Frontiers in Clinical Drug Research - Anti Infectives: Volume 9 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Clinical Drug Research-Anti Infectives:
- Sprache: Englisch
Frontiers in Clinical Drug Research – Anti Infectives (Volume 9) is a book series that provides updated reviews on the latest advancements in development of pharmaceutical agents for treating infectious diseases. The series covers various topics, including chemistry, pharmacology, molecular biology, and biochemistry of natural and synthetic drugs. Additionally, it addresses multi-drug resistance and pre-clinical/clinical findings on antibiotics, vaccines, antifungal agents, and antitubercular drugs. This series is an invaluable resource for pharmaceutical scientists and postgraduate students, offering critical information to support clinical trials and research in anti-infective drug discovery and epidemiology.
The ninth volume presents five in-depth reviews, with topics including mature drugs and antivirals for COVID-19, bacteriocins as potent anti-infective agents, therapeutic interventions targeting free radicals in viral diseases, and a detailed exploration of natural anti-infective agents.
The five reviews included in this volume are:
- The role of mature drugs in the COVID-19 era
- Antivirals to treat COVID-19
- Ribosomally synthesized bacteriocins as potent anti-infective agents
- Therapeutic interventions against free radicals in viral diseases
- A comprehensive overview of natural anti-infective agents
Readership: Graduate students and researchers.
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Seitenzahl: 373
Veröffentlichungsjahr: 2024
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PREFACE
The 9th volume of Frontiers in Clinical Drug Research – Anti-Infectives comprises five chapters that cover several important topics, including the role of mature drugs in COVID-19, antivirals to treat COVID-19, ribosomally synthesized bacteriocins as potent anti-infective agents and natural anti-infective agents.
In Chapter 1, Haller et al., discuss the potential positioning of three mature innovative drugs—OM-85, calcium dobesilate, and its salt form, etamsylate. These drugs have demonstrated anti-viral and anti-inflammatory properties, which could be of potential use for the treatment of COVID-19. Bhattacharyya, in Chapter 2, addresses the issues associated with available antivirals, including their modes of action, adverse effects, and drug interactions.
Elkhateeb et al., in Chapter 3, highlight the importance of bacteriocins as anti-infective agents, describing their common mechanisms of action and recent clinical and therapeutic applications. Bhattacharyya et al., in the next chapter, summarize the relationship between oxidative stress, viral infection, and various therapeutic strategies involving antioxidants. Finally, Padwad et al., in the last chapter of the volume, discuss phytomolecules, their biological potential, and how these molecules regulate innate and adaptive immune responses in infectious diseases.
I would like to thank all the authors for their excellent contributions, which should be of great interest to readers. I am also grateful for the timely efforts of the editorial personnel, especially Mr. Mahmood Alam (Editorial Director), Mr. Obaid Sadiq (In-charge, Books Department), and Miss Asma Ahmed (Senior Manager, Publications) at Bentham Science Publishers.
List of Contributors
The Place of Mature Drugs in COVID-19 Era
Christian Pasquali4,*,Daniel Zingg1,*,Stefania Ballarini1,*,Giovanni A. Rossi2,Hermann Haller3Abstract
COVID-19 infection, caused by the SARS-CoV-2 virus, is associated with substantial morbidity and mortality. COVID-19 infection has three distinct phases: 1, early infection phase; 2, pulmonary phase; and 3, the hyperinflammatory phase. Despite a major focus on vaccines and new therapeutics, existing drugs sharing some known mechanistic with this virus, have also gained interest. The potential positioning of three mature innovative drugs, which could be of potential use in this pandemic environment, is discussed in this chapter: OM-85 and calcium dobesilate, and their salt form etamsylate, have revealed anti-viral and anti-inflammatory properties. OM-85, a bacterial extract originating from 21 pathogenic strains isolated from human lungs and indicated for the prevention of recurrent respiratory tract infections, stimulates both innate and adaptive immunity, resulting in non-specific loco-regional immune responses. It has shown anti-viral activity in a number of virus infection models, including influenza H1N1, rhinovirus, and more recently, coronaviruses. It has also shown some immunoregulatory properties. Accordingly, there is a rationale for further investigations on OM-85 to be used as prophylaxis for other respiratory infections and potentially in long-COVID. For calcium dobesilate, currently indicated for the treatment of microvascular diseases while preserving microvascular integrity via antioxidant and anti-inflammatory properties, there are cumulating data that could promote its potential use for the treatment during phase 2 to protect the vascular endothelium. Calcium dobesilate has anti-viral properties and was recently shown to interfere with the SARS-CoV-2 spike-protein binding to the ACE2 receptor. Accordingly, one could also postulate to use it during phase 1. Etamsylate, an anti-haemorrhagic and antiangiogenic agent that improves platelet adhesiveness and restores capillary resistance, is indicated for the prevention and treatment of capillary haemorrhages. Considering its mechanism of action, etamsylate could be envisage for use as potential treatment during phase 3 for viral-induced complications. Importantly,
none of these afore mentioned drugs are currently approved for the prevention or treatment of SARS-CoV-2 viral infection. Further, the conduction of well-designed clinical trials is warranted.
