Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

Abstract

Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-β superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.

Keywords: COVID-19; GDF-15; adaptive metabolic response; biomarker; disease tolerance.

Figure 1

Contribution of a GDF-15 signaling pathway in COVID-19 pathogenesis. Lungs infected with SARS-CoV-2 lead to tissue damage, hypoxia, and endothelialitis. Tobacco smoke, ultrafine particles, and air pollutants act as a co-stimulant in the direct release of GDF15 in the lung epithelial cells. The virus enters the host cell via ACE2 on type II pneumocytes causing the recruitment of leucocytes, hence, elevated innate immune response. SARS-COV-2 also causes direct endothelialitis after the destruction of the alveolar epithelia. The transmigration of leucocytes causes a massive release of proinflammatory cytokines IL-6, IL-8, TNF alpha, IP-10, IL-1beta, IFN gamma, GM-CSF, and Notch pathway. The hippo pathway favors IL-17 differentiation and the Wnt pathway inhibits Treg suppressor function mediated by GDF15 resulting in overwhelming immune system activation. Together with the formation of the syncytium, hyperactivation of immune response commenced leading to cytokine storm, hypercoagulation and elevated neutrophils-lymphocytes ratio critical in severe outcomes in patients affected with SARS-COV-2 especially with comorbidities. GDF, growth differentiation factor; IL, interleukin; ARDS, acute respiratory distress syndrome; ACE, angiotensin-converting enzyme; UFP, ultrafine particles; HF, heart failure; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular diseases; CD, cluster differentiation; GM-CSF, granulocyte monocyte-colony stimulating factor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ESKD, end-stage kidney disease; IDA, iron-deficiency anemia; T reg, regulatory T cells; ICU, intensive care unit; NK cells, natural killer cells.