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1.
J Investig Med ; 70(4): 934-938, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1745675

ABSTRACT

Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19-) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55-70.48) vs 14.2 (IQR 5.95-18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01-0.73) vs 0.89 (IQR 0.19-3.82) ng/mL, p=0.035; 2003 (IQR 1355-2447) vs 4713 (IQR 2082-7774) pg/mL, p=0015), respectively) compared with the COVID-19- group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19-, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19- group.


Subject(s)
COVID-19 , Growth Differentiation Factor 15 , Hepcidins/metabolism , Humans , Iron/metabolism , SARS-CoV-2 , Transferrin/analysis
3.
Semin Hematol ; 58(3): 182-187, 2021 07.
Article in English | MEDLINE | ID: covidwho-1500774

ABSTRACT

Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.


Subject(s)
COVID-19 , Iron/metabolism , COVID-19/immunology , COVID-19/metabolism , Humans , Immunity, Innate , Lymphocytes , Pandemics
4.
Mol Biol Rep ; 49(1): 747-754, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1491296

ABSTRACT

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.


Subject(s)
COVID-19/complications , Hyperferritinemia , Mucormycosis , Fungi/isolation & purification , Fungi/pathogenicity , Humans , Hyperferritinemia/complications , Hyperferritinemia/microbiology , Immunosuppressive Agents/adverse effects , India/epidemiology , Iron/metabolism , Mortality , Mucormycosis/epidemiology , Mucormycosis/etiology , Mucormycosis/microbiology , Opportunistic Infections/epidemiology , Opportunistic Infections/microbiology , Rhizopus oryzae/isolation & purification , Rhizopus oryzae/pathogenicity
5.
Trends Endocrinol Metab ; 32(11): 875-889, 2021 11.
Article in English | MEDLINE | ID: covidwho-1401891

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Endothelium, Vascular/immunology , Growth Differentiation Factor 15/immunology , Iron/metabolism , Apoptosis/immunology , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Glial Cell Line-Derived Neurotrophic Factor Receptors/immunology , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Growth Differentiation Factor 15/metabolism , Humans , Immunologic Factors/therapeutic use , Oxidative Stress/immunology , Prognosis , Pyroptosis/immunology , SARS-CoV-2
6.
Int J Mol Sci ; 22(6)2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1389394

ABSTRACT

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.


Subject(s)
Antiviral Agents/chemistry , Metals/chemistry , Methisazone/chemistry , Molecular Docking Simulation , SARS-CoV-2/chemistry , Antiviral Agents/metabolism , COVID-19/drug therapy , Calcium/chemistry , Calcium/metabolism , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Drug Design , Humans , Iron/chemistry , Iron/metabolism , Magnesium/chemistry , Magnesium/metabolism , Manganese/chemistry , Manganese/metabolism , Metals/metabolism , Methisazone/metabolism , Models, Molecular , Molecular Dynamics Simulation , Protein Binding , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Zinc/chemistry , Zinc/metabolism
8.
Pharmacol Res ; 158: 104904, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318936

ABSTRACT

The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.


Subject(s)
Betacoronavirus/drug effects , Chloroquine/pharmacology , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Homeostasis/drug effects , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Iron/metabolism , Pneumonia, Viral/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/metabolism , Humans , Pandemics , Pneumonia, Viral/metabolism , SARS-CoV-2
9.
Molecules ; 26(11)2021 May 28.
Article in English | MEDLINE | ID: covidwho-1320599

ABSTRACT

Deferoxamine B is an outstanding molecule which has been widely studied in the past decade for its ability to bind iron and many other metal ions. The versatility of this metal chelator makes it suitable for a number of medicinal and analytical applications, from the well-known iron chelation therapy to the most recent use in sensor devices. The three bidentate hydroxamic functional groups of deferoxamine B are the centerpiece of its metal binding ability, which allows the formation of stable complexes with many transition, lanthanoid and actinoid metal ions. In addition to the ferric ion, in fact, more than 20 different metal complexes of deferoxamine b have been characterized in terms of their chemical speciation in solution. In addition, the availability of a terminal amino group, most often not involved in complexation, opens the way to deferoxamine B modification and functionalization. This review aims to collect and summarize the available data concerning the complex-formation equilibria in solutions of deferoxamine B with different metal ions. A general overview of the progress of its applications over the past decade is also discussed, including the treatment of iron overload-associated diseases, its clinical use against cancer and neurodegenerative disorders and its role as a diagnostic tool.


