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Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021

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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: closed (30 June 2022) | Viewed by 50977

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Prof. Dr. Evgenii Gusev

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Institute of Immunology and Physiology of the Ural Branch of the Russian Academy of Sciences (IIP UB RAS), Laboratory for Immunology of Inflammation, 620049 Ekaterinburg, Russia
Interests: immunology of inflammation; systemic inflammation; typical pathological processes
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

COVID-19 as a global public health challenge will eventually go down in history. However, the doors for a potential new generation of CoV infections, as well global epidemics of a different etiological nature, will remain open and that will lead to severe social consequences.

Thus, the time has come for preliminary analysis and generalization of the lessons learned from SARS-CoV-2.

Firstly, this concerns the separation of the unique and distinctive mechanisms of SARS-CoV-2 invasion from the general patterns of the infectious processes and the development of critical complications. The latter concerns the characteristics of not only the general molecular mechanisms of various pathologies but also the integral laws of pathology (models of pathological systems). We will inevitably face the consequences whether these issues are resolved.

Secondly, this applies to general strategies of viral invasions, targeted suppression of infectious agent infects via mechanisms of innate and adaptive host immunity, and the reorientation of these mechanisms against the organism during the development of systemic inflammation.

Thus, it is advisable to reconsider the data of both applied and general principles of pathogenetic therapy, to systematize the analysis of genetic and environmental risk factors for CoV infections, and the role of comorbid diseases in them.

We hope that the planned special issue "Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021" will be a significant step towards solving these pressing problems.

Prof. Dr. Evgenii Gusev
Guest Editor

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Keywords

COVID-19
SARS-CoV-2
pathogenesis
inflammation
typical pathological processes

Related Special Issue

Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2022 in International Journal of Molecular Sciences (21 articles)

Published Papers (11 papers)

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Editorial

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3 pages, 195 KiB

Open AccessEditorial

Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021

by Evgenii Gusev

Int. J. Mol. Sci. 2022, 23(22), 14210; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214210 - 17 Nov 2022

Cited by 1 | Viewed by 1031

Abstract

The purpose of this special issue is to highlight the main problems of the COVID-19 epidemic and to outline some ways to solve these problems, including research into the biology of the SARS-CoV-2 virus, general pathological and particular patterns of COVID-19 pathogenesis, acute and long-term complications of COVID-19, and evaluation of high-potential general and specific prevention methods and etiological and pathogenetic therapies for COVID-19 [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

Research

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16 pages, 2711 KiB

Open AccessArticle

Short-Term Effect of SARS-CoV-2 Spike Protein Receptor-Binding Domain-Specific Antibody Induction on Neutrophil-Mediated Immune Response in Mice

by Elena L. Bolkhovitina, Julia D. Vavilova, Andrey O. Bogorodskiy, Yuliya A. Zagryadskaya, Ivan S. Okhrimenko, Alexander M. Sapozhnikov, Valentin I. Borshchevskiy and Marina A. Shevchenko

Int. J. Mol. Sci. 2022, 23(15), 8234; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158234 - 26 Jul 2022

Cited by 1 | Viewed by 1883

Abstract

Vaccination protects against COVID-19 via the spike protein receptor-binding domain (RBD)-specific antibody formation, but it also affects the innate immunity. The effects of specific antibody induction on neutrophils that can cause severe respiratory inflammation are important, though not completely investigated. In the present study, using a mouse model mimicking SARS-CoV-2 virus particle inhalation, we investigated neutrophil phenotype and activity alterations in the presence of RBD-specific antibodies. Mice were immunized with RBD and a week after a strong antibody response establishment received 100 nm particles in the RBD solution. Control mice received injections of a phosphate buffer instead of RBD. We show that the application of 100 nm particles in the RBD solution elevates neutrophil recruitment to the blood and the airways of RBD-immunized mice rather than in control mice. Analysis of bone marrow cells of mice with induced RBD-specific antibodies revealed the increased population of CXCR2⁺CD101⁺ neutrophils. These neutrophils did not demonstrate an enhanced ability of neutrophil extracellular traps (NETs) formation compared to the neutrophils from control mice. Thus, the induction of RBD-specific antibodies stimulates the activation of mature neutrophils that react to RBD-coated particles without triggering excessive inflammation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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13 pages, 3399 KiB

Open AccessArticle

Mutations of Omicron Variant at the Interface of the Receptor Domain Motif and Human Angiotensin-Converting Enzyme-2

by Puja Adhikari, Bahaa Jawad, Rudolf Podgornik and Wai-Yim Ching

Int. J. Mol. Sci. 2022, 23(5), 2870; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052870 - 06 Mar 2022

