Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach

Hopp, Marie-Thérèse; Domingo‐Fernándéz, Daniel; Gadiya, Yojana; Detzel, Milena S.; Graf, Regina; Schmalohr, Benjamin Franz; Kodamullil, Alpha Tom; Imhof, Diana; Hofmann‐Apitius, Martin

doi:10.3390/biom11050644

“…The inclusion of hemoglobin should not be surprising, even when levels fell within normal range in this study, as others have reported a significant drop in hemoglobin values associated with disease severity [ 57 ]. Other authors have also reported remarkably low levels of hemoglobin and albumin in COVID-19 patients, probably due to the rapid turnover of red blood cells that led to hemoglobin degradation [ 58 ]. So, apart from the classic pulmonary immune-inflammation explanation, the occurrence of an oxygen-deprived blood disease (i.e., hemoglobinopathies with iron metabolism dysregulation) appears to be playing a major role in the pathophysiology of this infection [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Kynurenine and Hemoglobin as Sex-Specific Variables in COVID-19 Patients: A Machine Learning and Genetic Algorithms Approach

Celaya-Padilla

¹

,

Villagrana-Bañuelos

²

,

Oropeza-Valdez

³

et al. 2021

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Differences in clinical manifestations, immune response, metabolic alterations, and outcomes (including disease severity and mortality) between men and women with COVID-19 have been reported since the pandemic outbreak, making it necessary to implement sex-specific biomarkers for disease diagnosis and treatment. This study aimed to identify sex-associated differences in COVID-19 patients by means of a genetic algorithm (GALGO) and machine learning, employing support vector machine (SVM) and logistic regression (LR) for the data analysis. Both algorithms identified kynurenine and hemoglobin as the most important variables to distinguish between men and women with COVID-19. LR and SVM identified C10:1, cough, and lysoPC a 14:0 to discriminate between men with COVID-19 from men without, with LR being the best model. In the case of women with COVID-19 vs. women without, SVM had a higher performance, and both models identified a higher number of variables, including 10:2, lysoPC a C26:0, lysoPC a C28:0, alpha-ketoglutaric acid, lactic acid, cough, fever, anosmia, and dysgeusia. Our results demonstrate that differences in sexes have implications in the diagnosis and outcome of the disease. Further, genetic and machine learning algorithms are useful tools to predict sex-associated differences in COVID-19.

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“…Nearly 75% of human iron is contained in hemoglobin; in view of the iron deranged metabolism in COVID-19, a number of articles have investigated a possible hemoglobin denaturation in these patients 1,3,22,63,126,[128][129][130] Though no sound evidence of a direct hemoglobin viral attack has been documented so far, free circulating heme has been described in a few papers 132,240,241 ; moreover, some recruitment of hemoglobin and its metabolites (hemin and protoporphyrin IX) by a few SARS-CoV-2 proteins was documented in a computational biology study. 241 An analogue scientific debate is underway about the alteration of the dissociation curves of hemoglobin in these patients, regardless of whether hypoxia may not be regarded as solely generated by pneumolysis/lung disease.…”

Section: G) Hemoglobin Hemementioning

confidence: 99%

“…121 Additionally, considering the possible autoimmune hemolysis (and piastrinopenia) consequent to the viral interaction with RBC receptors (namely CD147 and sialylated membrane glycoproteins), [122][123][124][125] the possibility of free circulating heme has been taken in consideration with reference to the hypothetical pathomechanisms of COVID-19. 1,[126][127][128][129][130][131][132] More recently, an indirect demonstration of the SARS-CoV-2-induced hemolysis has been reported through liquid chromatography, with a documented increase of protoporphyrin IX in blood of COVID-19 patients. 133 Overall, scientific research has early focused on the possible role of hemoglobin morpho-functional alterations in this disease, as reported above, though a homogenous and direct evidence about hemoglobin dysregulation in COVID-19 has not been reached; similarly, literature reports contrasting papers about the related hypoxia and about the altered hemoglobin dissociation-curves.…”

Section: Introductionmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Cavezzi

¹

,

Menicagli

²

,

Troiani³

et al. 2022

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Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

