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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 10757

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Special Issue Editors

Prof. Dr. Pavel Avdonin

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Guest Editor

NK Koltsov Institute of Developmental Biology RAS, Moscow 119334, Russia
Interests: COVID-19; signaling; endothelial cells

Dr. Evgeny E. Bezsonov

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Guest Editor

1. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
2. Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Center of Surgery”, 117418 Moscow, Russia
3. Department of Biology and General Genetics, I.M. Sechenov First Moscow State Medical University (Sechenov University), 105043 Moscow, Russia
Interests: atherosclerosis; mitophagy; atherogenicity; atherosclerosis; autoantibodies; inflammation; innate immunity; amyloid
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Special Issue Information

Dear Colleagues,

More than two years have passed since the start of the COVID-19 pandemic. During this time, thanks to the creation of effective vaccines, the development of new treatment protocols, the emergence of mass immunity, and the evolution of the virus towards less dangerous variants, the severity of coronavirus infection and mortality have decreased significantly; however, as a result of the mutations of SARS-CoV-2, the effectiveness of existing vaccines is reduced and the use of drugs that affect links of the pathological process, such as the interaction of the viral part with receptors and its reproduction in cells, is becoming more and more relevant. In this regard it is necessary to conduct research on the creation of new targeted drugs that inactivate SARS-CoV-2, as well as on the use of already-known drugs (drug repurposing) that can suppress the transport of viral particles into cells and neutralize the proinflammatory effect of coronavirus on the body. Despite progress in understanding the pathogenesis of COVID-19, it remains unclear as to what determines a predisposition to severe COVID-19. Further work is required to identify therapy indicators and genetic factors that can serve as prognostic signs of the development of a severe form of this disease. The canonical receptor for SARS-CoV-2 is ACE2; however, new data are emerging regarding the binding of SARS-CoV-2 onto the plasma membrane and the mechanisms of the penetration of viral particles into cells. The role of alternative SARS-CoV-2 receptors in the damage of organs and tissues of the body has not been fully elucidated. After the end of the peak phase of the pandemic, the focus in the fight against COVID-19 is shifting towards overcoming the consequences of this disease, which include musculoskeletal, digestive, and neurological symptoms, pediatric inflammatory multisystem syndrome, and disorders of the blood coagulation system as well as microcirculation. Therefore, it is important to discuss the pathogenetic mechanisms of post-COVID syndrome.

The purpose of this Special Issue is to discuss the issues raised, summarize the accumulated information, and present new data on the pathogenesis of COVID-19.

Prof. Dr. Pavel Avdonin
Dr. Evgeny E. Bezsonov
Guest Editors

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Keywords

COVID-19
pathogenesis
SARS-CoV-2 receptors
drug repurposing
drug targets and potential treatments
prevention of post-COVID syndrome
thrombosis
kidney disease

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Published Papers (7 papers)

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Research

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13 pages, 956 KiB

Open AccessArticle

Novel Clinical, Immunological, and Metabolic Features Associated with Persistent Post-Acute COVID-19 Syndrome

by Karina Santana-de Anda, Jiram Torres-Ruiz, Nancy R. Mejía-Domínguez, Beatriz Alcalá-Carmona, José L. Maravillas-Montero, José Carlos Páez-Franco, Ana Sofía Vargas-Castro, Jaquelin Lira-Luna, Emmanuel A. Camacho-Morán, Guillermo Juarez-Vega, David Meza-Sánchez, Carlos Núñez-Álvarez, Marina Rull-Gabayet and Diana Gómez-Martín

Int. J. Mol. Sci. 2024, 25(17), 9661; https://doi.org/10.3390/ijms25179661 - 6 Sep 2024

Viewed by 1164

Abstract

The coronavirus disease 2019 (COVID-19) survivors are frequently observed to present persistent symptoms constituting what has been called “post-acute COVID-19 syndrome” (PACS) or “long COVID-19”. Some clinical risk factors have been identified to be associated with PACS development; however, specific mechanisms responsible for PACS pathology remain unknown. This study investigates clinical, immunological, and metabolomic risk factors associated with post-acute COVID-19 syndrome (PACS) in 51 patients, assessed 7–19 months after acute infection. Among the participants, 62.7% were male and 37.2% were female, with an average age of 47.8 years. At the follow-up, 37.2% met the criteria for PACS, revealing significant differences in immunological and metabolomic profiles at the time of acute infection. Patients with PACS were characterized by elevated levels of mature low-density granulocytes (LDGs), interleukin-8 (IL-8), pyruvate, pseudouridine, and cystine. Baseline multivariate analysis showed increased pyruvate and decreased alpha tocopherol levels. At follow-up, there was a decrease in absolute B lymphocytes and an increase in non-classical monocytes and 3-hydroxyisovaleric acid levels. These findings suggest that specific immunological and metabolomic markers during acute infection can help identify patients at higher risk of developing persistent PACS. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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17 pages, 1902 KiB

