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Molecular Research and Insights into COVID-19: 2nd Edition

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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: closed (20 March 2025) | Viewed by 13135

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Dr. Manuela Rizzi

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Department of Health Sciences, Università del Piemonte Orientale (UPO), 28100 Novara, Italy
Interests: biomaterials; nanomaterials; regenerative medicine; vitamin D; extracellular matrix; inflammatory and rheumatic diseases; cardiovascular diseases; translational research
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Dr. Pier Paolo Sainaghi

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Internal Medicine Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
Interests: multiple sclerosis; autoimmune diseases; anti-rheumatic drug therapy; osteoporosis; hypovitaminosis D; chronic inflammatory demyelinating polyneuropathy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are now entering the fourth year of the COVID-19 pandemic, but the molecular mechanisms underlying SARS-CoV-2 infection, host immune response, and the rationale of therapeutic interventions are still not fully understood. Though the worldwide mass vaccination campaign reduced the risk of developing the most severe disease symptoms, the high tendency of SARS-CoV-2 to undergo genetic mutation is a barrier to the development of an effective therapy for COVID-19.

This Special Issue aims to publish papers on the most recent advances in molecular research on COVID-19, considering the pathogenic mechanisms as well as the host immune response and the molecular pathways activated by therapeutic interventions. For this Special Issue, we welcome the submission of both original articles and comprehensive reviews concerning the molecular pathways involved in COVID-19 pathophysiology and disease resolution.

Dr. Manuela Rizzi
Dr. Pier Paolo Sainaghi
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
COVID-19
prognostic and diagnostic biomarkers
molecular mechanism of infection
molecular pathophysiology
immune response

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Published Papers (9 papers)

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Research

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13 pages, 1705 KiB

Open AccessArticle

Prognostic Value of Erythrogram Indicators and C-Reactive Protein Levels in Predicting Outcomes of Patients with Coronavirus Disease 2019

by Maria Eduarda Andretta, Matias Nunes Frizzo, Pauline Brendler Goettems-Fiorin, Thiago Gomes Heck, Lucas Machado Sulzbacher, Maicon Machado Sulzbacher, Mirna Stela Ludwig, Gaia Favero, Rita Rezzani and Vitor Antunes de Oliveira

Int. J. Mol. Sci. 2025, 26(9), 4135; https://doi.org/10.3390/ijms26094135 - 27 Apr 2025

Viewed by 263

Abstract

Coronavirus disease 2019 (COVID-19) has posed unprecedented challenges to global public health, highlighting the importance of prognostic biomarkers in critically ill patients. The oxidative stress developed in COVID-19 is associated with impairment in various human organs and systems, and it is related to erythrocyte injury, leading to an elevation in red cell distribution width (RDW) and systemic inflammation. This study aims to assess the prognostic value of erythrogram indicators and C-reactive protein (CRP) levels in 91 intensive care unit-admitted COVID-19 patients, categorized into survivor patients (discharge group) and non-survivor patients (death group). The results were presented using descriptive statistics and the Mann–Whitney test. The most severe cases of respiratory failure in which the patients did not survive showed higher red cell distribution width (RDW) and lower values of red blood cell count, hemoglobin, and hematocrit. RDW may be an important indicator of mortality, as demonstrated by the receiver operating characteristic (ROC) curve analysis. Furthermore, this increase in RDW is correlated with elevated CRP levels, another important clinical outcome for these patients. In conclusion, elevated RDW and CRP levels at admission may be reliable predictors of unfavorable outcomes, emphasizing the utility of these indicators in clinical assessments of COVID-19 patients. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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17 pages, 4671 KiB

Open AccessArticle

A Fraction of Escherichia coli Bacteria Induces an Increase in the Secretion of Extracellular Vesicle Polydispersity in Macrophages: Possible Involvement of Secreted EVs in the Diagnosis of COVID-19 with Bacterial Coinfections

by Francisco Sierra-López, Vanessa Iglesias-Vazquez, Lidia Baylon-Pacheco, Emmanuel Ríos-Castro, Juan Carlos Osorio-Trujillo, Anel Lagunes-Guillén, Bibiana Chávez-Munguía, Susana Bernardo Hernández, Gustavo Acosta-Altamirano, Patricia Talamás-Rohana, José Luis Rosales-Encina and Mónica Sierra-Martínez