INTRODUCTION
The global coronavirus disease 2019 (COVID-19) pandemic, which was declared by the World Health Organization (WHO) on 11 March 2020 [1], is an ongoing infectious respiratory disease caused by the recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2]. SARS-CoV-2, a novel coronavirus, originated in the city of Wuhan, the capital of Hubei Province in China, at the end of 2019, and caused an outbreak of unusual viral pneumonia [2]. Due to its high transmissibility, the virus spread rapidly throughout China and thereafter to the rest of the world [3], resulting in a global pandemic [4].
Although initially identified as viral pneumonia, with symptoms of cough, fever, and dyspnoea plus bilateral lung infiltration in more severe cases [5, 6], COVID-19 has a broad range of clinical manifestations [6, 7]. Cases include asymptomatic infection, mild upper respiratory tract infection (URTI), pneumonia, and severe disease with complications including acute respiratory distress syndrome (ARDS), RNAaemia, acute cardiac injury, and secondary infection, which result in death in many cases [6-8]. SARS-CoV-2 RNAaemia and plasma viral RNA load are associated with critical illness, indicating that uncontrolled viral replication may play an important role in the pathogenesis of COVID-19 [8]. However, compared with other respiratory viruses, such as SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV), the viral load of SARS-CoV-2 at the time of infection does not always correlate with the severity of COVID-19 disease [9]. There is also evidence that the clinical manifestation of COVID-19 and its associated comorbidities vary between geographic locations, with the highest prevalence of comorbidities seen in the USA, the greatest severity of COVID-19 seen in Asia, and the highest mortality seen in Latin America and Europe [10]. In addition, a number of genetic variants have emerged, with some labelled as variants of concern due to their potentially greater transmissibility, increased morbidity and/or mortality, and resistance to antibodies or vaccines [11].
In addition to the rapid development of vaccines to prevent SARS-CoV-2 infection and transmission, drug repurposing has been a major focus of research during the pandemic to find agents that would be suitable for both the prevention [12-15] and the treatment [13-22] of COVID-19. Agents investigated or proposed as treatment options have included anti-cancer agents [23], anti-virals [17, 21, 24], heparin [14, 25], immunomodulators [13, 17], anti-inflammatory drugs [13, 17], and kinase inhibitors [15]. The anti-viral remdesivir, an inhibitor of the viral RNA-dependent RNA polymerase, was originally developed for the treatment of Ebola [26]. It was shown to be effective for the treatment of COVID-19 in a randomised, double-blind, placebo-controlled, phase 3 study of patients with lower RTI (LRTI), reducing the recovery time [27]. Remdesivir was approved by the U.S. Food and Drug Administration (FDA) in May 2020 for the treatment of adults and children with COVID-19. On 24 June 2021, the FDA issued an emergency-use authorisation (EUA) for the monoclonal antibody tocilizumab for the treatment of hospitalised adults and paediatric patients (2 years of age and older) who were receiving systemic corticosteroids and required supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. The FDA has also issued other EUAs for several monoclonal antibodies for the treatment of mild or moderate COVID-19 in adults and paediatric patients (aged 2 years and older, weighing at least 40 kilograms) with positive results upon direct SARS-CoV-2 viral testing, who are at high risk for progressing to severe COVID-19 and/or hospitalisation. The anticoagulant effects of heparin/low molecular-weight heparin are thought to be responsible for its beneficial effects on mortality [25]. The glucocorticoid dexamethasone has been shown to improve survival in COVID-19 patients who require oxygen, particularly those who need mechanical ventilation [28]. The use of oral or injectable dexamethasone in patients with COVID-19 who require supplemental oxygen therapy was endorsed by the European Medicines Agency (EMA) on 18 September 2020 [29]. Another glucocorticoid, budesonide, was shown to reduce the time to recovery and hospital admission compared with usual care if administered within 7 days of the onset of mild COVID-19 symptoms in a randomised, controlled, open-label, phase 2 clinical study [30]. However, in 2021, the EMA’s COVID-19 taskforce (COVID-ETF) pointed out that there was currently insufficient evidence that inhaled corticosteroids were beneficial for outpatients with COVID-19 [31]. Attention should be paid to the duration of corticosteroid therapy and the potential side effects of prolonged use, such as pulmonary fibrosis [32]. Guidelines on the use of corticosteroids were issued by the WHO in 2020, which included a strong recommendation for a 7-10-day course in patients with severe or critical COVID-19 and a conditional recommendation that they should not be used in patients with non-severe COVID-19 [4].