Open AccessArticle

The Association of Genetic Markers Involved in Muscle Performance Responding to Lactate Levels during Physical Exercise Therapy by Nordic Walking in Patients with Long COVID Syndrome: A Nonrandomized Controlled Pilot Study

by Ángel Lizcano-Álvarez, David Varillas-Delgado, Roberto Cano-de-la-Cuerda, Carmen Jiménez-Antona, Alberto Melián-Ortiz, Alberto Molero-Sánchez and Sofía Laguarta-Val

Int. J. Mol. Sci. 2024, 25(15), 8305; https://doi.org/10.3390/ijms25158305 - 30 Jul 2024

Viewed by 945

Abstract

Several genetic markers have shown associations with muscle performance and physical abilities, but the response to exercise therapy is still unknown. The aim of this study was to test the response of patients with long COVID through an aerobic physical therapy strategy by the Nordic walking program and how several genetic polymorphisms involved in muscle performance influence physical capabilities. Using a nonrandomized controlled pilot study, 29 patients who previously suffered from COVID-19 (long COVID = 13, COVID-19 = 16) performed a Nordic walking exercise therapy program for 12 sessions. The influence of the ACE (rs4646994), ACTN3 (rs1815739), AMPD1 (rs17602729), CKM (rs8111989), and MLCK (rs2849757 and rs2700352) polymorphisms, genotyped by using single nucleotide primer extension (SNPE) in lactic acid concentration was established with a three-way ANOVA (group × genotype × sessions). For ACE polymorphism, the main effect was lactic acid (p = 0.019). In ACTN3 polymorphism, there were no main effects of lactic acid, group, or genotype. However, the posthoc analysis revealed that, in comparison with nonlong COVID, long COVID increased lactic acid concentrations in Nordic walking sessions in CT and TT genotypes (all p < 0.05). For AMPD1 polymorphism, there were main effects of lactic acid, group, or genotype and lactic acid × genotype or lactic acid × group × genotype interactions (all p < 0.05). The posthoc analysis revealed that, in comparison with nonlong COVID, long COVID increased lactic acid concentrations in Nordic walking sessions in CC and CT genotypes (all p < 0.05). Physical therapy strategy through Nordic walking enhanced physical capabilities during aerobic exercise in post-COVID19 patients with different genotypes in ACTN3 c.1729C>T and AMPD1 c.34C>T polymorphisms. These findings suggest that individuals who reported long COVID who presumably exercised less beforehand appeared to be less able to exercise, based on lactate levels, and the effect of aerobic physical exercise enhanced physical capabilities conditioned by several genetic markers in long COVID patients. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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12 pages, 2115 KiB

Open AccessArticle

Natural-Target-Mimicking Translocation-Based Fluorescent Sensor for Detection of SARS-CoV-2 PLpro Protease Activity and Virus Infection in Living Cells

by Elena L. Sokolinskaya, Olga N. Ivanova, Irina T. Fedyakina, Alexander V. Ivanov and Konstantin A. Lukyanov

Int. J. Mol. Sci. 2024, 25(12), 6635; https://doi.org/10.3390/ijms25126635 - 17 Jun 2024

Viewed by 1290

Abstract

Papain-like protease PLpro, a domain within a large polyfunctional protein, nsp3, plays key roles in the life cycle of SARS-CoV-2, being responsible for the first events of cleavage of a polyprotein into individual proteins (nsp1–4) as well as for the suppression of cellular immunity. Here, we developed a new genetically encoded fluorescent sensor, named PLpro-ERNuc, for detection of PLpro activity in living cells using a translocation-based readout. The sensor was designed as follows. A fragment of nsp3 protein was used to direct the sensor on the cytoplasmic surface of the endoplasmic reticulum (ER) membrane, thus closely mimicking the natural target of PLpro. The fluorescent part included two bright fluorescent proteins—red mScarlet I and green mNeonGreen—separated by a linker with the PLpro cleavage site. A nuclear localization signal (NLS) was attached to ensure accumulation of mNeonGreen into the nucleus upon cleavage. We tested PLpro-ERNuc in a model of recombinant PLpro expressed in HeLa cells. The sensor demonstrated the expected cytoplasmic reticular network in the red and green channels in the absence of protease, and efficient translocation of the green signal into nuclei in the PLpro-expressing cells (14-fold increase in the nucleus/cytoplasm ratio). Then, we used PLpro-ERNuc in a model of Huh7.5 cells infected with the SARS-CoV-2 virus, where it showed robust ER-to-nucleus translocation of the green signal in the infected cells 24 h post infection. We believe that PLpro-ERNuc represents a useful tool for screening PLpro inhibitors as well as for monitoring virus spread in a culture. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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13 pages, 7590 KiB