Int. J. Mol. Sci. 2025, 26(8), 3741; https://doi.org/10.3390/ijms26083741 - 16 Apr 2025

Viewed by 858

Abstract

Extracellular vesicles (EVs) can transport molecules that combat viruses, such as RNA against SARS-CoV-2. Bacterial coinfections can help establish certain viruses and worsen diseases. Thus, we designed a model to induce the secretion of polydisperse EVs shown with SARS-CoV-2 and bacterial coinfection using macrophages and E. coli fractions as in vitro inducers. We obtained short and large macrophage EVs. The E. coli fraction was designated as SDS-soluble bacterial membrane fraction and its associated proteins (SDS-SBMF). The proteins were identified using a mass spectrometer. SDS-SBMF contained mainly OmpF, OmpA, OmpC, OmpX, and lpp. The SDS-SBMF macrophages induced the secretion of polydisperse EVs at 30 min, reaching optimal secretion at 120 min, as observed via scanning electron microscopy and confocal microscopy. Macrophage EVs contained mainly HSP7C, actin, apolipoprotein, GAPDH, annexin A5, PKM, moesin, and cofilin. We observed an increase in EVs in the bloodstream of patients with SARS-CoV-2 and bacterial coinfection, in addition to the presence of SARS-CoV-2 genes (E, ORF) in EVs. This in vitro method for inducing EVs has the potential to be used to obtain larger samples for study and for the detection of diagnostic and prognostic biomarkers of different diseases. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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13 pages, 1690 KiB

Open AccessArticle

Higher Serum Monolaurin Is Associated with a Lower Risk of COVID-19: Results from a Prospective Observational Cohort Study

by Daniele Sola, Stelvio Tonello, Giuseppe Francesco Casciaro, Eleonora Rizzi, Davide D’Onghia, Mario Pirisi, Francesca Caldera, Manuela Rizzi, Donato Colangelo, Nicoletta Del Duca, Massimo Scacchi, Elia Amede, Denise Marradi, Elettra Barberis, Annalisa Chiocchetti, Marcello Manfredi and Pier Paolo Sainaghi

Int. J. Mol. Sci. 2025, 26(6), 2452; https://doi.org/10.3390/ijms26062452 - 10 Mar 2025

Cited by 1 | Viewed by 1274

Abstract

The COVID-19 pandemic has stimulated the search for effective preventive and therapeutic agents. In recent years, many studies have considered the effects of different nutrients. This study aimed to investigate the association between serum monolaurin levels and the risk of developing COVID-19 among healthcare workers. In this prospective observational cohort study, 2712 healthcare workers from the University Hospital “Maggiore della Carità” in Novara, Italy were enrolled. Participants underwent blood sampling and were followed up for six months to evaluate the protective role of serum monolaurin against COVID-19 infection. Monolaurin levels were quantified using targeted metabolomic analysis. The study cohort consisted of 1000 individuals with a mean age of 46.4 years, predominantly female. Higher serum monolaurin concentrations were significantly associated with a lower risk of SARS-CoV-2 infection at both 3- and 6-month follow-ups. The optimal cut-off value for serum monolaurin, which provides protective efficacy, was identified as 0.45 µg/mL. Higher serum monolaurin levels appear to be associated with a reduced risk of COVID-19, suggesting its potential as a protective dietary supplement against SARS-CoV-2 infection. This study contributes to the growing body of evidence supporting the role of dietary factors in the management and prevention of infectious diseases and highlights the potential of targeted metabolomics in identifying prophylactic biomarkers. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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17 pages, 1233 KiB