Subject(s)
Chelating Agents/chemistry , Deferoxamine/chemistry , Animals , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Chelating Agents/pharmacology , Chemistry, Pharmaceutical/methods , Electrochemistry/methods , Electrolytes , Humans , Hydrogen-Ion Concentration , Ions , Iron/metabolism , Iron Chelating Agents/chemistry , Iron Overload/drug therapy , Kinetics , Ligands , Metals/chemistry , Neoplasms/drug therapy , Potentiometry , SARS-CoV-2 , Temperature , Zirconium/chemistry
10.
Chem Biol Interact ; 344: 109501, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1309181

ABSTRACT

The pandemic of SARS-CoV-2 stimulates significant efforts and approaches to understand its global spread. Although the recent introduction of the vaccine is a crucial prophylactic step, the effective treatment for SARS-CoV-2 is still undiscovered. An in-depth analysis of symptoms and clinical parameters, as well as molecular changes, is necessary to comprehend COVID-19 and propose a remedy for affected people to fight that disease. The analysis of available clinical data and SARS-CoV-2 infection markers underlined the main pathogenic process in COVID-19 is cytokine storm and inflammation. That led us to suggest that the most important pathogenic feature of SARS-CoV-2 leading to COVID-19 is oxidative stress and cellular damage stimulated by iron, a source of Fenton reaction and its product hydroxyl radical (•OH), the most reactive ROS with t1/2-10-9s. Therefore we suggest some scavenging agents are a reasonable choice for overcoming its toxic effect and can be regarded as a treatment for the disease on the molecular level.


Subject(s)
COVID-19/metabolism , COVID-19/prevention & control , Oxidative Stress/physiology , Pandemics/prevention & control , Cytokine Release Syndrome/metabolism , Cytokines/metabolism , Humans , Hydroxyl Radical/metabolism , Inflammation/metabolism , Iron/metabolism , Oxidation-Reduction , Reactive Oxygen Species/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism
11.
Int J Mol Sci ; 22(13)2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1304662

ABSTRACT

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.


Subject(s)
Cell Size/drug effects , Erythrocytes/drug effects , Erythrocytes/pathology , Protein Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adolescent , Biomarkers , Cell Differentiation/drug effects , Cell Line , Child , Child, Preschool , Erythrocyte Indices , Erythrocytes/metabolism , Everolimus/administration & dosage , Everolimus/adverse effects , Everolimus/pharmacology , Flow Cytometry , Humans , Iron/metabolism , K562 Cells , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects
12.
Sci Rep ; 11(1): 13431, 2021 06 28.
Article in English | MEDLINE | ID: covidwho-1286474

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.


Subject(s)
COVID-19/pathology , Iron/blood , Adult , Aged , COVID-19/complications , COVID-19/virology , Female , Ferritins/blood , Hospitalization , Humans , Iron/metabolism , Logistic Models , Male , Middle Aged , Respiratory Insufficiency/etiology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Transferrin/analysis
14.
Science ; 373(6551): 236-241, 2021 07 09.
Article in English | MEDLINE | ID: covidwho-1266364

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.


Subject(s)
Coenzymes/metabolism , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cyclic N-Oxides/pharmacology , Iron/metabolism , SARS-CoV-2/drug effects , Sulfur/metabolism , Amino Acid Motifs , Animals , Antiviral Agents/pharmacology , Binding Sites , Catalytic Domain , Chlorocebus aethiops , Coenzymes/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/pharmacology , Iron/chemistry , Protein Domains , RNA Helicases/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/physiology , Spin Labels , Sulfur/chemistry , Vero Cells , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects , Zinc/metabolism
15.
Eur Rev Med Pharmacol Sci ; 25(10): 3772-3790, 2021 05.
Article in English | MEDLINE | ID: covidwho-1264762

ABSTRACT

Multiple epidemiological studies have suggested that industrialization and progressive urbanization should be considered one of the main factors responsible for the rising of atherosclerosis in the developing world. In this scenario, the role of trace metals in the insurgence and progression of atherosclerosis has not been clarified yet. In this paper, the specific role of selected trace elements (magnesium, zinc, selenium, iron, copper, phosphorus, and calcium) is described by focusing on the atherosclerotic prevention and pathogenesis plaque. For each element, the following data are reported: daily intake, serum levels, intra/extracellular distribution, major roles in physiology, main effects of high and low levels, specific roles in atherosclerosis, possible interactions with other trace elements, and possible influences on plaque development. For each trace element, the correlations between its levels and clinical severity and outcome of COVID-19 are discussed. Moreover, the role of matrix metalloproteinases, a family of zinc-dependent endopeptidases, as a new medical therapeutical approach to atherosclerosis is discussed. Data suggest that trace element status may influence both atherosclerosis insurgence and plaque evolution toward a stable or an unstable status. However, significant variability in the action of these traces is evident: some - including magnesium, zinc, and selenium - may have a protective role, whereas others, including iron and copper, probably have a multi-faceted and more complex role in the pathogenesis of the atherosclerotic plaque. Finally, calcium and phosphorus are implicated in the calcification of atherosclerotic plaques and in the progression of the plaque toward rupture and severe clinical complications. In particular, the role of calcium is debated. Focusing on the COVID-19 pandemia, optimized magnesium and zinc levels are indicated as important protective tools against a severe clinical course of the disease, often related to the ability of SARS-CoV-2 to cause a systemic inflammatory response, able to transform a stable plaque into an unstable one, with severe clinical complications.