The immune system, inflammation, airways epithelium, endothelium, and angiogenesis all play a role in the process of SARS-CoV-2 infection, the development of COVID-19 symptoms and complications, and the resulting outcomes, and so are key targets for the prevention and treatment of the disease [33, 34]. This chapter reviews the role of these factors in SARS-CoV-2 infection and the potential for the repurposing of three drugs for the management of COVID-19: OM-85, an oral immunomodulator with anti-viral and anti-inflammatory properties, indicated for the prevention of recurrent RTIs; calcium dobesilate, a venoactive drug with vascular protective activity; and etamsylate, a haemostatic agent that acts during the first phase of haemostasis.
OVERVIEW OF COVID-19 INFECTION
Phases of COVID-19 Infection
COVID-19 infection can be divided into three distinct phases or stages, shown in Fig. (1), which are associated with different degrees of pathology and symptoms: phase 1, the early infection phase; phase 2, the pulmonary phase; and phase 3, the hyperinflammatory phase [35-38]. In addition, a post-infection phase 4, known as post-COVID syndrome, long COVID, or long-haul COVID, occurs in some people, with symptoms such as extreme fatigue, dyspnoea, chest pain or tightness, and problems with memory or concentration [39-42].
Fig. (1)) Phases of COVID-19 infection and potential phase-dependent treatment with OM-85, calcium dobesilate or etamsylate. Adapted from Aguilar et al. 2020 [35], Romagnoli et al. 2020 [37], and Siddiqi and Mehra 2020 [38].Phase 1: Early Infection
During the early infection phase [35-38], which usually lasts for 2 to 11 days, the virus is multiplying inside the body, with an average incubation period of approximately 5-6 days. The initial symptoms typically last for approximately 5-7 days, coinciding with the peak in viral load of upper-respiratory specimens, which occurs 2-3 days after the onset of symptoms [43]. The viral load in upper-respiratory specimens has been found to be similar in asymptomatic and symptomatic patients [44], and patients are likely to become infectious 1-3 days before the onset of symptoms [45, 46], indicating the importance of this phase of the infection for the viral transmission. It has been estimated that 20-75% of cases are due to transmission from asymptomatic individuals [47] and 6-44% from pre-symptomatic individuals [48-50]. Symptoms are usually mild, although some patients may remain asymptomatic throughout the course of the disease [6]. Typical symptoms are cough, fatigue, aches, and fever, which may be mistaken for influenza or the common cold. Other symptoms may also include abdominal pain, headache, dysgeusia, and anosmia. Dysgeusia and anosmia are typical symptoms of COVID-19 that may differentiate it from influenza or a common cold [51, 52].
Phase 2: Pulmonary Phase
The pulmonary phase is characterised by a decreased viral load, an increased inflammatory response, which is initially localised in the lungs, tissue damage, and respiratory dysfunction [35-38, 53]. The inflammatory response includes increased endothelial permeability, leukocyte recruitment, and vasodilation [37], and there may be an increase in markers of systemic inflammation [38]. The progressively severe respiratory involvement is demonstrated by the pulmonary bilateral infiltrates or ground-glass opacities that are typically seen on chest X-rays or computed tomography scans [35, 36, 38, 54]. The symptom course is usually 5-7 days [35] and typical symptoms include cough, fever, dyspnoea, and olfactory and gustatory dysfunction [36, 55, 56]. Phase 2 can be divided into two sub-stages, 2A and 2B, depending on whether or not a patient has hypoxaemia [35]. Patients with phase 2 COVID-19 infection require hospitalisation for close observation and treatment.
Phase 3: Hyperinflammatory Phase
During the hyperinflammatory phase, which is the most severe stage of the illness, the immune system is hyperactivated, with systemic hyperinflammation resulting in damage to a number of other organs, such as the heart, liver, and kidneys, in addition to the lungs [35-38, 57, 58]. Overall, the virus can cause organ injury by either direct infection or systemic effects including host immune-clearance or immune-tolerance disorders, endothelium-mediated vasculitis, thrombus formation, glucose- or lipid-metabolism disorders, and hypoxia. Morbidity and mortality are substantial in this phase due to the uncontrolled systemic inflammation [35, 58]. However, only a minority of patients, estimated to be approximately 10-15%, progress to this phase [35].