Open AccessArticle

Genetic Variants in Genes Related to Lung Function and Interstitial Lung Diseases Are Associated with Worse Outcomes in Severe COVID-19 and Lung Performance in the Post-COVID-19 Condition

by Ingrid Fricke-Galindo, Salvador García-Carmona, Brandon Bautista-Becerril, Gloria Pérez-Rubio, Ivette Buendia-Roldan, Leslie Chávez-Galán, Karol J. Nava-Quiroz, Jesús Alanis-Ponce, Juan M. Reséndiz-Hernández, Esther Blanco-Aguilar, Jessica I. Erives-Sedano, Yashohara Méndez-Velasco, Grecia E. Osuna-Espinoza, Fidel Salvador-Hernández, Rubén Segura-Castañeda, Uriel N. Solano-Candia and Ramcés Falfán-Valencia

Int. J. Mol. Sci. 2025, 26(5), 2046; https://doi.org/10.3390/ijms26052046 - 26 Feb 2025

Viewed by 963

Abstract

Genetic variants related to susceptibility to chronic respiratory conditions such as interstitial lung disease (ILD) could share critical pathways in the pathogenesis of COVID-19 and be implicated in COVID-19 outcomes and post-COVID-19. We aimed to identify the participation of genetic variants in lung function and ILD genes in severe COVID-19 outcomes and post-COVID-19 condition. We studied 936 hospitalized patients with COVID-19. The requirement of invasive mechanical ventilation (IMV) and the acute respiratory distress syndrome (ARDS) classification were considered. The mortality was assessed as the in-hospital death. The post-COVID-19 group included 102 patients evaluated for pulmonary function tests four times during the year after discharge. Five variants (FAM13A rs2609255, DSP rs2076295, TOLLIP rs111521887, TERT rs2736100, and THSD4 rs872471) were genotyped using TaqMan assays. A multifactor dimensionality reduction method (MDR) was performed for epistasis estimation. The TERT rs2736100 and THSD4 rs872471 variants were associated with differential risk for ARDS severity (moderate vs. severe, CC + CA, p = 0.044, OR = 0.66, 95% CI = 0.44–0.99; and GG p = 0.034, OR = 2.22, 95% CI = 1.04–4.72, respectively). These variants and FAM13A rs2609255 were also related to pulmonary function post-COVID-19. The MDR analysis showed differential epistasis and correlation of the genetic variants included in this study. The well-known variants in recognized genes related to pulmonary function worsening and interstitial disorders are related to the severity and mortality of COVID-19 and lung performance in the post-COVID-19 condition. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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17 pages, 4537 KiB

Open AccessArticle

Detection of Double-Stranded RNA Intermediates During SARS-CoV-2 Infections of Syrian Golden Hamsters with Monoclonal Antibodies and Its Implications for Histopathological Evaluation of In Vivo Studies

by Georg Beythien, Madeleine de le Roi, Stephanie Stanelle-Bertram, Federico Armando, Laura Heydemann, Malgorzata Rosiak, Svenja Becker, Mart M. Lamers, Franziska K. Kaiser, Bart L. Haagmans, Malgorzata Ciurkiewicz, Gülşah Gabriel, Albert D. M. E. Osterhaus and Wolfgang Baumgärtner

Int. J. Mol. Sci. 2024, 25(21), 11425; https://doi.org/10.3390/ijms252111425 - 24 Oct 2024

Cited by 1 | Viewed by 1290

Abstract

The SARS-CoV-2 pandemic has highlighted the challenges posed by the emergence and rapid global spread of previously unknown viruses. Early investigations on the pathogenesis of newly identified viruses are often hampered by a lack of appropriate sample material and conventional detection methods. In this study, viral replication within the lungs of SARS-CoV-2-infected Syrian golden hamsters was assessed by immunolabeling dsRNA intermediates with three different monoclonal antibodies in formalin-fixed, paraffin-embedded tissue samples. The presence of dsRNA was compared to viral antigen levels, viral titers, and genomic RNA replicates using three different variants of concern and an ancestral virus strain at a single time point and during the course of infection with an ancestral variant, and then validated using fluorescent 2-plex in situ hybridization. The results indicate that the detection of viral infection using anti-dsRNA antibodies is restricted to an early phase of infection with high viral replication activity. Additionally, the combined detection of dsRNA intermediates and viral antigens may help to bridge the interpretation gaps between viral antigen levels and viral titers at a single time point. Further testing in other viral infections or species is needed to assess the potential of dsRNA as an early marker for viral infections. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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21 pages, 7884 KiB