Subject(s)
Atherosclerosis/pathology , Trace Elements/metabolism , Atherosclerosis/metabolism , COVID-19/pathology , COVID-19/virology , Calcium/blood , Calcium/metabolism , Copper/blood , Copper/metabolism , Humans , Iron/blood , Iron/metabolism , Magnesium/blood , Magnesium/metabolism , Matrix Metalloproteinases/metabolism , Phosphorus/blood , Phosphorus/metabolism , Risk , SARS-CoV-2/isolation & purification , Selenium/blood , Selenium/metabolism , Severity of Illness Index , Trace Elements/blood , Zinc/blood , Zinc/metabolism
16.
Free Radic Res ; 55(7): 745-756, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1258678

ABSTRACT

It has been shown that the development of coronavirus infection (COVID-19), especially in severe cases, is accompanied by hypoxia as a result of several pathological processes: alveolar blood supply disorders, hemolysis, COVID-associated coagulopathy. Under these conditions, the level of reactive oxygen species is increased and it is more likely that free-radical damage to biomolecules is caused by the process of free-radical fragmentation than oxidation. In contrast to the oxidation process, free-radical fragmentation reactions are more effectively inhibited by oxidizing agents than reducing agents. Therefore, the use of substances possessing both reducing and oxidizing properties, such as natural and synthetic quinones, bioflavonoids, curcuminoids, should reduce the probability of biomolecule destruction by oxidation as well as free-radical fragmentation processes.HighlightsCOVID-19 is accompanied by the iron release from the heme and «silent¼ hypoxiaROS initiate fragmentation reactions of biomolecules under conditions of hypoxiaBlocking of fragmentation process by oxidizers may lead to mitigation of COVID-19.


Subject(s)
COVID-19/metabolism , Free Radicals/metabolism , SARS-CoV-2/metabolism , COVID-19/pathology , COVID-19/virology , Free Radicals/adverse effects , Heme/metabolism , Humans , Iron/metabolism , Oxidation-Reduction/drug effects , Reactive Oxygen Species/adverse effects , Reactive Oxygen Species/metabolism , SARS-CoV-2/pathogenicity
17.
Cells ; 10(5)2021 05 04.
Article in English | MEDLINE | ID: covidwho-1223957

ABSTRACT

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Subject(s)
COVID-19/diagnosis , Iron Overload/etiology , Liver Failure/etiology , Liver/pathology , Severity of Illness Index , Adult , Aged , Antiviral Agents , Biopsy , COVID-19/complications , COVID-19/mortality , COVID-19/therapy , Female , Ferritins/analysis , Hepatocytes/cytology , Hepatocytes/pathology , Humans , Iron/analysis , Iron/metabolism , Iron Overload/mortality , Iron Overload/pathology , Iron Overload/therapy , Liver/cytology , Liver/metabolism , Liver Failure/mortality , Liver Failure/pathology , Liver Failure/therapy , Liver Function Tests , Male , Middle Aged , Mitochondria/pathology , Positive-Pressure Respiration , SARS-CoV-2/isolation & purification
18.
Autoimmunity ; 54(4): 213-224, 2021 06.
Article in English | MEDLINE | ID: covidwho-1201340

