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Molecular Research and Insights into COVID-19: Third 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 2026) | Viewed by 64752

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Special Issue Editors

Dr. Manuela Rizzi

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Guest Editor

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
Special Issues, Collections and Topics in MDPI journals

Dr. Pier Paolo Sainaghi

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Guest Editor

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 fifth year of the COVID-19 pandemic, but the molecular mechanisms underlying SARS-CoV-2 infections, host immune responses, and the rationale of therapeutic interventions are still not fully understood. Though the worldwide mass vaccination campaign that was carried out reduced the risk of people developing severe disease symptoms, the frequency with which SARS-CoV-2 undergoes 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 the molecular research on COVID-19 in terms of its pathogenic mechanisms, the host’s immune response, and the molecular pathways activated by therapeutic interventions. This Special Issue welcomes the submission of both original articles and comprehensive reviews concerning the molecular pathways involved in COVID-19’s pathophysiology and resolution.

Dr. Manuela Rizzi
Dr. Pier Paolo Sainaghi
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 250 words) can be sent to the Editorial Office for assessment.

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

SARS-CoV-2
COVID-19
prognostic and diagnostic biomarkers
molecular mechanism of infection
molecular pathophysiology
immune response

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Published Papers (8 papers)

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Research

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11 pages, 367 KB

Open AccessArticle

Higher 25(OH)D Levels at Admission Predict a Favorable Disease Evolution in Moderate-to-Severe COVID-19 Patients

by Manuela Rizzi, Federica Vincenzi, Stelvio Tonello, Eleonora Rizzi, Giuseppe Francesco Casciaro, Erica Matino, Martina Costanzo, Erika Zecca, Alessandro Croce, Anita Pedrinelli, Veronica Vassia, Raffaella Landi, Iris Zeqaj, Francesca Boccafoschi, Paolo Amedeo Tillio, Roberta Rolla, Umberto Dianzani, Luigi Mario Castello, Mario Pirisi, Donato Colangelo and Pier Paolo Sainaghi Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(8), 3541; https://doi.org/10.3390/ijms27083541 - 16 Apr 2026

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Abstract

Research into effective predictive markers and therapeutic interventions for COVID-19 remains of considerable interest. Vitamin D may be relevant, especially in frail populations in whom deficiency is more prevalent. In this prospective observational cohort study, 139 patients with moderate-to-severe COVID-19 who were hospitalized during the third wave of the pandemic in Italy were enrolled. Plasma vitamin D concentrations (both 25-hydroxyvitamin D-25(OH)D and 1,25-dihydroxyvitamin D-1,25(OH)₂D) together with parathyroid hormone levels were measured using a chemiluminescent assay validated for clinical use on automated laboratory platforms. Plasma vitamin D levels were below the sufficiency threshold. Notably, 25(OH)D concentrations were significantly lower in patients who experienced a negative outcome (11.10 [8.80–16.20] vs. 15.25 [9.90–24.80] ng/mL, p = 0.0450) and significantly higher in patients with rapid clinical recovery (15.25 [10.70–24.80] vs. 13.30 [7.47–19.60] ng/mL, p = 0.0446) compared with all other patients. Through multivariable logistic regression analysis, higher 25(OH)D levels at the time of hospitalization were confirmed as an independent predictor of favorable outcome. A plasma 25(OH)D concentration above 11.10 ng/mL predicted favorable disease resolution, with a positive likelihood ratio of 1.40 (IQR: 1.05–1.87). In conclusion, our findings support plasma vitamin D levels as an independent predictor of clinical outcomes in patients hospitalized with COVID-19 pneumonia. Full article

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

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13 pages, 496 KB

Open AccessArticle

The Functional OAS1 rs10774671A>G Variant Is Associated with COVID-19 Susceptibility in Mexican Patients

by Isela Montúfar-Robles, Blanca M. Zapotitla-Román, Gilberto Vargas-Alarcón, José Manuel Fragoso, Silvia Jiménez-Morales, Jorge Flavio Mendoza-Rincón, Alberto Cedro-Tanda, Rosa Elda Barbosa-Cobos, Gustavo Rojas-Velazco and Julian Ramírez-Bello

Int. J. Mol. Sci. 2026, 27(7), 2965; https://doi.org/10.3390/ijms27072965 - 25 Mar 2026