Open AccessArticle

SARS-CoV-2-Specific T-Cell as a Potent Therapeutic Strategy against Immune Evasion of Emerging COVID-19 Variants

by Keon-Il Im, Nayoun Kim, Junseok Lee, Ui-Hyeon Oh, Hye-Won Lee, Dong-Gun Lee, Gi-June Min, Raeseok Lee, Jinah Lee, Seungtaek Kim and Seok-Goo Cho

Int. J. Mol. Sci. 2024, 25(19), 10512; https://doi.org/10.3390/ijms251910512 - 29 Sep 2024

Viewed by 2274

Abstract

Despite advances in vaccination and therapies for coronavirus disease, challenges remain due to reduced antibody longevity and the emergence of virulent variants like Omicron (BA.1) and its subvariants (BA.1.1, BA.2, BA.3, and BA.5). This study explored the potential of adoptive immunotherapy and harnessing the protective abilities using virus-specific T cells (VSTs). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) VSTs were generated by stimulating donor-derived peripheral blood mononuclear cells with spike, nucleocapsid, and membrane protein peptide mixtures. Phenotypic characterization, including T-cell receptor (TCR) vβ and pentamer analyses, was performed on the ex vivo-expanded cells. We infected human leukocyte antigen (HLA)-partially matched human Calu-3 cells with various authentic SARS-CoV-2 strains in a Biosafety Level 3 facility and co-cultured them with VSTs. VSTs exhibited a diverse TCR vβ repertoire, confirming their ability to target a broad range of SARS-CoV-2 antigens from both the ancestral and mutant strains, including Omicron BA.1 and BA.5. These ex vivo-expanded cells exhibited robust cytotoxicity and low alloreactivity against HLA-partially matched SARS-CoV-2-infected cells. Their cytotoxic effects were consistent across variants, targeting conserved spike and nucleocapsid epitopes. Our findings suggest that third-party partial HLA-matching VSTs could counter immune-escape mechanisms posed by emerging variants of concern. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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13 pages, 1730 KiB

Open AccessArticle

Calprotectin, a Promising Serological Biomarker for the Early Diagnosis of Superinfections with Multidrug-Resistant Bacteria in Patients with COVID-19

by Dennis Keller, Patricia Mester, Ulrich Räth, Sabrina Krautbauer, Stephan Schmid, Verena Greifenberg, Martina Müller, Claudia Kunst, Christa Buechler and Vlad Pavel

Int. J. Mol. Sci. 2024, 25(17), 9294; https://doi.org/10.3390/ijms25179294 - 27 Aug 2024

Cited by 1 | Viewed by 1515

Abstract

Bacterial and fungal superinfections are common in COVID-19, and early diagnosis can enable timely intervention. Serum calprotectin levels increase with bacterial, fungal, and viral infections. This study evaluated serum calprotectin as a diagnostic and prognostic tool for microbial superinfections in COVID-19. Serum samples from adult patients with moderate and severe COVID-19 were collected during hospitalization from 2020 to 2024. Calprotectin levels were measured using an enzyme-linked immunosorbent assay in 63 patients with moderate COVID-19, 60 patients with severe COVID-19, and 34 healthy individuals. Calprotectin serum levels were elevated in patients with moderate COVID-19 compared with controls, and these levels were further increased in the severe cases. Patients with severe COVID-19 and vancomycin-resistant enterococci (VRE) bacteremia had elevated calprotectin levels, but their C-reactive protein and procalcitonin levels were not increased. Fungal superinfections and herpes simplex virus reactivation did not change the calprotectin levels. A calprotectin concentration of 31.29 µg/mL can be used to diagnose VRE bloodstream infection with 60% sensitivity and 96% specificity. These data suggest that serum calprotectin may be a promising biomarker for the early detection of VRE bloodstream infections in patients with COVID-19. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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14 pages, 2179 KiB

