A Journey into the Clinical Relevance of Heme Oxygenase 1 for Human Inflammatory Disease and Viral Clearance: Why Does It Matter on the COVID-19 Scene?

Abstract

Heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme degradation, is involved in the maintenance of cellular homeostasis, exerting a cytoprotective role by its antioxidative and anti-inflammatory functions. HO-1 and its end products, biliverdin, carbon monoxide and free iron (Fe²⁺), confer cytoprotection against inflammatory and oxidative injury. Additionally, HO-1 exerts antiviral properties against a diverse range of viral infections by interfering with replication or activating the interferon (IFN) pathway. Severe cases of coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are characterized by systemic hyperinflammation, which, in some cases, leads to severe or fatal symptoms as a consequence of respiratory failure, lung and heart damage, kidney failure, and nervous system complications. This review summarizes the current research on the protective role of HO-1 in inflammatory diseases and against a wide range of viral infections, positioning HO-1 as an attractive target to ameliorate clinical manifestations during COVID-19.

Keywords: COVID-19; Dengue virus; Ebola virus; Hepatitis virus; SARS-CoV-2; Zika virus; heme oxygenase 1; human immunodeficiency virus; influenza A virus; respiratory syncytial virus.

Figure 1

Inducers of HO-1. HO-1 degrades heme producing equimolar amounts of carbon monoxide (CO), biliverdin (BV) and Fe²⁺. HO-1′s inducers are grouped into protoporphyrins, a type of porphyrins that forms heme; phytochemicals, natural antioxidants compounds contained in plants; and approved drugs, compounds that were previously approved by the FDA. CoPP: cobalt protoporphyrin IX; 5-ALA: 5-aminolevulinic acid; DMF: dimethyl fumarate; 5-ASA: 5-aminosalicylic acid; CORMs: CO-releasing molecules; HYCOs: Hybrid carbon monoxide-releasing molecules; BR: bilirubin. The images of HO-1 and CoPP were taken from RCSB PDB (PDB ID: 1N3U) and The National Center for Biotechnology Information [107,108].

Figure 2

HO-1 and inflammatory lung diseases. HO-1 is expressed in pulmonary cells and confers protection against inflammatory lung diseases such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and SARS-CoV-2 infection. Schematic representation displaying HO-1′s reaction and its products’ protective effects in the lung tissue.

Figure 3

HO-1′s induction and its effect on different viral infections. Table containing previously reported studies about HO-1 involvement in influenza A virus (IAV), respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), ebola virus (EBOV), dengue virus (DENV), zika virus (ZIKV), hepatitis C virus (HCV), hepatitis B virus (HBV), herpes simplex virus 2 (HSV-2), enterovirus 71 (EV71) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The table includes the experimental model, HO-1 inducers, its mechanism of action, its effect and the study’s PMID. CoPP: cobalt protoporphyrin IX, DMO-CAP: 6-demethoxy-4′-O-methylcapillarisin, ROS: Reactive oxygen species, IFN: interferon, MDM: monocyte derived macrophages, BV: Biliverdin, CO: carbon monoxide, CORM-2: CO-releasing molecule-2.

Figure 4

HO-1′s role in different sites that can be affected upon SARS-CoV-2 infection. Extra pulmonary manifestations of COVID-19 are grouped according to their site or body system. HO-1′s reported functions in different experimental conditions or diseases are grouped according to the model or system in which they are studied. The image of the human body has been adapted from Uhlén et al. (Human Protein Atlas, proteinatlas.org) [208].