The main complication is ARDS [59] and a key feature is cytokine-release syndrome (CRS) or cytokine storm; this is a severe systemic inflammatory response caused by the SARS-CoV-2 infection, which is associated with a significant increase in the levels of numerous inflammatory markers including interleukin-1 beta (IL-1β) due to SARS-CoV-2 activation of the NLRP3 inflammasome, IL-2, IL-6, IL-7, IL-10, C-reactive protein (CRP), C-X-C motif chemokine 10 (CXCL10), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1-alpha (MIP-1α), monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-α) [7, 59-62]. Lung histopathology reveals diffuse alveolar damage with activated pneumocytes, microvascular thromboemboli, capillary congestion, protein-enriched interstitial oedema, and inflammatory infiltrates, consistent with the development of ARDS [53, 63]. Excessive recruitment and activation of inflammatory cells are followed by the production of proteases and oxygen radicals that induce parenchymal injury and diffuse microvascular damage [64, 65].
Hyperinflammation includes pro-thrombotic effects such as complement activation, endothelial dysfunction, plaque instability, and platelet activation, which result in the development of microvascular and macrovascular thrombosis [37, 66-68]. Macrovascular complications, such as pulmonary embolism, deep-vein thrombosis, and acute coronary syndrome, are frequently seen in patients with severe COVID-19 [69, 70]. The immune dysregulation caused by SARS-CoV-2 infection results in extensive T-cell dysfunction and T-cell apoptosis, with a decrease in helper (Th), suppressor (Ts) and regulatory (Treg) T-cell counts [71, 72].
The renin-angiotensin-aldosterone system (RAAS) also plays an important role in phase 3. The RAAS is a multi-hormonal system consisting of a complex cascade of vasoactive peptides, which is a key regulator of cardiovascular homeostasis, controlling blood pressure, tissue perfusion, and extracellular volume [73]. The RAAS regulates blood pressure, fluid volume, and sodium and potassium balance through its vasoactive peptides, and plays a key role in the initiation and maintenance of vascular inflammation and remodelling, which leads to endothelial dysfunction [74, 75].
Angiotensin-converting enzyme 2 (ACE2) has a key role in the RAAS via its carboxypeptidase activity, which generates angiotensin fragments, Ang-(1-9) and Ang-(1-7), which have vasodilatory, antifibrotic, and anti-inflammatory activity [73, 76].
Endothelial dysfunction facilitates the migration of inflammatory cells into the vascular wall and stimulates the proliferation of smooth-muscle cells, which results in reduced vascular function and the development of cardiovascular disease and tissue injury [75]. The binding of SARS-CoV-2 to the ACE2 receptor on the host-cell surface is associated with downregulation of membrane-bound ACE2, dysregulation of the RAAS, with an increase in angiotensin II activity and a decrease in angiotensin (1-7) activity, resulting in the deterioration of cardiovascular homeostasis, with vasoconstriction, inflammation, fibrosis, and damage to the lungs and heart [73, 77-79].
Phase 4: Post-COVID Syndrome
A post-infection phase 4, known as post-COVID syndrome, long COVID or long-haul COVID, occurs after the initial infection in some people due to persistent immunosuppression, continuing organ dysfunction, and multisystem inflammatory syndrome with cardiac, vascular, and pulmonary fibrosis [39-42]. Post-COVID syndrome can involve numerous body systems and includes a wide variety of symptoms such as coronary artery atherosclerosis, acute myocardial infarction, vasculitis, chronic rheumatological disease, myalgia, pulmonary fibrosis, chronic respiratory failure, fatigue, generalised muscle atrophy, and neuronal demyelination [42]. One in 10 people still has at least one moderate-to -severe symptom 8 months after mild COVID-19 infection [80].
