane (MP), nucleocapsid (NP), and envelope protein (EP), then the heart and other organs such as the liver, kidney, lung, intestine, and muscle were examined for signs of inflammation or other damage. Our results showed no significant inflammation or signs of pathology in any of these organs as a result of the immunization with these different viral protein sequences. In summary, immunization with different SARS-CoV-2 spike-, membrane-, nucleocapsid-, and envelope-protein peptides does not significantly affect the heart or other organ systems adversely, even when using a highly susceptible mouse strain for experimental autoimmune diseases. This suggests that inducing an immune reaction against these peptides of the SARS-CoV-2 virus alone is not sufficient to cause inflammation and/or dysfunction of the myocardium or other studied organs. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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Open AccessArticle

SARS-CoV-2 Positive Serology and Islet Autoantibodies in Newly Diagnosed Pediatric Cases of Type 1 Diabetes Mellitus: A Single-Center Cohort Study

Anca Andreea Boboc

Carmen Nicoleta Novac

Alexandra Gabriela Marin

Mara Ioana Ieșanu

Cristina Plătică

Teodora Buzescu

Maria Teodora Coșoreanu

and

Felicia Galoș

Int. J. Mol. Sci. 2023, 24(10), 8885; https://doi.org/10.3390/ijms24108885 - 17 May 2023

Viewed by 751

Abstract

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, although presenting less severe forms of the disease in children, seems to play a role in the development of other conditions, including type 1 diabetes mellitus (T1DM). After the beginning of the pandemic, an increase in the number of T1DM pediatric patients was observed in several countries, thus leading to many questions about the complex relationship between SARS-CoV-2 infection and T1DM. Our study aimed to highlight possible correlations between SARS-CoV-2 serology and T1DM onset. Therefore, we performed an observational retrospective cohort study that included 158 children diagnosed with T1DM in the period April 2021–April 2022. The presence or absence of SARS-CoV-2 and T1DM-specific antibodies and other laboratory findings were assessed. In the group of patients with positive SARS-CoV-2 serology, a higher percentage had detectable IA-2A antibodies, more children were positive for all three islet autoantibodies determined (GADA, ICA, and IA-2A), and a higher mean HbA1c value was found. No difference existed between the two groups regarding DKA presence and severity. A lower C-peptide level was found in the patients presenting diabetic ketoacidosis (DKA) at T1DM onset. When compared to a group of patients diagnosed before the pandemic, an increased incidence of both DKA and severe DKA, as well as a higher age at diagnosis and higher levels of HbA1c were present in our study group. These findings have important implications for the ongoing monitoring and management of children with T1DM after the COVID-19 pandemic and highlight the need for further research to better understand the complex relationship between SARS-CoV-2 infection and T1DM. Full article

(This article belongs to the Special Issue Coronavirus Disease (COVID-19): Pathophysiology 4.0)

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