PMC:7271924 / 20171-25088 JSONTXT

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{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7271924","sourcedb":"PMC","sourceid":"7271924","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7271924","text":"COVID-19 and Lactoferrin\nCOVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many COVID-19 patients develop acute respiratory distress syndrome (ARDS), which leads to pulmonary edema and lung failure, and have liver, heart, and kidney damages. These symptoms are associated with a cytokine storm (166, 167) manifesting elevated serum levels of interleukin (IL) IL-1β, IL-2, IL-7, IL-8, IL-9, IL-10, IL-17, granulocyte colony-stimulating factor (G-CSF), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), interferon (IFN)γ, tumor necrosis factor (TNF)α, Interferon gamma-induced protein 10 (IP10), Monocyte Chemoattractant Protein-1 (MCP1), macrophage inflammatory protein 1(MIP1)A and MIP1B (168). IL-22, in collaboration with IL-17 and TNFα, induces antimicrobial peptides in the mucosal organs. IL-22 also upregulates mucins, fibrinogen, anti-apoptotic proteins, serum amyloid A, and LPS binding protein (169); therefore, IL-22 may contribute to the formation of life-threatening oedema with mucins and fibrin (170), seen in SARS-CoV-22 and SARS-CoV patients (168).\nThe 2003 SARS-CoV strain, that also causes severe acute respiratory syndrome, attaches to host cells via host receptor ACE2 (171). This type I integral membrane protein receptor is a well-known receptor for respiratory viruses, and is abundantly expressed in tissues lining the respiratory tract (111). During COVID-19 infection, SARS-CoV-2 also enters host cells via the ACE2 receptor (172). ACE2 is highly expressed on human lung alveolar epithelial cells, enterocytes of the small intestine, and the brush border of the proximal tubular cells of the kidney (99). HSPGs are also one of the preliminary docking sites on the host cell surface and play an important role in the process of SARS-CoV cell entry (99). There is no current confirmed information that SARS-CoV-2 binds to HSPGs, however, LF blocks the infection of SARS-CoV by binding to HSPGs (99). It is not presently known whether LF binds to ACE2, but it does bind to HSPGs (99). Whether SARS-CoV-2 also enters host cells via HPSGs in the same way, as does (the 2003) SARS-CoV clearly warrants further investigation.\nOf particular interest, and in the context of this paper, is the set of interactions between SARS-CoV-2 and host platelets. This is of importance, as COVID-19 infection, can cause hyperinflammation due to a cytokine storm (166). Pathogens like the influenza virus and Francisella tularensis, do trigger life-threatening cytokine storms (173). Such a cytokine storm will significantly affect platelets, as platelets have many receptors where these inflammatory molecules may bind (173) (see Figure 5). Circulating cytokines and inflammagens will hyperactivate platelets, causing low platelet count (thrombocytopenia), and a significant chance of hypercoagulation. Thrombocytopenia is associated with increased risk of severe disease and mortality in patients with COVID-19, and thus serves as clinical indicator of worsening illness during hospitalization (174, 175). Patients with type 2 diabetes are also particularly prone to increased levels of circulating inflammatory cytokines and hypercoagulation (76). COVID-19 patients without other comorbidities but with diabetes are at higher risk of severe pneumonia, excessive uncontrolled inflammatory responses and a hypercoagulable state (176). Guo and co-workers in 2020 also found that serum levels of IL-6, C-reactive protein, serum ferritin, and D-dimer, were significantly higher in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of the patient with COVID-19 (140). Acute pulmonary embolism has also been reported in COVID-19 infection (177). Focal accumulation of activated platelets within the oedematous area ex vivo correlated well with the size of the pulmonary embolism (178). Interestingly, anticoagulant therapy, mainly with (intravenous) heparin (and mainly with low molecular weight heparin, LMWH), appears to be associated with better prognosis in severe COVID-19 patients (179).\nFigure 5 Simplified platelet signaling and receptor activation during disease with main dysregulated molecules thrombin, fibrin(ogen), von Willebrand Factor (vWF) interleukins (IL) like IL-1α, IL-1β, and IL17A and cytokines like TNF-α. Diagram created with BioRender (https://biorender.com/). In COVID-19 infection, LF may have a role to play in not only sequestering iron and inflammatory molecules that are severely increased during the cytokine burst, but also possibly in assisting in occupying receptors and HSPGs to prevent virus binding. Receptor occupancy is an important characteristic of LF, when taken as supplement. Furthermore, it may assist in preventing thrombocytopenia, and hypercoagulation, both prominent features of COVID-19 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