Protein CD47 Found To Be Contributing Factor To COVID-19 Disease Severity

A new study led by researchers from University of Kent-UK and Goethe University-Germany has discovered that a protein that is a component of the human immune system called CD47, found on cell surfaces plays a contributing factor to COVID-19 disease severity.

Typically most SARS-CoV-2 infections are mild or even asymptomatic. However, a small fraction of infected individuals develops severe, life-threatening disease, which is caused by an uncontrolled immune response resulting in hyperinflammation.

However, the factors predisposing individuals to severe disease remain poorly understood.
 
The study team shows that levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells, are elevated in SARS-CoV-2-infected Caco-2 cells, Calu-3 cells, and air−liquid interface cultures of primary human bronchial epithelial cells.
 
Moreover, SARS-CoV-2 infection increases SIRPalpha levels, the binding partner of CD47, on primary human monocytes. Systematic literature searches further indicated that known risk factors such as older age and diabetes are associated with increased CD47 levels.

High CD47 levels contribute to vascular disease, vasoconstriction, and hypertension, conditions that may predispose SARS-CoV-2-infected individuals to COVID-19-related complications such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury.
 
Hence, age-related and virus-induced CD47 expression is a candidate mechanism potentially contributing to severe COVID-19, as well as a therapeutic target, which may be addressed by antibodies and small molecules. Further research will be needed to investigate the potential involvement of CD47 and SIRPalpha in COVID-19 pathology.

The study findings should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.
 
The study findings were published in the peer reviewed journal: Molecular Biology. https://www.mdpi.com/1467-3045/43/3/86/htm
 
The study team identified the protein CD47 that may critically contribute to severe forms of COVID-19.
 
Although most people with COVID-19 disease develop only mild or no symptoms upon SARS-CoV-2 infection, others develop severe, life-threatening disease.
 
The COVID-19 Research team had found that the infection of cells with SARS-CoV-2 results in increased levels of a protein called CD47 on the cell surface.
 
Interestingly CD47 is a so-called ‘do not eat me’ signal to the immune system’s defenses that protect cells from being destroyed.

Virus-induced CD47 on the surface of infected cells is likely to protect them from immune system recognition, enabling the production of larger amounts of virus, resulting in more severe disease.
 
It was found that well-known risk factors for severe COVID-19 such as older age and diabetes are associated with higher CD47 levels. High CD47 levels also contribute to high blood pressure, which is a large risk factor for COVID-19 complications such as heart attack, stroke, and kidney disease.

The study findings suggest that age and virus-induced high CD47 levels contribute to severe COVID-19 by preventing an effective immune response and increasing disease-associated tissue and organ damage.
 
As therapeutics targeting CD47 are already in development, this discovery may result in improved COVID-19 therapies.
 
Co-corresponding author, Dr Martin Michaelis, a professor at the School of Biosciences, University of Kent told Thailand Medical News, “This is exciting. We may have identified a major factor associated with severe COVID-19. This is a huge step in combatting the disease and we can now look forward to further progress in the design of therapeutics.”
 
Dr Jindrich Cinatl, a professor from the Institute for Medical Virology, Goethe University and also a co-corresponding author added, “These additional insights into the disease processes underlying COVID-19 may help us to design better therapies, as well as appreciation for the importance of the breadth of research being conducted. Through this avenue, we have achieved a major breakthrough and exemplified that the fight against the disease continues.”

CD47 and COVID-19 risk factors
To further investigate a potential role of CD47 as biomarker indicating a high risk from COVID-19, we performed systematic literature searches on the relationship of CD47 and the known COVID-19 risk factors ‘ageing’, ‘diabetes’, and ‘obesity’.

CD47 and ageing

The risk of severe COVID-19 disease and COVID-19 death increases with age [Hokello et al., 2020]. A literature search in PubMed (https://pubmed.ncbi.nlm.nih.gov, 17th February 2020) using the terms ‘CD47’ and aging’ resulted in 62 hits (Suppl. Table 1). Eight of these articles contained information that support a link between age-related increased CD47 levels and an elevated risk of severe COVID-19 (Figure 2, Suppl. Table 1).

One article suggested that alpha-tocopherol reduced age-associated streptococcus pneumoniae lung infection in mice by CD47 downregulation [Ghanem et al., 2015], which is in accordance with the known immunosuppressive functions of CD47 [Cham et al., 2020; Kaur et al., 2020].

The remaining seven articles reported on age-related increased CD47 levels in vascular cells that are associated with reduced vasodilatation and blood flow (Suppl. Table 1), as CD47 signalling inhibits NO-mediated activation of soluble guanylate cyclase and in turn vasodilatation [Isenberg et al., 2008; Miller et al., 2010]. Since reduced vasodilatation can cause hypertension [Touyz et al., 2018], we performed a follow-up literature search using the search terms “CD47 hypertension” (Suppl. Table 2). This resulted in 20 hits, including a further seven relevant studies (Figure 2B, Suppl. Table 2).

Initial experiments showed that loss or inhibition of CD47 prevented age- and diet-induced vasculopathy and reduced damage caused by ischaemic injury in mice [Isenberg et al., 2007]. CD47-deficient mice indicated that CD47 functions as vasopressor and were also shown to be leaner and to display enhanced physical performance and a more efficient metabolism [Isenberg et al., 2009; Frazier et al., 2011].

In agreement, CD47 was upregulated in clinical pulmonary hypertension and contributed to pulmonary arterial vasculopathy and dysfunction in mouse models [Bauer et al., 2012; Rogers et al., 2017]. Age-related increased CD47 levels further affected peripheral blood flow and wound healing in mice [Rogers et al., 2013] and NO-mediated vasodilatation of coronary arterioles of rats [Nevitt et al., 2016]. Moreover, thrombospondin-1/ CD47 signalling was shown to induce ageing-associated senescence in endothelial cells [Gao et al., 2016; Meijles et al., 2017] and age-associated deterioration in angiogenesis, blood flow, and glucose homeostasis [Ghimire et al., 2020].

Increased CD47 levels were also detected in the lung of a sickle cell disease patient with pulmonary arterial hypertension, and vasculopathy and pulmonary hypertension were reduced in a CD47-null mouse model of sickle cell disease [Rogers et al., 2013a; Novelli et al., 2019]. Finally, anti-CD47 antibodies reversed fibrosis in various organs in mouse models [Wernig et al., 2017], which may be relevant in the context of COVID-19-associated pulmonary fibrosis [Leeming et al., 2021].

In addition to immunosuppressive activity, ageing-related increased CD47 levels may thus be involved in vascular disease, vasoconstriction, and hypertension and predispose COVID-19 patients to related pathologies such as pulmonary hypertension, lung fibrosis, myocardial injury, stroke, and acute kidney injury [Soto-Pantoja et al., 2013; Rogers et al., 2017a; Cruz Rodriguez et al., 2020; Fabrizi et al., 2020; Karmouty-Quintana et al., 2020; Scutelnic and Heldner, 2020; Leeming et al., 2021; Sanghvi et al., 2021; Shah et al., 2021].

reference link : https://www.biorxiv.org/content/10.1101/2021.03.01.433404v1.full