Open AccessArticle

Recombinant Rod Domain of Vimentin Reduces SARS-CoV-2 Viral Replication by Blocking Spike Protein–ACE2 Interactions

by Fong Wilson Lam, Cameron August Brown and Shannon Elizabeth Ronca

Int. J. Mol. Sci. 2024, 25(5), 2477; https://doi.org/10.3390/ijms25052477 - 20 Feb 2024

Cited by 2 | Viewed by 1366

Abstract

Although the SARS-CoV-2 vaccination is the primary preventive intervention, there are still few antiviral therapies available, with current drugs decreasing viral replication once the virus is intracellular. Adding novel drugs to target additional points in the viral life cycle is paramount in preventing future pandemics. The purpose of this study was to create and test a novel protein to decrease SARS-CoV-2 replication. We created the recombinant rod domain of vimentin (rhRod) in E. coli and used biolayer interferometry to measure its affinity to the SARS-CoV-2 S1S2 spike protein and the ability to block the SARS-CoV-2–ACE2 interaction. We performed plaque assays to measure rhRod’s effect on SARS-CoV-2 replication in Vero E6 cells. Finally, we measured lung inflammation in SARS-CoV-2-exposed K18-hACE transgenic mice given intranasal and intraperitoneal rhRod. We found that rhRod has a high affinity for the S1S2 protein with a strong ability to block S1S2–ACE2 interactions. The daily addition of rhRod decreased viral replication in Vero E6 cells starting at 48 h at concentrations >1 µM. Finally, SARS-CoV-2-infected mice receiving rhRod had decreased lung inflammation compared to mock-treated animals. Based on our data, rhRod decreases SARS-CoV-2 replication in vitro and lung inflammation in vivo. Future studies will need to evaluate the protective effects of rhRod against additional viral variants and identify the optimal dosing scheme that both prevents viral replication and host lung injury. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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23 pages, 17813 KiB

Open AccessArticle

Three-Dimensional Structural Stability and Local Electrostatic Potential at Point Mutations in Spike Protein of SARS-CoV-2 Coronavirus

by Svetlana H. Hristova and Alexandar M. Zhivkov

Int. J. Mol. Sci. 2024, 25(4), 2174; https://doi.org/10.3390/ijms25042174 - 11 Feb 2024

Cited by 2 | Viewed by 1298

Abstract

The contagiousness of SARS-CoV-2 β-coronavirus is determined by the virus–receptor electrostatic association of its positively charged spike (S) protein with the negatively charged angiotensin converting enzyme-2 (ACE2 receptor) of the epithelial cells. If some mutations occur, the electrostatic potential on the surface of the receptor-binding domain (RBD) could be altered, and the S-ACE2 association could become stronger or weaker. The aim of the current research is to investigate whether point mutations can noticeably alter the electrostatic potential on the RBD and the 3D stability of the S1-subunit of the S-protein. For this purpose, 15 mutants with different hydrophilicity and electric charge (positive, negative, or uncharged) of the substituted and substituting amino acid residues, located on the RBD at the S1-ACE2 interface, are selected, and the 3D structure of the S1-subunit is reconstructed on the base of the crystallographic structure of the S-protein of the wild-type strain and the amino acid sequence of the unfolded polypeptide chain of the mutants. Then, the Gibbs free energy of folding, isoelectric point, and pH-dependent surface electrostatic potential of the S1-subunit are computed using programs for protein electrostatics. The results show alterations in the local electrostatic potential in the vicinity of the mutant amino acid residue, which can influence the S-ACE2 association. This approach allows prediction of the relative infectivity, transmissibility, and contagiousness (at equal social immune status) of new SARS-CoV-2 mutants by reconstruction of the 3D structure of the S1-subunit and calculation of the surface electrostatic potential. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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14 pages, 2191 KiB