Open AccessArticle

Genetic, Clinical, Epidemiological, and Immunological Profiling of IgG Response Duration after SARS-CoV-2 Infection

by Flávia Póvoa da Costa, Kevin Matheus Lima de Sarges, Rosilene da Silva, Erika Ferreira dos Santos, Matheus Holanda do Nascimento, Alice Maciel Rodrigues, Marcos Henrique Damasceno Cantanhede, Fabíola Brasil Barbosa Rodrigues, Maria de Nazaré do Socorro de Almeida Viana, Mauro de Meira Leite, Camille Ferreira de Oliveira, Pablo Fabiano Moura das Neves, Gabriel dos Santos Pereira Neto, Mioni Thieli Figueiredo Magalhães de Brito, Andréa Luciana Soares da Silva, Daniele Freitas Henriques, Juarez Antônio Simões Quaresma, Luiz Fábio Magno Falcão, Maria Alice Freitas Queiroz, Izaura Maria Vieira Cayres Vallinoto, Antonio Carlos Rosário Vallinoto, Giselle Maria Rachid Viana and Eduardo José Melo dos Santos Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(16), 8740; https://doi.org/10.3390/ijms25168740 - 10 Aug 2024

Cited by 1 | Viewed by 1765

Abstract

The IgG response against SARS-CoV-2 infection can persist for over six months (long response; LR). However, among 30% of those infected, the duration can be as short as three months or less (short response; SR). The present study assembled serological data on the anti-SARS-CoV-2 IgG response duration of two previous studies and integrated these results with the plasmatic cytokine levels and genetic profile of 10 immune-relevant SNPs that were also previously published, along with the plasmatic total IgG, IgA, and IgM levels, allowing for the genetic, clinical, immunological, and epidemiological aspects of the post-COVID-19 IgG response duration to be understood. The SR was associated with previous mild acute COVID-19 and with an SNP (rs2228145) in IL6R related to low gene expression. Additionally, among the SR subgroup, no statistically significant Spearman correlations were observed between the plasma levels of IL-17A and the Th17 regulatory cytokines IFN-γ (rs = 0.2399; p = 0.1043), IL-4 (rs = 0.0273; p = 0.8554), and IL-2 (rs = 0.2204; p = 0.1365), while among the LR subgroup, weaker but statistically significant Spearman correlations were observed between the plasma levels of IL-17A and IFN-γ (rs = 0.3873; p = 0.0016), IL-4 (rs = 0.2671; p = 0.0328), and IL-2 (rs = 0.3959; p = 0.0012). These results suggest that the Th17 response mediated by the IL-6 pathway has a role in the prolonged IgG response to SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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Open AccessReview

Cholesterol and Cholesterol-Lowering Medications in COVID-19—An Unresolved Matter

by Thomas Grewal, Mai Khanh Linh Nguyen and Christa Buechler

Int. J. Mol. Sci. 2024, 25(19), 10489; https://doi.org/10.3390/ijms251910489 - 29 Sep 2024

Viewed by 1959

Abstract

Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 2019 (COVID-19), a disease with very heterogeneous symptoms. Dyslipidaemia is prevalent in at least 20% of Europeans, and dyslipidaemia before SARS-CoV-2 infection increases the risk for severe COVID-19 and mortality by 139%. Many reports described reduced serum cholesterol levels in virus-infected patients, in particular in those with severe disease. The liver is the major organ for lipid homeostasis and hepatic dysfunction appears to occur in one in five patients infected with SARS-CoV-2. Thus, SARS-CoV-2 infection, COVID-19 disease severity and liver injury may be related to impaired cholesterol homeostasis. These observations prompted efforts to assess the therapeutic opportunities of cholesterol-lowering medications to reduce COVID-19 severity. The majority of studies implicate statins to have beneficial effects on disease severity and outcome in COVID-19. Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have also shown potential to protect against COVID-19. This review describes the relationship between systemic cholesterol levels, liver injury and COVID-19 disease severity. The potential effects of statins and PCSK9 in COVID-19 are summarised. Finally, the relationship between cholesterol and lung function, the first organ to be affected by SARS-CoV-2, is described. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: 2nd Edition)

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