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“…Nearly 75% of human iron is contained in hemoglobin; in view of the iron deranged metabolism in COVID-19, a number of articles have investigated a possible hemoglobin denaturation in these patients 1,3,22,61,124,[126][127][128] Though no sound evidence of a direct hemoglobin viral attack has been documented so far, free circulating heme has been described in a few papers 130,238,239 ; moreover, some recruitment of hemoglobin and its metabolites (hemin and protoporphyrin IX) by a few SARS-CoV-2 proteins was documented in a computational biology study. 239 An analogue scientific debate is underway about the alteration of the dissociation curves of hemoglobin in these patients, regardless of whether hypoxia may not be regarded as solely generated by pneumolysis/lung disease.…”

Section: G) Hemoglobin Hemementioning

confidence: 99%

“…119 Additionally, considering the possible autoimmune hemolysis (and piastrinopenia) consequent to the viral interaction with RBC receptors (namely CD147 and sialylated membrane glycoproteins), [120][121][122][123] the possibility of free circulating heme has been taken in consideration with reference to the hypothetical pathomechanisms of COVID-19. 1,[124][125][126][127][128][129][130] More recently, an indirect demonstration of the SARS-CoV-2-induced hemolysis has been reported through liquid chromatography, with a documented increase of protoporphyrin IX in blood of COVID-19 patients. 131 Overall, scientific research has early focused on the possible role of hemoglobin morpho-functional alterations in this disease, as reported above, though a homogenous and direct evidence about hemoglobin dysregulation in COVID-19 has not been reached; similarly, literature reports contrasting papers about the related hypoxia and about the altered hemoglobin dissociation-curves.…”

Section: Introductionmentioning

confidence: 99%

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

Cavezzi

¹

,

Menicagli

²

,

Troiani

³

et al. 2022

View full text Add to dashboard Cite

Background: iron and calcium dysmetabolism, with hyperferritinemia, hypoferremia, hypocalcemia and anemia have been documented in the majority of COVID-19 patients at later/worse stages. Furthermore, complementary to ACE2, both sialic acid (SA) molecules and CD147 proved relevant host receptors for SARS-CoV-2 entry, which explains the viral attack to multiple types of cells, including erythrocytes, endothelium and neural tissue. Several authors advocated that cell ferroptosis may be the core and final cell degenerative mechanism. Methods: a literature research was performed in several scientific search engines, such as PubMed Central, Cochrane Library, Chemical Abstract Service. More than 500 articles were retrieved until mid-December 2021, to highlight the available evidence about the investigated issues. Results: based on COVID-19 literature data, we have highlighted a few pathophysiological mechanisms, associated with virus-based cation dysmetabolism, multi-organ attack, mitochondria degeneration and ferroptosis. Our suggested elucidated pathological sequence is: a) spike protein subunit S1 docking with sialylated membrane glycoproteins/receptors (ACE2, CD147), and S2 subunit fusion with the lipid layer; b) cell membrane morpho-functional changes due to the consequent electro-chemical variations and viroporin action, which induce an altered ion channel function and intracellular cation accumulation; c) additional intracellular iron concentration due to a deregulated hepcidin-ferroportin axis, with higher hepcidin levels. Viral invasion may also affect erythrocytes/erythroid precursors, endothelial cells and macrophages, through SA and CD147 receptors, with relative hemoglobin and iron/calcium dysmetabolism. AB0 blood group, hemochromatosis, or environmental elements may represent possible factors which affect individual susceptibility to COVID-19. Conclusions: our literature analysis confirms the combined role of SA molecules, ACE2, CD147, viroporins and hepcidin in determining the cation dysmetabolism and final ferroptosis in the cells infected by SARS-CoV-2. The altered ion channels and electrochemical gradients of the cell membrane have a pivotal role in the virus entry and cell dysmetabolism, with subsequent multi-organ immune-inflammatory degeneration and erythrocyte/hemoglobin alterations.

show abstract

Linking COVID-19 and Heme-Driven Pathophysiologies: A Combined Computational–Experimental Approach

Cited by 18 publications

References 101 publications

Kynurenine and Hemoglobin as Sex-Specific Variables in COVID-19 Patients: A Machine Learning and Genetic Algorithms Approach

Kynurenine and Hemoglobin as Sex-Specific Variables in COVID-19 Patients: A Machine Learning and Genetic Algorithms Approach

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

COVID-19, Cation Dysmetabolism, Sialic Acid, CD147, ACE2, Viroporins, Hepcidin and Ferroptosis: A Possible Unifying Hypothesis

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