Epithelium: COVID-19 Cell Attachment and Entry
SARS-CoV-2, a member of the family Coronaviridae and genus Betacoronavirus, is a positive-sense, single-stranded, enveloped RNA coronavirus [81]. The characteristic spike protein, which the virus uses for attachment and entry into host cells [82], is found on the surface of the envelope [22, 83]. Host-cell entry is an essential first step in viral infection, and receptor recognition is an important factor in SARS-CoV-2 infection and pathogenesis. Cell entry is achieved by the binding of viral spike proteins to host-cell receptors as well as spike protein priming and activation by host-cell proteases [82, 84]. This activity has been studied for different viruses, such as other coronaviruses and influenza A virus subtype H1N1 and some co-receptors, such as transmembrane protease serine 2 (TMPRSS2), TMPRSS11A, TMPRSS11D, TMPRSS11E1, and TMPRSS4, have been identified [85]. TMPRSS2 activity is considered to be crucial for cell entry and SARS-CoV-2 viral pathogenesis. Receptor docking is made possible by cleavage of the spike protein and proteolytic activation by TMPRSS2 [85]. SARS-CoV-2 initially infects the airways, mainly ciliated bronchial epithelial cells and type 2 pneumocytes, using ACE2 as an entry receptor [82, 86-88]. Increased ACE2 gene expression has been found to be associated with active smoking, hypertension, and obesity, which are known risk factors for severe COVID-19 disease [86]. In addition, the expression of COVID-19-related genes is associated with the host and environmental factors and also, possibly, genetic variation [86]. Because ACE2 is highly expressed in various organs and tissues, COVID-19 attacks other organs in addition to the lungs that have high ACE2 expression, such as the heart, kidneys, liver, skeletal muscle, central nervous system, adrenal glands, and thyroid glands [87].
Heparan sulphate proteoglycans (HSPGs) are composed of unbranched, negatively charged heparan sulphate polysaccharides that are attached to a number of cell-surface or extracellular matrix proteins [89]. HSPGs, which are widely expressed and mediate numerous biological activities, including cell homeostasis and angiogenesis, are used by viruses to attach to the surface of host cells [89]. Attachment of the SARS-CoV-2 virus to the target-cell membrane requires heparan sulphate as a necessary co-factor (Fig. 2) [84, 90]. The SARS-CoV-2 spike protein interacts with heparan sulphate and ACE2, which have adjacent binding sites, via its receptor-binding domain [90]. Heparin, which is structurally similar to heparan sulphate, can inhibit viral binding by inducing a conformational change in the spike protein receptor-binding domain [14]. The presence of sialic acids on ACE2 on the host target cell has been shown to prevent efficient interaction between the spike protein and ACE2 [84]. However, the SARS-CoV-2 virus is able to partly overcome this sialic acid-mediated restriction, enabling partial entry into target cells [84].
Proteolytic priming and activation of the spike protein are essential for membrane fusion, infection of host cells and, thence, viral replication [82, 84]. Proteolytic activation of the spike protein occurs at the S1/S2 and S2′ sites and begins with cleavage of the protein by pro-protein convertases such as furin [84]. Further cleavage of the spike protein occurs during entry of SARS-CoV-2 into the host cell, which is mediated by host proteases including TMPRSS2 [82, 84]. TMPRSS2 is essential for the entry and viral spread of SARS-CoV-2 due to its interaction with the ACE2 receptor [22, 82]. In lung tissue, the expression of TMPRSS2 is highest in ciliated cells and type I alveolar epithelial cells [91]. The expression of TMPRSS2 increases with age, which may explain the increased susceptibility of older adults to SARS-CoV-2 infection compared with younger adults and children [91]. Efficient replication of SARS-CoV-2 in human lung epithelial cells has been found to be dependent on a furin-like cleavage site in the S1/S2 junction of the spike protein [84, 92].
Fig. (2)) Current hypothetical mechanism-of-action of the anti-viral activity of OM-85 and calcium dobesilate. Mechanism-of-action of the anti-viral activity of OM-85 and calcium dobesilate (CaD). (A) SARS-CoV-2 cellular-infection process. (B) OM-85 downregulates ACE2 and TMPRSS2 transcription as well as ACE2 and TMPRSS2 mRNA expression, decreasing the number of both receptors from the cell surface. Furthermore, it inhibits SARS-CoV-2 S-1 protein binding to, and entry into, epithelial cells and, importantly, viral replication. Calcium dobesilate binds to the virus heparan sulfate binding site, thus reducing SARS-CoV-2 virus binding to ACE2 and subsequent infection. Adapted from Clausen et al. 2020 [90].Immune System and Inflammation
SARS-CoV-2 is highly transmissible, virulent, and a potent inducer of inflammatory mediators, inducing a cytokine cascade by activating immune cells, such as T cells, macrophages, and monocytes, to secrete a range of inflammatory cytokines, including interferon-delta (IFN-δ), IFN-gamma (IFN-γ), IL-1β, IL-6, IL-7, IL-8, IL-10, IL-12, IL-18, TNF-α, transforming growth factor-beta (TGF-β), and chemokines, including CC-chemokine ligand 2 (CCL2), CCL3, CXCL8, CXCL9, and CXCL10, producing a cytokine storm that is responsible, among other factors, for the resulting organ damage [59-61, 74, 93, 94].
