Linking COVID-19 and heme-driven pathophysiologies: A combined computational-experimental approach

Abstract

The SARS-CoV-2 outbreak has been declared a worldwide pandemic in 2020. Infection triggers the respiratory tract disease COVID-19, which is accompanied by serious changes of clinical biomarkers such as hemoglobin and interleukins. The same parameters are altered during hemolysis, which is characterized by an increase in labile heme. We present two computational-experimental approaches that aim at analyzing a potential link between heme-related and COVID-19 pathophysiologies. Herein, we performed a detailed analysis of the common pathways induced by heme and SARS-CoV-2 by superimposition of knowledge graphs covering heme biology and COVID-19 pathophysiology. Focus was laid on inflammatory pathways and distinct biomarkers as the linking elements. In a second approach, four COVID-19-related proteins, the host cell proteins ACE2 and TMPRSS2 as well as the viral protein 7a and S protein, were computationally analyzed as potential heme-binding proteins with an experimental validation. The results contribute to the understanding of the progression of COVID-19 infections in patients with different clinical backgrounds and might allow for a more individual diagnosis and therapy in the future.

Effect of COVID-19 on Hemoglobin: Theories and recommended Drugs

“…No absorbance occurs to free heme when measured at the wavelength range. 29 Hopp, Marie-Thérèse et al, were proposing a study of common pathways performed by superimposing two knowledge graphs, namely the "Heme KG"and the "COVID-19 KG", which contained information about theme-driven and COVID-19 pathophysiology on a molecular level. 29 Several biomarkers from proinflammatory pathways (cytokines, such as TNF), the complement system (e.g., C3), the blood and coagulation system (e.g., ferritin, platelets), and organ-specific indicators (i.e., LDH and bilirubin) developed to support the evidently shared clinical 22 .…”

“…With the use of the web tool HeMoQuest and manual refining, the hemebinding potential of these proteins was determined, revealing two possible HBMs on the surface of protein 7a, three for S protein, five for ACE2, and ten motifs for TMPRSS2. 29 Finally, a link between COVID-19 infection symptoms and the consequences of excess heme does not have to be relevant for every patient; but, in certain circumstances, it may correlate or even create a more severe illness development due to pre-existing hemolytic diseases or hemolysis-provoking events. 29…”

“…29 Finally, a link between COVID-19 infection symptoms and the consequences of excess heme does not have to be relevant for every patient; but, in certain circumstances, it may correlate or even create a more severe illness development due to pre-existing hemolytic diseases or hemolysis-provoking events. 29…”

Covid-19: acquired acute porphyria hypothesis

“…Preliminary work from the University of Bonn and Fraunhofer Institute (Hopp et al, 2021) suggests multiple potential heme-binding motifs in SARS-Cov-2 proteins, spike and 7a. Initial lists of potential heme-binding motifs were compiled using HeMo Quest, a primary structure-based HBM prediction server, trained on a large array of heme-binding peptides that has 92% accuracy (Paul George et al, 2020;Hopp et al, 2021). The initial list was refined on the basis of surface accessibility of the motifs within isomers or oligomers of the proteins.…”

Host and viral proteins involved in SARS‐CoV‐2 infection differentially bind heme

“…While heme has been shown to inhibit SARS‐CoV‐2 attachment to endothelial cells and/or intracellular replication in kidney epithelial cells in a dose‐dependent manner, which was mainly attributed to heme‐driven upregulation of heme oxygenase 1 expression, 27–29 an antiviral potency of heme toward SARS‐CoV‐2 infection has been disproven by others as demonstrated in kidney and airway epithelial cell lines 30 . Beyond an impact of heme on the attachment and replication of SARS‐CoV‐2, direct interaction of heme with SARS‐CoV‐2 proteins of the intra‐ and extravirion (i.e., spike glycoprotein, 20,28,31 nucleoprotein, 28 membrane protein, 28 the nonstructural proteins [NSP] 3 and 7, 28 and protein 7a 20 ) as well as heme binding to the in SARS‐CoV‐2 infection participating human host cell proteins TMPRSS2 and ACE2 20 has been proposed. Suitable heme‐binding motifs were identified and experimentally studied only for spike glycoprotein, protein 7a, TMPRSS2, and ACE2 20,31 .…”