The Potential Role of Osteopontin and Furin in Worsening Disease Outcomes in COVID-19 Patients with Pre-Existing Diabetes

Adu-Agyeiwaah, Yvonne; Grant, Maria B.; Obukhov, Alexander G.

doi:10.3390/cells9112528

Cited by 23 publications

(37 citation statements)

References 93 publications

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“…Furin is a second protease involved in S-protein priming during SARS-CoV-2 infection, and also has a role in intracellular processing (241). Furin is present in both membrane-bound and secreted, soluble states with the latter usually associated with a variety of pathologies, such as diabetes or infection (242)(243)(244). Cheng et al recently reported that small molecule inhibitors of furin prevent SARS-CoV-2 infection as well as intracellular processing in vitro (245).…”

Section: Fibrinolysis and Serpins In Sars-cov-2 Infection And The Covid-19 Pandemicmentioning

confidence: 99%

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Yaron

Zhang

Guo

et al. 2021

Front. Cardiovasc. Med.

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The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, “off-the-shelf” system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are the serine protease inhibitors, termed serpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a “respiratory” coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

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Section: Fibrinolysis and Serpins In Sars-cov-2 Infection And The Covid-19 Pandemicmentioning

confidence: 99%

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Yaron

Zhang

Guo

et al. 2021

Front. Cardiovasc. Med.

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“…Furin belongs to the family of type I transmembrane serine-proteases. The enzymatic activity is connected to the subtilisin-like catalytic domain [ 61 , 62 ]. The role of furin as an activator of various substrates is well investigated [ 63 ].…”

Section: The Ocular Tropism Of Sars-cov-2mentioning

confidence: 99%

The Transmission of SARS-CoV-2 Infection on the Ocular Surface and Prevention Strategies

Kitazawa

Deinhardt‐Emmer

Inomata

et al. 2021

Cells

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health problem. Although the respiratory system is the main impaired organ, conjunctivitis is one of its common findings. However, it is not yet understood if SARS-CoV-2 can infect the eye and if the ocular surface can be a potential route of SARS-CoV-2 transmissions. Our review focuses on the viral entry mechanisms to give a better understanding of the interaction between SARS-CoV-2 and the eye. We highlighted findings that give evidence for multiple potential receptors of SARS-CoV-2 on the ocular surface. Additionally, we focused on data concerning the detection of viral RNA and its spike protein in the various ocular tissues from patients. However, the expression level seemed to be relatively low compared to the respiratory tissues as a result of a unique environment surrounding the ocular surface and the innate immune response of SARS-CoV-2. Nevertheless, our review suggests the ocular surface as a potential route for SARS-CoV-2 transmission, and as a result of this study we strongly recommend the protection of the eyes for ophthalmologists and patients at risk.

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“…OPN knockout mice survived longer than wild-type mice upon intranasal infection of Streptococcus pneumoniae , which indicates the detrimental effect of OPN on anti-bacterial defense in the pulmonary compartment during pneumonia [ 58 ]. During COVID-19 infection, OPN-induced furin may enhance the entry of SARS-CoV2 to target cells [ 59 ]. Furthermore, OPN levels were associated with the severity of COVID-19 infection and white blood cell numbers [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

Bai

Furushima

Niki

et al. 2021

IJMS

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Numbers of patients with coronavirus disease 2019 (COVID-19) have increased rapidly worldwide. Plasma levels of full-length galectin-9 (FL-Gal9) and osteopontin (FL-OPN) as well as their truncated forms (Tr-Gal9, Ud-OPN, respectively), are representative inflammatory biomarkers. Here, we measured FL-Gal9, FL-OPN, Tr-Gal9, and Ud-OPN in 94 plasma samples obtained from 23 COVID-19-infected patients with mild clinical symptoms (CV), 25 COVID-19 patients associated with pneumonia (CP), and 14 patients with bacterial infection (ID). The four proteins were significantly elevated in the CP group when compared with healthy individuals. ROC analysis between the CV and CP groups showed that C-reactive protein had the highest ability to differentiate, followed by Tr-Gal9 and ferritin. Spearman’s correlation analysis showed that Tr-Gal9 and Ud-OPN but not FL-Gal9 and FL-OPN, had a significant association with laboratory markers for lung function, inflammation, coagulopathy, and kidney function in CP patients. CP patients treated with tocilizumab had reduced levels of FL-Gal9, Tr-Gal9, and Ud-OPN. It was suggested that OPN is cleaved by interleukin-6-dependent proteases. These findings suggest that the cleaved forms of OPN and galectin-9 can be used to monitor the severity of pathological inflammation and the therapeutic effects of tocilizumab in CP patients.

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The Potential Role of Osteopontin and Furin in Worsening Disease Outcomes in COVID-19 Patients with Pre-Existing Diabetes

Cited by 23 publications

References 93 publications

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

The Transmission of SARS-CoV-2 Infection on the Ocular Surface and Prevention Strategies

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

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