The cytokine storm produced by SARS-CoV-2 is triggered by the interaction of the virus spike protein with ACE2 and the downregulation of ACE2 mediated by the virus, which leads to hyper inflammation and increased cytokine production [74]. Four molecular axes that are thought to be involved in this process are dysregulation of RAAS, attenuation of the Mas receptor, increased activation of [des-Arg9]-bradykinin, and activation of the complement system [74]. Levels of CRP, which is produced by the liver mainly in response to IL-6 and is a reliable biomarker of inflammation, are substantially raised and higher levels correlate with increased COVID-19 severity [95]. IFN-γ, IL-1, IL-6, IL-18, and TNF-α are key cytokines that are often found in increased levels in the cytokine storm and are considered to play a key role in pathogenesis [93]. The cytokine storm involves a complex, inter-connected network of cells, signalling pathways, cytokines, and chemokines. It is a life-threatening systemic inflammatory syndrome that involves increased levels of circulating cytokines and chemokines together with hyperactivation of immune cells and organ dysfunction that can lead to multiorgan failure [93].
The cytokine storm is due, in part, to the immunological properties of the host-virus interaction. The clinical presentation varies from individual to individual. In severe cases, it occurs because of an aberrant immune-system reaction—precisely, a failure of negative-feedback mechanisms involving, but not limited to, Treg activity. This was exemplified by a clinical study in which distinct immunological signatures, including T-cell lymphopenia, were identified in the peripheral blood of patients with mild-to-moderate and severe COVID-19, which were more consistent with peripheral hypo- than hyper-immune activation [96]. The anti-inflammatory properties of IL-10-secreting Treg cells are characteristic of more-severe COVID-19 cases.
SARS-CoV-2 infection can rapidly activate Th1 cells to secrete pro-inflammatory cytokines, such as IL-6 and GM-CSF, which in turn activates monocytes to secrete other cytokines such as TNF-α and IL-6 [60]. High expression of TNF-α, IL-6, and IL-1β, a potent inflammasome activator, is characteristic of the cytokine storm produced by SARS-CoV-2 [60]. Cytokine secretion is also induced by IFN-γ and neutrophil extracellular traps [60]. IL-6 may be an important factor for the involvement of endothelial cells in inflammatory and immune reactions, and IL-6 activity has been reported to be upregulated by fibroblast growth factor (FGF) [97].
ARDS and symptoms such as fever associated with the cytokine storm may be the direct result of cytokine-induced tissue damage, physiological changes or may indirectly result from immune cell-mediated responses [93]. Progression to disseminated intravascular coagulation with vascular occlusion or catastrophic haemorrhage, haemostatic imbalance, vasodilatory shock, and death can occur rapidly. The combination of hyperinflammation, coagulopathy, and low platelet count can lead to a high risk of spontaneous haemorrhage while a combination of renal dysfunction, hypoalbuminemia, and endothelial-cell death can lead to capillary-leak syndrome [93].
Growth Factor Receptors
Growth factor receptors (GFRs) regulate a number of biological functions including cell growth. FGF consists of a family of polypeptides with diverse biological functions that depend on their binding to FGF receptors (FGFRs) [98, 99]. Heparan sulphate, which is abundant on the cell surface and in the extracellular matrix, is essential for the binding of FGFs to FGFRs [19, 98]. The activity of FGFRs is also co-regulated by heparan sulphate, which increases the efficacy of many FGF/FGFR interactions by cross-binding into trimeric complexes and facilitates receptor activation and downstream signalling pathways [19]. FGFs also play a role in the pathogenesis of many diseases including cardiovascular disease, chronic kidney disease, inflammatory diseases, genetic disorders, and cancer [99-101]. Increased expression of FGFs or FGFRs and/or abnormal receptor signalling is frequently seen in a number of cancers [102].
A number of GFRs are involved in the process of viral infection, with many viruses, including coronaviruses, using the receptors to attach to the cell surface, internalise into the host cell, and replicate by diverting receptor tyrosine-kinase signalling [19]. FGFR activation may also play a role in the long-term effects of viral infection. The activation of the FGFR1 signalling pathway by the Epstein-Barr virus promotes aerobic glycolysis and the transformation of nasopharyngeal epithelial cells in non-keratinising nasopharyngeal carcinoma [103]. In addition, MERS-CoV, which is closely related to SARS-CoV-2, induces cell apoptosis in the lung and kidneys by upregulation of FGF2, which can result in ARDS and renal failure [104].