Cited by 13 | Viewed by 2276

Abstract

The most recent Omicron variant of SARS-CoV-2 has caused global concern and anxiety. The only thing certain about this strain, with a large number of mutations in the spike protein, is that it spreads quickly, seems to evade immune defense, and mitigates the benefits of existing vaccines. Based on the ultra-large-scale ab initio computational modeling of the receptor binding motif (RBM) and the human angiotensin-converting enzyme-2 (ACE2) interface, we provide the details of the effect of Omicron mutations at the fundamental atomic scale level. In-depth analysis anchored in the novel concept of amino acid-amino acid bond pair units (AABPU) indicates that mutations in the Omicron variant are connected with (i) significant changes in the shape and structure of AABPU components, together with (ii) significant increase in the positive partial charge, which facilitates the interaction with ACE2. We have identified changes in bonding due to mutations in the RBM. The calculated bond order, based on AABPU, reveals that the Omicron mutations increase the binding strength of RBM to ACE2. Our findings correlate with and are instrumental to explain the current observations and can contribute to the prediction of next potential new variant of concern. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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16 pages, 1727 KiB

Open AccessArticle

Self-Assembled Particles Combining SARS-CoV-2 RBD Protein and RBD DNA Vaccine Induce Synergistic Enhancement of the Humoral Response in Mice

by Mariya B. Borgoyakova, Larisa I. Karpenko, Andrey P. Rudometov, Ekaterina A. Volosnikova, Iuliia A. Merkuleva, Ekaterina V. Starostina, Alexey M. Zadorozhny, Anastasiya A. Isaeva, Valentina S. Nesmeyanova, Daniil V. Shanshin, Konstantin O. Baranov, Natalya V. Volkova, Boris N. Zaitsev, Lyubov A. Orlova, Anna V. Zaykovskaya, Oleg V. Pyankov, Elena D. Danilenko, Sergei I. Bazhan, Dmitry N. Shcherbakov, Alexander V. Taranin and Alexander A. Ilyichev Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(4), 2188; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042188 - 16 Feb 2022

Cited by 15 | Viewed by 3161

Abstract

Despite the fact that a range of vaccines against COVID-19 have already been created and are used for mass vaccination, the development of effective, safe, technological, and affordable vaccines continues. We have designed a vaccine that combines the recombinant protein and DNA vaccine approaches in a self-assembled particle. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 was conjugated to polyglucin:spermidine and mixed with DNA vaccine (pVAXrbd), which led to the formation of particles of combined coronavirus vaccine (CCV-RBD) that contain the DNA vaccine inside and RBD protein on the surface. CCV-RBD particles were characterized with gel filtration, electron microscopy, and biolayer interferometry. To investigate the immunogenicity of the combined vaccine and its components, mice were immunized with the DNA vaccine pVAXrbd or RBD protein as well as CCV-RBD particles. The highest antigen-specific IgG and neutralizing activity were induced by CCV-RBD, and the level of antibodies induced by DNA or RBD alone was significantly lower. The cellular immune response was detected only in the case of DNA or CCV-RBD vaccination. These results demonstrate that a combination of DNA vaccine and RBD protein in one construct synergistically increases the humoral response to RBD protein in mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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17 pages, 4282 KiB

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Computational Design of Miniproteins as SARS-CoV-2 Therapeutic Inhibitors

by Bahaa Jawad, Puja Adhikari, Kun Cheng, Rudolf Podgornik and Wai-Yim Ching

Int. J. Mol. Sci. 2022, 23(2), 838; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020838 - 13 Jan 2022

Cited by 10 | Viewed by 2968

Abstract

A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications: structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a −1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinder:RBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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Review

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18 pages, 6132 KiB

Open AccessReview

Theophylline: Old Drug in a New Light, Application in COVID-19 through Computational Studies

by Luis M. Montaño, Bettina Sommer, Juan C. Gomez-Verjan, Genaro S. Morales-Paoli, Gema Lizbeth Ramírez-Salinas, Héctor Solís-Chagoyán, Zuly A. Sanchez-Florentino, Eduardo Calixto, Gloria E. Pérez-Figueroa, Rohan Carter, Ruth Jaimez-Melgoza, Bianca S. Romero-Martínez and Edgar Flores-Soto

Int. J. Mol. Sci. 2022, 23(8), 4167; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084167 - 09 Apr 2022

Cited by 19 | Viewed by 4429

Abstract

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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14 pages, 2740 KiB

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Molecular and Cellular Mechanisms of M. tuberculosis and SARS-CoV-2 Infections—Unexpected Similarities of Pathogenesis and What to Expect from Co-Infection

by Anna A. Starshinova, Igor Kudryavtsev, Anna Malkova, Ulia Zinchenko, Vadim Karev, Dmitry Kudlay, Angela Glushkova, Anastasiya Y. Starshinova, Jose Dominguez, Raquel Villar-Hernández, Irina Dovgalyk and Piotr Yablonskiy

