Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis

Leeming, Diana Julie; Genovese, Federica; Sand, J.M.B.; Rasmussen, Daniel Guldager Kring; Christiansen, Claus; Jenkins, Gisli; Maher, Toby M.; Vestbo, Jørgen; Karsdal, Morten A.

doi:10.1186/s12931-020-01590-y

Cited by 30 publications

(44 citation statements)

References 32 publications

(49 reference statements)

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“…Increased CD47 levels were also detected in the lungs 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 [47,48]. Finally, anti-CD47 antibodies reversed fibrosis in various organs in mouse models [49], which may be relevant in the context of COVID-19-associated pulmonary fibrosis [50].…”

Section: Referencementioning

confidence: 81%

A Potential Role of the CD47/SIRPalpha Axis in COVID-19 Pathogenesis

McLaughlin

Bojkova

Kandler

et al. 2021

CIMB

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The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. 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. Here, we show 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. Our data should encourage other research groups to consider the potential relevance of the CD47/ SIRPalpha axis in their COVID-19 research.

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Section: Referencementioning

confidence: 81%

A Potential Role of the CD47/SIRPalpha Axis in COVID-19 Pathogenesis

McLaughlin

Bojkova

Kandler

et al. 2021

CIMB

View full text Add to dashboard Cite

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“…Results indicated an ageing-related increase in CD47 expression, which may contribute the increased COVID-19 vulnerability in older patients [Hokello et al, 2020]. Moreover, high CD47 levels are known to be involved in vascular disease, vasoconstriction, and hypertension, which may predispose SARS-CoV-2-infected individuals to various conditions associated with severe COVID-19 related, including 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].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Cd47 and Ageingmentioning

confidence: 99%

CD47 as a potential biomarker for the early diagnosis of severe COVID-19

McLaughlin

Bojkova

Bechtel

et al. 2021

Preprint

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The coronavirus SARS-CoV-2 is the cause of the ongoing COVID-19 pandemic. 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. Antiviral interventions are only effective prior to the onset of hyperinflammation. Hence, biomarkers are needed for the early identification and treatment of high-risk patients. Here, we show in a range of model systems and data from post mortem samples that SARS-CoV-2 infection results in increased levels of CD47, which is known to mediate immune escape in cancer and virus-infected cells. Systematic literature searches also 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 which 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, CD47 is a candidate biomarker for severe COVID-19. Further research will have to show whether CD47 is a reliable diagnostic marker for the early identification of COVID-19 patients requiring antiviral therapy.

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“…For example, we found strong TGF-β mediated immune-epithelial cell interactions in aged severe COVID-19 patients. TGF-β plays a crucial role in pulmonary fibrosis 53,54 , which is a common complication in severe COVID-19 patients 55 . The nucleocapsid protein of SARS-CoV-1 also upregulates TGF-β expression 56 .…”

Section: Discussionmentioning

confidence: 99%

Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients

Hou

Zhou

Gack

et al. 2021

Preprint

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Coronavirus Disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio) are significantly associated with age-specific COVID-19 severities. We identified the reduced abundance of naive CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID-19 patients. Older individuals with severe COVID-19 displayed type I & II interferons deficiencies, which is correlated with SARS-CoV-2 viral load. Elevated expression of SARS-CoV-2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID-19 in aged individuals. Mechanistically, we identified strong TGF-beta mediated immune-epithelial cell interactions (i.e., secretory-T regulatory cells) in aged individuals with critical COVID-19. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.

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Can biomarkers of extracellular matrix remodelling and wound healing be used to identify high risk patients infected with SARS-CoV-2?: lessons learned from pulmonary fibrosis

Cited by 30 publications

References 32 publications

A Potential Role of the CD47/SIRPalpha Axis in COVID-19 Pathogenesis

A Potential Role of the CD47/SIRPalpha Axis in COVID-19 Pathogenesis

CD47 as a potential biomarker for the early diagnosis of severe COVID-19

Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients

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