FGFs and FGFRs have also been found to play a role in anti-viral defence, which is partly mediated via control of the cellular IFN response, and FGF antagonism of IFN signalling has been shown to promote viral replication [100]. In vitro and in vivo experiments in mice showed that by suppressing IFN-induced expression of IFN-stimulated genes, FGFs promoted the replication of the DNA virus herpes simplex virus I (HSV-1) and the RNA viruses lymphocytic choriomeningitis virus and Zika virus [100]. The role of FGFs and FGFRs in the SARS-CoV-2 infection process is under investigation.
Vascular Endothelium Involvement and Angiogenesis
Vascular Endothelium and Endothelial Dysfunction
Although SARS-CoV-2 infection primarily affects the lungs, the cardiovascular system is also a key target, with SARS-CoV-2 using ACE2 binding to attach to and infect vascular endothelial cells, pericytes, and cardiomyocytes, similar to the processes by which pneumocytes in the lung are infected [105, 106]. The vascular endothelium, together with the surrounding pericytes, performs a number of functions including the prevention of inflammation and the inhibition of coagulation [107].
Vascular endothelial dysfunction is the foundation of the multiorgan failure seen in patients with severe COVID-19 disease, with endothelial cells playing a key role in the initiation and progression of the infection [67, 73, 108-111]. Angiopoietin-2, FMS-like tyrosine kinase-3 ligand (Flt3L), and plasminogen activator inhibitor-1 (PAI-1), which are markers of endothelial injury, have been found to be elevated in critically ill COVID-19 patients [112]. In addition, raised angiopoietin-2, PAI-1, and follistatin, another marker of endothelial injury, have been found to be strongly predictive of in-hospital mortality [112]. Endothelial dysfunction is also a feature of many comorbidities associated with an increased risk for severe COVID-19, such as diabetes, heart failure, and coronary artery disease [73, 108].
Vascular endothelial cells are infected by SARS-CoV-2, causing endotheliitis with diffuse endothelial inflammation and widespread endothelial injury, which is found in patients with advanced COVID-19 [67, 68, 108, 110, 113]. Increased endothelial dysfunction induced by SARS-CoV-2 may impair organ perfusion and produce a pro-coagulatory state that results in microvascular and macrovascular thrombotic events [67, 68, 108].
The pro-inflammatory cytokine storm that is induced by SARS-CoV-2 in severe COVID-19, with high levels of cytokines such as IL-6, IL-8, MCP-1 and TNF-α, may play a role in endothelial dysfunction in the microvasculature [67]. The lungs from patients with COVID-19 show distinctive vascular features [105], and venous thromboembolism, arterial thrombosis, and thrombotic microangiopathy are significant contributors to the increased morbidity and mortality in patients with COVID-19 [114]. It may also play a role in microvascular dysfunction, resulting in the activation of platelets and complement, dysregulation of coagulation, and recruitment of leukocytes in the microvasculature [67].
Angiogenesis
Angiogenesis plays a role in the pathogenesis of lung disease [115], and viruses are known to be important regulators of angiogenesis [116]. Both sprouting angiogenesis, the primary route for vascular formation, and intussusceptive angiogenesis, in which an existing blood vessel splits into two, are involved [115]. Viral regulation of angiogenesis results in changes to a number of processes including endothelial cell proliferation, migration and adhesion, and vascular permeability [116]. A significant increase in the growth of new blood vessels via intussusceptive angiogenesis has been reported in the lungs of patients who died from COVID-19 and the angiogenesis-associated gene FGF2 has been found to be upregulated [105].
FGF2 has pro-angiogenic effects that are mediated by chemokines and inflammatory cells, and interacts with several endothelial cell-surface receptors, such as heparan sulphate, tyrosine kinases, and integrins [117]. FGF2-regulated angiogenesis may be promoted by inflammation and hypoxia [115, 117]. Vascular endothelial growth factor A (VEGF-A), platelet-derived growth factor (PDGF)-AA, and PDGF-AB/BB, which are markers of angiogenesis, have been found to be increased in patients hospitalised with non-critical COVID-19 infection [112].