Int. J. Mol. Sci. 2022, 23(4), 2235; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042235 - 17 Feb 2022

Cited by 9 | Viewed by 3548

Abstract

Tuberculosis is still an important medical and social problem. In recent years, great strides have been made in the fight against M. tuberculosis, especially in the Russian Federation. However, the emergence of a new coronavirus infection (COVID-19) has led to the long-term isolation of the population on the one hand and to the relevance of using personal protective equipment on the other. Our knowledge regarding SARS-CoV-2-induced inflammation and tissue destruction is rapidly expanding, while our understanding of the pathology of human pulmonary tuberculosis gained through more the 100 years of research is still limited. This paper reviews the main molecular and cellular differences and similarities caused by M. tuberculosis and SARS-CoV-2 infections, as well as their critical immunological and pathomorphological features. Immune suppression caused by the SARS-CoV-2 virus may result in certain difficulties in the diagnosis and treatment of tuberculosis. Furthermore, long-term lymphopenia, hyperinflammation, lung tissue injury and imbalance in CD4+ T cell subsets associated with COVID-19 could propagate M. tuberculosis infection and disease progression. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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34 pages, 2589 KiB

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SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

by Evgenii Gusev, Alexey Sarapultsev, Liliya Solomatina and Valeriy Chereshnev

Int. J. Mol. Sci. 2022, 23(3), 1716; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031716 - 02 Feb 2022

Cited by 105 | Viewed by 15471

Abstract

The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus’s protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming of the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2’s ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperergic mechanisms of systemic inflammation is critical at this stage of infection. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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20 pages, 1765 KiB

Open AccessReview

Could Lower Testosterone in Older Men Explain Higher COVID-19 Morbidity and Mortalities?

by Luis M. Montaño, Bettina Sommer, Héctor Solís-Chagoyán, Bianca S. Romero-Martínez, Arnoldo Aquino-Gálvez, Juan C. Gomez-Verjan, Eduardo Calixto, Georgina González-Avila and Edgar Flores-Soto

Int. J. Mol. Sci. 2022, 23(2), 935; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020935 - 15 Jan 2022

Cited by 11 | Viewed by 4409

Abstract

The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection’s outcome and might be related to a dysfunctional cell Ca²⁺ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca²⁺-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca²⁺ concentrations. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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19 pages, 7389 KiB

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ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review

by Lihua Qu, Chao Chen, Tong Yin, Qian Fang, Zizhan Hong, Rui Zhou, Hongbin Tang and Huifen Dong

Int. J. Mol. Sci. 2021, 22(21), 11483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111483 - 25 Oct 2021

Cited by 8 | Viewed by 3888

Abstract

Despite the protracted battle against coronavirus acute respiratory infection (COVID-19) and the rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no specific and effective drugs have to date been reported. Angiotensin-converting enzyme 2 (ACE2) is a zinc metalloproteinase and a critical modulator of the renin-angiotensin system (RAS). In addition, ACE2 has anti-inflammatory and antifibrosis functions. ACE has become widely known in the past decade as it has been identified as the primary receptor for SARS-CoV and SARS-CoV-2, being closely associated with their infection. SARS-CoV-2 primarily targets the lung, which induces a cytokine storm by infecting alveolar cells, resulting in tissue damage and eventually severe acute respiratory syndrome. In the lung, innate immunity acts as a critical line of defense against pathogens, including SARS-CoV-2. This review aims to summarize the regulation of ACE2, and lung host cells resist SARS-CoV-2 invasion by activating innate immunity response. Finally, we discuss ACE2 as a therapeutic target, providing reference and enlightenment for the clinical treatment of COVID-19. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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14 pages, 1264 KiB

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Metabolic Reprogramming in COVID-19

by Tao Shen and Tingting Wang

Int. J. Mol. Sci. 2021, 22(21), 11475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111475 - 25 Oct 2021

Cited by 36 | Viewed by 5928

Abstract

Plenty of research has revealed virus induced alternations in metabolic pathways, which is known as metabolic reprogramming. Studies focusing on COVID-19 have uncovered significant changes in metabolism, resulting in the perspective that COVID-19 is a metabolic disease. Reprogramming of amino acid, glucose, cholesterol and fatty acid is distinctive characteristic of COVID-19 infection. These metabolic changes in COVID-19 have a critical role not only in producing energy and virus constituent elements, but also in regulating immune response, offering new insights into COVID-19 pathophysiology. Remarkably, metabolic reprogramming provides great opportunities for developing novel biomarkers and therapeutic agents for COVID-19 infection. Such novel agents are expected to be effective adjuvant therapies. In this review, we integrate present studies about major metabolic reprogramming in COVID-19, as well as the possibility of targeting reprogrammed metabolism to combat virus infection. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Pathogenesis, Prevention, and Therapy of COVID-19: Summarizing the Results of 2021)

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