CMV Seropositive Status Increases Heparanase SNPs Regulatory Activity, Risk of Acute GVHD and Yield of CD34+ Cell Mobilization.

Olga Ostrovsky,Avichai Shimoni,Arnon Nagler,Angel Cid-Arregui,Nira Bloom,Israel Vlodavsky,Yan Morgulis,Katia Beider

doi:10.3390/cells10123489

Olga Ostrovsky, Avichai Shimoni + Show 6 more

Open Access

PDF Available

https://doi.org/10.3390/cells10123489

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Heparanase is an endo-β-glucuronidase that is best known for its pro-cancerous effects but is also implicated in the pathogenesis of various viruses. Activation of heparanase is a common strategy to increase viral spread and trigger the subsequent inflammatory cascade. Using a Single Nucleotide Polymorphisms (SNP)-associated approach we identified enhancer and insulator regions that regulate HPSE expression. Although a role for heparanase in viral infection has been noticed, the impact of HPSE functional SNPs has not been determined. We investigated the effect of cytomegalovirus (CMV) serostatus on the involvement of HPSE enhancer and insulator functional SNPs in the risk of acute graft versus host disease (GVHD) and granulocyte-colony stimulating factor related CD34+ mobilization. A significant correlation between the C alleles of insulator rs4364254 and rs4426765 and CMV seropositivity was found in healthy donors and patients with hematological malignancies. The risk of developing acute GVHD after hematopoietic stem cell transplantation was identified only in CMV-seropositive patients. A significant correlation between the enhancer rs4693608 and insulator rs28649799 and CD34+ cell mobilization was demonstrated in the CMV-seropositive donors. It is thus conceivable that latent CMV infection modulates heparanase regulatory regions and enhances the effect of functional SNPs on heparanase function in normal and pathological processes.

Highlights

Heparanase (HPSE) is an endo-β-glucuronidase that cleaves the saccharide chains of heparan sulfate (HS) proteoglycans (HSPG), key components of the cell surface, basement membrane and extracellular matrix (ECM)
HS has long been known to serve as an attachment receptor for a large variety of human viruses, including herpes simplex virus (HSV), dengue virus (DENV), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), Epstein–Barr virus (EBV), Vaccinia virus (VACV) and others [4,5,6,7,8,9,10,11,12,13,14]
We identified two regulatory regions of the HPSE gene, a strong enhancer, located in intron 2 [20], and a 200 bp insulator mapped in intron 9 [21]

Summary

Introduction

Heparanase (HPSE) is an endo-β-glucuronidase that cleaves the saccharide chains of heparan sulfate (HS) proteoglycans (HSPG), key components of the cell surface, basement membrane and extracellular matrix (ECM). Cleavage of HS by active heparanase results in impairment of the basement membrane and ECM integrity and the release of HS-bound chemokines, cytokines and growth-promoting factors [1]. HS has long been known to serve as an attachment receptor for a large variety of human viruses, including herpes simplex virus (HSV), dengue virus (DENV), respiratory syncytial virus (RSV), varicella-zoster virus (VZV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), Epstein–Barr virus (EBV), Vaccinia virus (VACV) and others [4,5,6,7,8,9,10,11,12,13,14]. Of particular importance is the binding of the SARS-CoV-2 spike protein to HS prior to its interaction with the angiotensin-converting enzyme-2 (ACE2) receptor [18]

Methods

Results

Conclusion