COVID-19 COMORBIDITIES
Comorbid illnesses are common in patients with COVID-19 infection and several studies have shown that patients with comorbidities are more likely to have a worse or fatal clinical outcome compared to those without [118, 119]. In a systematic review and meta-analysis of 34 studies, which included 16,110 patients from nine different countries (Australia, China, France, Italy, Korea, Singapore, Spain, the UK, and the USA), the most prevalent chronic comorbidities identified in patients with severe or fatal COVID-19 infection were obesity (42%), hypertension (40%), diabetes (17%), cardiovascular disease (13%), respiratory disease (8%), cerebrovascular disease (6%), malignancy (4%), kidney disease (3%), and liver disease (2%) [119]. The comorbidities that were most strongly predictive of a severe or fatal outcome were chronic respiratory disease (odds ratio [OR] 3.56), hypertension (OR 3.17), cardiovascular disease (OR 3.13), kidney disease (OR 3.02), cerebrovascular disease (OR 2.74), malignancy (OR 2.73), diabetes (OR 2.63), and obesity (OR 1.72) [119]. Despite being the most common comorbidity, obesity was not a strong predictor of COVID-19 severity [119].
In a retrospective analysis of 1,590 patients from 575 hospitals across 31 regions in China, 25.1% of patients had a least one comorbidity and 8.2% of patients had two or more comorbidities [118]. The most prevalent comorbidities were hypertension (16.9%), diabetes (8.2%), cardiovascular disease (3.7%), cerebrovascular disease (1.9%), hepatitis B infection (1.8%), chronic obstructive pulmonary disease (COPD) (1.5%), chronic kidney disease (1.3%), malignancy (1.1%), and immunodeficiency (0.2%). The most common comorbidities associated with worse clinical outcomes, after adjusting for age and smoking status—including admission to an intensive care unit (ICU), the use of invasive ventilation, and death—were malignancy (hazard ratio [HR] 3.50), COPD (HR 2.681), diabetes (HR 1.59), and hypertension (HR 1.58) [118]. In addition, patients who had two or more comorbidities were at greater risk of a poor clinical outcome that those with one comorbidity and patients with any comorbidity were at greater risk of a poor clinical outcome than those without comorbidity [118].
Patients with COPD are vulnerable and highly susceptible to respiratory exacerbations from viral RTIs, and COPD increases the odds of poor clinical outcomes in patients with COVID-19, so these patients should be considered a high-risk group [120]. Although bacterial co-infections are infrequent in COVID-19 patients, the risk of infection increases with the severity of COVID-19, and bacterial co-infections have been detected in up to 46% of patients admitted to an ICU [121].
A number of studies have shown that patients with COVID-19 and comorbid diabetes, predominantly type 2 diabetes but also type 1 diabetes, are at a greater risk of more severe COVID-19 disease, worse clinical outcomes, and death than those without diabetes [122-125]. Notably, microvascular and macrovascular diabetic complications were found in 46.8% and 40.8% of cases, respectively, and these were independently associated with the risk of death in people with diabetes hospitalised for COVID-19 [123]. Patients with COVID-19 and comorbid diabetes or obesity have a high incidence of venous thromboembolism, arterial thrombosis, and thrombotic microangiopathy, which contribute to the high mortality seen in these patients [114]. The high prevalence of comorbid diabetes in COVID-19 patients may be due to the fact that diabetes is known to be associated with an increased risk for infections, particularly RTIs [122]. Endothelial cell dysfunction, which is a hallmark of diseases such as diabetes, represents an additional feature linked with higher susceptibility to COVID-19 complications [126].
Factors that are thought to be involved in the increased risk for worse outcomes in patients with COVID-19 and diabetes include age, gender, and ethnicity together with comorbidities that are commonly seen in patients with diabetes including obesity, cardiovascular disease, hypertension, hyper-coagulation, and a pro-inflammatory state [122, 124, 127, 128]. In addition, the severe ARDS that can result from SARS-CoV-2 infection may be a risk factor for adverse outcomes in patients with diabetes, as it may lead to acute metabolic complications via a direct effect on beta (β)-cell function [122]. Therefore, special attention should be paid, in particular, to elderly people with long-standing diabetes and related advanced complications, people with increased body mass index (overweight and obesity), as well as those with COPD [120, 122].
IMMUNOTHERAPY AND IMMUNOMODULATORY THERAPY FOR THE PREVENTION AND TREATMENT OF SARS-CoV-2 INFECTION
The rationale for using immunotherapy or immunomodulatory therapy for the prevention of SARS-CoV-2 infection is to target the processes involved in viral attachment, entry to host cells and viral replication, and to reinforce the first-line cellular defences to limit airway epithelial-cell infection and viral spread. Curcumin or diferuloylmethane, a plant polyphenol that has immunomodulatory activities, has been shown to inhibit the entry of enveloped viruses such as hepatitis C, H1NI (swine flu), and zika, into host cells in vitro [129, 130]. Evidence also indicates that curcumin may be effective in preventing SARS- CoV-2 infection by binding to ACE2 receptors, thus inhibiting attachment of the virus to the cell membrane, and also by inhibiting viral replication [129, 130].
