Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity.

Luz E Cabrera,Olli Vapalahti,Satu Mäkelä,Sanna Lehtonen,Antti Vaheri,Jukka Mustonen,Tomas Strandin,Moin A Saleem,Constanze Schmotz

doi:10.3390/v14030450

Abstract

Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus–caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS–associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus–infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus–infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.

Highlights

Licensee MDPI, Basel, Switzerland.Orthohantaviruses are zoonotic pathogens able to cause two major clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS)
These parameters significantly correlated with several important inflammatory markers describing disease severity and the extent of acute kidney injury (AKI): urinary syndecan–1 was associated with indicators of systemic inflammation, whereas urinary
Acute PUUV–HFRS presented with elevation of HPSE and syndecan–1 levels in urine

Summary

Introduction

Orthohantaviruses are zoonotic pathogens able to cause two major clinical syndromes: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). Different orthohantavirus species possess varying pathogenicity in humans. The prototype orthohantavirus Hantaan (HTNV, circulates in Eastern Asia) causes a more severe form of HFRS with mortality up to 5%, whereas Puumala orthohantavirus (PUUV, mainly in Northern Europe) causes a mild form of the disease often referred to as nephropathia published maps and institutional affil-. Orthohantaviruses circulating in the Americas are associated with the highly severe HCPS (mortality > 30%) [1]. HFRS is characterized by changes in the endothelial barrier functions, fluid alterations including extravasation, increased glomerular permeability and proteinuria [2,3,4]

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