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Abstract

OAS1 (2′–5′-oligoadenylate synthetase 1) and OAS3 have been identified through a genome-wide association study as major loci associated with COVID-19. The rs10774671A>G variant affects alternative splicing and generates two distinct mRNA and protein isoforms. The A allele produces the shorter p42 isoform, which has been associated with increased susceptibility, greater disease severity, and higher mortality from COVID-19, whereas the G allele produces the longer p46 isoform, which has been associated with a protective effect. In addition, the functional variants OAS1 rs4767027C>T, OAS1 rs1131454A>G, and OAS3 rs10735079A>G have also been associated with susceptibility to and/or severity of COVID-19. Therefore, the aim of this study was to determine whether four variants in the OAS1 and OAS3 genes are associated with susceptibility to COVID-19 and with the clinical signs and symptoms of the disease. We included 305 patients with COVID-19 and 288 healthy controls. We genotyped the OAS1 rs10774671A>G, rs4767027C>T, rs1131454A>G, and OAS3 rs10735079A>G variants using TaqMan^® assays. The association between OAS1 and OAS3 variants and disease susceptibility or severity was assessed using binary logistic regression adjusted for age and sex. The Hardy–Weinberg equilibrium was evaluated using SNPStats, whereas haplotypes and linkage disequilibrium were analyzed with Haploview. Statistical power was calculated using Quanto. Logistic regression analysis adjusted for age and sex revealed an association between the OAS1 rs10774671A risk allele and susceptibility to COVID-19 (G vs. A: OR = 1.9, p = 0.007). In contrast, no associations with COVID-19 susceptibility were observed for the rs4767027C>T, rs1131454A>G, or rs10735079A>G variants. However, the rs1131454A>G and rs10735079A>G variants showed associations with sore throat. Overall, our findings suggest that OAS1 acts as a susceptibility factor for COVID-19 and the rs1131454A>G and rs10735079A>G SNVs are associated with sore throat in the Mexican population. Full article

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

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17 pages, 561 KB

Open AccessArticle

Circulating Liver-Enriched miR-122 in COVID-19 Patients: A Longitudinal Real-Life Study

by Nicoleta Mihai, Cătălin Tilișcan, Iulia Virginia Iancu, Oana-Alexandra Ganea, Aida-Isabela Adamescu, Ștefan Sorin Aramă, Andreea Letiția Arsene, Simona-Maria Ruță and Victoria Aramă

Int. J. Mol. Sci. 2026, 27(5), 2288; https://doi.org/10.3390/ijms27052288 - 28 Feb 2026

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Abstract

Abnormal liver function tests are frequently reported in patients with COVID-19. This study aimed to identify potential treatment-associated hepatocellular injury in COVID-19 patients by dynamically assessing circulating miR-122, a biomarker with high hepatic specificity and sensitivity. An exploratory approach was additionally used, given the limited evidence regarding factors influencing miR-122 expression in this setting. We performed a prospective cohort study including 96 adult participants enrolled at a tertiary hospital in Bucharest, Romania, between March 2022 and July 2023: 78 COVID-19 patients (57 with baseline and follow-up miR-122 assessment after 5 days of treatment and 21 with a single measurement) and 18 non-COVID-19 participants included for comparison. Plasma miR-122 levels were measured using quantitative polymerase chain reaction, normalized to U6 small nuclear RNA, and expressed as log₁₀(2^−ΔCt). No associations were observed between miR-122 expression and remdesivir administered for standard treatment durations (3–5 days) or other COVID-19–specific therapies. However, a duration-dependent relationship with remdesivir cannot be excluded. Moreover, therapeutic paracetamol use prior to presentation was positively associated with miR-122 expression at follow-up and remained significant after adjustment. Additionally, bivariate analyses revealed inverse correlations between baseline miR-122 and inflammatory biomarkers, with multivariable analysis showing an independent positive association with lymphocyte count. Full article

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

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14 pages, 310 KB

Open AccessArticle

Cytokine Dynamics in Severe COVID-19 vs. Influenza A Elderly Patients: A Prospective Comparative Study

by Mihai Aronel Rus, Adina Huțanu, Daniel Corneliu Leucuța, Violeta Tincuța Briciu, Monica Iuliana Muntean, Angela Ionică and Mihaela Sorina Lupșe

Int. J. Mol. Sci. 2026, 27(3), 1463; https://doi.org/10.3390/ijms27031463 - 1 Feb 2026

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Abstract

COVID-19 and influenza A (FluA) cause severe respiratory infections in elderly patients, with cytokine dysregulation playing a central role. Direct comparative data in older adults remains limited. We aimed to characterize cytokine dynamics and their prognostic value in hospitalized elderly patients with COVID-19 vs. FluA. We performed a prospective cohort study including adults ≥ 60 years hospitalized with respiratory failure due to COVID-19 or FluA between March 2023 and March 2024. Serum IL-1β, IL-6, IL-10, IL-17A, IL-34, MCP-1, and CXCL10 were measured on Day 1 and Day 5 of hospitalization using Luminex^®. Cytokines and associations with non-invasive ventilation (NIV) were assessed by ROC analysis and multivariate logistic regression. 83 patients were included (39 COVID-19, median age 79 years; 44 FluA, median 77 years). At Day 1, COVID-19 exhibited significantly higher IL-6, IL-10, and CXCL10; FluA showed an attenuated cytokine response. At Day 5, cytokines declined in both groups. Baseline IL-6 independently predicted NIV (adjusted OR 3.02), whereas higher MCP-1 was associated with reduced NIV requirement. Early cytokine differences between COVID-19 and FluA are evident in elderly patients, but values converged by Day 5. IL-6 remains an informative early predictor of respiratory deterioration; MCP-1 may reflect a regulated innate response. Full article