Open AccessArticle

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein S1 Induces Methylglyoxal-Derived Hydroimidazolone/Receptor for Advanced Glycation End Products (MG-H1/RAGE) Activation to Promote Inflammation in Human Bronchial BEAS-2B Cells

by Dominga Manfredelli, Marilena Pariano, Claudio Costantini, Alessandro Graziani, Silvia Bozza, Luigina Romani, Paolo Puccetti, Vincenzo Nicola Talesa and Cinzia Antognelli

Int. J. Mol. Sci. 2023, 24(19), 14868; https://doi.org/10.3390/ijms241914868 - 3 Oct 2023

Cited by 4 | Viewed by 1757

Abstract

The pathogenesis of coronavirus disease 2019 (COVID-19) is associated with a hyperinflammatory response. The mechanisms of SARS-CoV-2-induced inflammation are scantly known. Methylglyoxal (MG) is a glycolysis-derived byproduct endowed with a potent glycating action, leading to the formation of advanced glycation end products (AGEs), the main one being MG-H1. MG-H1 exerts strong pro-inflammatory effects, frequently mediated by the receptor for AGEs (RAGE). Here, we investigated the involvement of the MG-H1/RAGE axis as a potential novel mechanism in SARS-CoV-2-induced inflammation by resorting to human bronchial BEAS-2B and alveolar A549 epithelial cells, expressing different levels of the ACE2 receptor (R), exposed to SARS-CoV-2 spike protein 1 (S1). Interestingly, we found in BEAS-2B cells that do not express ACE2-R that S1 exerted a pro-inflammatory action through a novel MG-H1/RAGE-based pathway. MG-H1 levels, RAGE and IL-1β expression levels in nasopharyngeal swabs from SARS-CoV-2-positive and -negative individuals, as well as glyoxalase 1 expression, the major scavenging enzyme of MG, seem to support the results obtained in vitro. Altogether, our findings reveal a novel mechanism involved in the inflammation triggered by S1, paving the way for the study of the MG-H1/RAGE inflammatory axis in SARS-CoV-2 infection as a potential therapeutic target to mitigate COVID-19-associated pathogenic inflammation. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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Review

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65 pages, 4863 KiB

Open AccessReview

Immunity and Coagulation in COVID-19

by Piotr P. Avdonin, Maria S. Blinova, Anastasia A. Serkova, Lidia A. Komleva and Pavel V. Avdonin

Int. J. Mol. Sci. 2024, 25(20), 11267; https://doi.org/10.3390/ijms252011267 - 19 Oct 2024

Viewed by 1251

Abstract

Discovered in late 2019, the SARS-CoV-2 coronavirus has caused the largest pandemic of the 21st century, claiming more than seven million lives. In most cases, the COVID-19 disease caused by the SARS-CoV-2 virus is relatively mild and affects only the upper respiratory tract; it most often manifests itself with fever, chills, cough, and sore throat, but also has less-common mild symptoms. In most cases, patients do not require hospitalization, and fully recover. However, in some cases, infection with the SARS-CoV-2 virus leads to the development of a severe form of COVID-19, which is characterized by the development of life-threatening complications affecting not only the lungs, but also other organs and systems. In particular, various forms of thrombotic complications are common among patients with a severe form of COVID-19. The mechanisms for the development of thrombotic complications in COVID-19 remain unclear. Accumulated data indicate that the pathogenesis of severe COVID-19 is based on disruptions in the functioning of various innate immune systems. The key role in the primary response to a viral infection is assigned to two systems. These are the pattern recognition receptors, primarily members of the toll-like receptor (TLR) family, and the complement system. Both systems are the first to engage in the fight against the virus and launch a whole range of mechanisms aimed at its rapid elimination. Normally, their joint activity leads to the destruction of the pathogen and recovery. However, disruptions in the functioning of these innate immune systems in COVID-19 can cause the development of an excessive inflammatory response that is dangerous for the body. In turn, excessive inflammation entails activation of and damage to the vascular endothelium, as well as the development of the hypercoagulable state observed in patients seriously ill with COVID-19. Activation of the endothelium and hypercoagulation lead to the development of thrombosis and, as a result, damage to organs and tissues. Immune-mediated thrombotic complications are termed “immunothrombosis”. In this review, we discuss in detail the features of immunothrombosis associated with SARS-CoV-2 infection and its potential underlying mechanisms. Full article

(This article belongs to the Special Issue New Advances in Molecular Research of Coronavirus)

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