ABSTRACT

Currently, the novel coronavirus pneumonia has been widespread globally, and there is no specific medicine. In response to the emergency, we employed bioinformatics methods to investigate the virus's pathogenic mechanism, finding possible control methods. We speculated in previous studies that E protein was associated with viral infectivity. The present study adopted the domain search techniques to analyse the E protein. According to the results, the E protein could bind iron or haem. The iron and haem bound by the E protein came from the attacked haemoglobin and phagocytes. When E protein was attached to haem, it synthesised oxygen and water into superoxide anions, hydrogen peroxide and hydroxyl radicals. When the iron-bound E protein and the haem-bound E protein worked together, they converted superoxide anions and hydrogen peroxide into oxygen and water. These were the "ROS attack" and "ROS escape" of the virus. "ROS attack" damaged the tissues or cells exposed on the surface of the virus, and "ROS escape" decomposed the superoxide anion and hydrogen peroxide that attacked the virus. When NK cells were exposed to infected cells, viruses that had not shed from the infected cells' surface damaged them through "ROS attack". In addition, lymphocytes such as T cells and B cells, which could be close to the antigen of the virus surface, were also easily damaged or killed by the "ROS attack", generating a decrease in lymphocytes. When memory B cells were exposed to the virus's surface antigen, they were also damaged by "ROS attack", resulting in the patient's re-infection. The virus applied the "ROS escape" to decompose hydrogen peroxide released by phagocytes into oxygen and water. The surrounding cells were replenished with oxygen, and the patient was in a "happy hypoxia" state. When the phagocytes swallowed the virus, the E protein converted superoxide anions into oxygen and water. In this way, the virus parasitized in the vesicles of the phagocyte. While virus was in the lysosome, the E protein generated ROS to damage nearby hydrolases. In this way, the virus parasitized the lysosome. Excessive hydroxyl free radicals destroyed the membrane structure of the lysosome, causing the hydrolase release from lysosome, autophagy of phagocytic cells and subsequent cell death. As a result, the colonizing phagocytes of the virus was associated with asymptomatic infection or retest-positive. Briefly, the virus inhibited the immune system through "ROS escape", and damaged the immune system by "ROS attack". The destruction instigated a strong cytokine storm, leading to organ failure and complications.


Subject(s)
COVID-19/etiology , COVID-19/metabolism , Disease Susceptibility , Host-Pathogen Interactions , Immune System/immunology , Immune System/metabolism , Iron/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2/physiology , Amino Acid Sequence , Catalysis , Computational Biology/methods , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immune System/pathology , Models, Molecular , Protein Conformation , Structure-Activity Relationship , Superoxide Dismutase/metabolism , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolism
19.
Metallomics ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1195731

ABSTRACT

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.


Subject(s)
COVID-19/metabolism , Ferritins/chemistry , Ferritins/metabolism , SARS-CoV-2 , Biomarkers/chemistry , Biomarkers/metabolism , Biotechnology , Ceruloplasmin/metabolism , Drug Delivery Systems , Ferritins/genetics , Ferroptosis/physiology , Glycosylation , Homeostasis , Humans , Inflammation/metabolism , Iron/metabolism , Nanotechnology , Neoplasms/diagnosis , Neoplasms/metabolism , Prognosis , Tissue Distribution
20.
Genome Med ; 12(1): 113, 2020 12 09.
Article in English | MEDLINE | ID: covidwho-964565

ABSTRACT

BACKGROUND: Antibiotic-resistant Klebsiella pneumoniae are a major cause of hospital- and community-acquired infections, including sepsis, liver abscess, and pneumonia, driven mainly by the emergence of successful high-risk clonal lineages. The K. pneumoniae sequence type (ST) 307 lineage has appeared in several different parts of the world after first being described in Europe in 2008. From June to October 2019, we recorded an outbreak of an extensively drug-resistant ST307 lineage in four medical facilities in north-eastern Germany. METHODS: Here, we investigated these isolates and those from subsequent cases in the same facilities. We performed whole-genome sequencing to study phylogenetics, microevolution, and plasmid transmission, as well as phenotypic experiments including growth curves, hypermucoviscosity, siderophore secretion, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance for an in-depth characterization of this outbreak clone. RESULTS: Phylogenetics suggest a homogenous phylogram with several sub-clades containing either isolates from only one patient or isolates originating from different patients, suggesting inter-patient transmission. We identified three large resistance plasmids, carrying either NDM-1, CTX-M-15, or OXA-48, which K. pneumoniae ST307 likely donated to other K. pneumoniae isolates of different STs and even other bacterial species (e.g., Enterobacter cloacae) within the clinical settings. Several chromosomally and plasmid-encoded, hypervirulence-associated virulence factors (e.g., yersiniabactin, metabolite transporter, aerobactin, and heavy metal resistance genes) were identified in addition. While growth, biofilm formation, desiccation resilience, serum survival, and heavy metal resistance were comparable to several control strains, results from siderophore secretion and hypermucoviscosity experiments revealed superiority of the ST307 clone, similar to an archetypical, hypervirulent K. pneumoniae strain (hvKP1). CONCLUSIONS: The combination of extensive drug resistance and virulence, partly conferred through a "mosaic" plasmid carrying both antibiotic resistance and hypervirulence-associated features, demonstrates serious public health implications.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/genetics , Iron/metabolism , Klebsiella Infections/microbiology , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Bacterial Proteins/genetics , Biofilms/growth & development , Disease Outbreaks , Genes, Bacterial/genetics , Germany/epidemiology , Humans , Klebsiella Infections/epidemiology , Klebsiella pneumoniae/classification , Klebsiella pneumoniae/growth & development , Phylogeny , Plasmids , Polymorphism, Single Nucleotide , Virulence/drug effects , Virulence/genetics , Virulence Factors/genetics , Whole Genome Sequencing
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