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

15 pages, 1237 KB

Open AccessArticle

Impaired Peripheral Blood Mononuclear Cell (PBMC) Mitochondrial Respiration Is Associated with Mortality and Long COVID Syndrome Severity in COVID-19 Patients

by Anne-Laure Charles, Léa Debrut, Walid Oulehri, Véronique Vincent, Héloise Delagreverie, Pauline Asael, Marianne Riou, Margherita Giannini, Alain Meyer and Bernard Geny

Int. J. Mol. Sci. 2025, 26(21), 10377; https://doi.org/10.3390/ijms262110377 - 24 Oct 2025

Cited by 3 | Viewed by 1694

Abstract

COVID-19 is a public health issue with a significant mortality rate and potential long-lasting disabling symptoms responsible for the long-COVID syndrome. Mitochondrial dysfunction is a key mechanism but whether peripheral blood mononuclear cell (PBMC) mitochondrial respiration changes might be associated with mortality and/or occurrence and severity of long-COVID syndrome remains to be investigated. We determined mitochondrial respiratory chain oxygen consumption in twenty COVID-19 patients hospitalized in the intensive care unit and analyzed their remaining symptoms at the third year after hospital release. PBMC mitochondrial respiration was decreased in COVID-19 patients compared to the control group (14.13 ± 2.35 vs. 6.21 ± 0.88 pmol/s/10⁶ cell, p = 0.0006 for the OXPHOS state by CII). Considering COVID severity, such a decrease was greater in long-COVID patients and in patients who deceased (4.91 ± 0.75, p = 0.008 and 4.94 ± 1.11 pmol/s/10⁶ cell, p = 0.04, respectively). PBMC markers of inflammation also increased with the severity of COVID (1.0 ± 0.08 vs. 14.45 ± 2.07, p = 0.02 for ISG15 in patients who died) and ISG15 negatively correlated with PBMC mitochondrial respiration (r = −0.67, p = 0.02 for CII). In conclusion, this study shows that the greater the impairment in PBMC mitochondrial respiration in patients hospitalized in the intensive care unit for COVID-19, the greater the mortality rate and the more severe the long-COVID symptoms—three years after hospital discharge. Further, PBMC markers of inflammation also increased with the severity of COVID and ISG15 negatively correlated with PBMC mitochondrial respiration. These results support that PBMC mitochondrial respiration might be a biomarker of COVID severity and further studies investigating whether modulation of PBMC mitochondrial respiration might improve COVID-19 patients’ prognosis. Full article

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

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13 pages, 1074 KB

Open AccessArticle

Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall

by Sara Polo-Alonso, Álvaro Hernáez, Irene R. Dégano, Ruth Martí-Lluch, Mel·lina Pinsach-Abuin, Roberto Elosua, Isaac Subirana, Marta Puigmulé, Alexandra Pérez, Raquel Cruz, Silvia Diz-de Almeida, Eulàlia Puigdecanet, Elisabet Selga, Xavier Nogues, Joan Ramon Masclans, Roberto Güerri-Fernández, Héctor Cubero-Gallego, Helena Tizon-Marcos, Beatriz Vaquerizo, Ramon Brugada, Rafel Ramos, Anna Camps-Vilaró and Jaume Marrugat Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(18), 9252; https://doi.org/10.3390/ijms26189252 - 22 Sep 2025

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Abstract

We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition. Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses. When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men. Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID. Full article

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

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Review

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40 pages, 1277 KB

Open AccessReview

Do Long COVID and COVID Vaccine Side Effects Share Pathophysiological Picture and Biochemical Pathways?

by Jean-François Lesgards, Dominique Cerdan and Christian Perronne

Int. J. Mol. Sci. 2025, 26(16), 7879; https://doi.org/10.3390/ijms26167879 - 15 Aug 2025

Cited by 9 | Viewed by 56680 | Correction

Abstract

COVID affects around 400 million individuals today with a strong economic impact on the global economy. The list of long COVID symptoms is extremely broad because it is derived from neurological, cardiovascular, respiratory, immune, and renal dysfunctions and damages. We review here these pathophysiological manifestations and the predictors of this multi-organ pathology like the persistence of the virus, altered endothelial function, unrepaired tissue damage, immune dysregulation, and gut dysbiosis. We also discuss the similarities between long COVID and vaccine side effects together with possible common immuno-inflammatory pathways. Since the spike protein is present in SARS-CoV-2 (and its variants) but also produced by the COVID vaccines, its toxicity may also apply to all mRNA or adenoviral DNA vaccines as they are based on the production of a very similar spike protein to the virus. After COVID infection or vaccination, the spike protein can last for months in the body and may interact with ACE2 receptors and mannan-binding lectin (MBL)/mannan-binding lectin serine protease 2 (MASP-2), which are present almost everywhere in the organism. As a result, the spike protein may be able to trigger inflammation in a lot of organs and systems similar to COVID infection. We suggest that three immuno-inflammatory pathways are particularly key and responsible for long COVID and COVID vaccine side effects, as it has been shown for COVID, which may explain in large part their strong similarities: the renin–angiotensin–aldosterone system (RAAS), the kininogen–kinin–kallikrein system (KKS), and the lectin complement pathway. We propose that therapeutic studies should focus on these pathways to propose better cures for both long COVID as well as for COVID vaccine side effects. Full article

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

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