Yellow fever disease severity and endothelial dysfunction are associated with elevated serum levels of viral NS1 protein and syndecan-1

Abstract

Yellow fever virus (YFV) infections can cause severe disease manifestations, including hepatic injury, endothelial damage, coagulopathy, hemorrhage, systemic organ failure, and shock, and are associated with high mortality in humans. While nonstructural protein 1 (NS1) of the related dengue virus is implicated in contributing to vascular leak, little is known about the role of YFV NS1 in severe YF and mechanisms of vascular dysfunction in YFV infections. Here, using serum samples from qRT-PCR-confirmed YF patients with severe (n=39) or non-severe (n=18) disease in a well-defined hospital cohort in Brazil, plus samples from healthy uninfected controls (n=11), we investigated factors associated with disease severity. We developed a quantitative YFV NS1 capture ELISA and found significantly increased levels of NS1, as well as syndecan-1, a marker of vascular leak, in serum from severe YF as compared to non-severe YF or control groups. We also showed that hyperpermeability of endothelial cell monolayers treated with serum from severe YF patients was significantly higher compared to non-severe YF and control groups as measured by transendothelial electrical resistance (TEER). Further, we demonstrated that YFV NS1 induces shedding of syndecan-1 from the surface of human endothelial cells. Notably, YFV NS1 serum levels significantly correlated with syndecan-1 serum levels and TEER values. Syndecan-1 levels also significantly correlated with clinical laboratory parameters of disease severity, viral load, hospitalization, and death. In summary, this study points to a role for secreted NS1 in YF disease severity and provides evidence for endothelial dysfunction as a mechanism of YF pathogenesis in humans.

A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection

“…Hemorrhagic fever, a hallmark of YFV-induced cardiovascular disease, arises from capillary damage and plasma leakage. Endothelial function deterioration is pivotal here, with YFV infection escalating the expression of endothelial damage biomarkers, such as angiopoietin-2 (Ang-2), matrix metallopeptidase 2 (MMP-2) and MMP-9, endothelin-1 (ET-1), acetyl tetrapeptide-1 (syndecan-1), vascular cell adhesion molecules1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) [ 45 , 46 , 47 ]. Elevated endothelin-1 levels, in particular, heighten inflammation and cytokine (IL-1β, TNF-α, and IL-6) production, disrupting the endothelial barrier and inducing hemorrhage.…”

“…Elevated endothelin-1 levels, in particular, heighten inflammation and cytokine (IL-1β, TNF-α, and IL-6) production, disrupting the endothelial barrier and inducing hemorrhage. Higher levels of syndecan-1, endothelin-1, and VCAM-1 are also associated with a worse prognosis in sepsis [ 45 ], underscoring their contributory role in exacerbating cardiovascular disease. This intricate interplay of viral action, inflammation, and endothelial damage underscores the complexity of YFV’s impact on the cardiovascular system.…”

“…These efforts will help mitigate the cardiovascular injuries caused by Flaviviridae virus infections and alleviate the burden of cardiovascular diseases associated with these viruses. Viral direct damage [20], viremia [31], organismal immunityviraemia [22], metabolic imbalance [27] YFV Sinus bradycardia, myocardial necrosis, myocardial inflammatory infiltration, acute endocarditis, Percarditis, and coronary branch thrombosis Myocardial cell necrosis [38], immune response [42], endothelial dysfunction [45] DENV Heart rate abnormalities, hypotension, myocarditis, pericarditis, heart failure, cardiac systolic and diastolic dysfunction, endothelial inflammation Virulence [59], immune response [64], endothelial dysfunction [65] ZIKV Myocarditis, pericarditis, heart failure, arrhythmias, perivascular and endothelial injury, venous thrombosis Virulence [70], inflammatory pathway [75], autophagy [81] WNV Institutional Review Board Statement: Not applicable.…”