Abstract
Aims: Human parvovirus B19 (B19V) infection directly induces apoptosis and modulates CXCR4 expression of infected marrow-derived circulating angiogenic cells (CACs). This leads to dysfunctional endogenous vascular repair. Treatment for B19V-associated disease is restricted to symptomatic treatment. Telbivudine, a thymidine analogue, established in antiviral treatment for chronic hepatitis B, modulates pathways that might influence induction of apoptosis. Therefore, we tested the hypothesis of whether telbivudine influences B19V-induced apoptosis of CAC. Methods and Results: Pretreatment of two CAC-lines, early outgrowth endothelial progenitor cells (eo-EPC) and endothelial colony-forming cells (ECFC) with telbivudine before in vitro infection with B19V significantly reduced active caspase-3 protein expression (−39% and −40%, both p < 0.005). Expression of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) was significantly downregulated by in vitro B19V infection in ECFC measured by qRT-PCR. BIRC3 downregulation was abrogated with telbivudine pretreatment (p < 0.001). This was confirmed by single gene PCR (p = 0.017) and Western blot analysis. In contrast, the missing effect of B19V on angiogenic gene expression postulates a post-transcriptional modulation of CXCR4. Conclusions: We for the first time show a treatment approach to reduce B19V-induced apoptosis. Telbivudine reverses B19V-induced dysregulation of BIRC3, thus, intervening in the apoptosis pathway and protecting susceptible cells from cell death. This approach could lead to an effective B19V treatment to reduce B19V-related disease.
Highlights
Human parvovirus B19 (B19V), belonging to the genus Erythrovirus of the Parvoviridae family, is a single-stranded DNA virus responsible for a wide range of clinical manifestations
Viruses 2019, 11, 227 different cell types belonging to the heterogenous group of marrow-derived circulating angiogenic cells (CACs) with similarities to the erythroid and endothelial lineage, to be targets for B19 infection [2]
TheThe results of this show show for thefor first anti-apoptotic effect of the nucleoside results of study this study thetime firstantime an anti-apoptotic effect of the nucleoside analogue telbivudine through normalisation of Baculoviral Inhibitor of apoptosis Repeat-Containing protein 3 (BIRC3) levelslevels in B19V-induced apoptosis in CACs, analogue telbivudine through normalisation of BIRC3 in B19V-induced apoptosis in CACs, providing a novel approach to protecting cells from. These results extend the knowledge providing a novel approach to protecting cells from B19V damage
Summary
Human parvovirus B19 (B19V), belonging to the genus Erythrovirus of the Parvoviridae family, is a single-stranded DNA virus responsible for a wide range of clinical manifestations. The majority of clinical disorders are generally self-limiting and subclinical [1], in certain cases, the disease may turn chronic and clinically relevant. The latter may result from either direct virus-mediated injury, increased apoptosis [2], inadequacy of the specific anti-viral immune response [3] or dysregulated trafficking of cells involved in endothelial regeneration [4]. Viruses 2019, 11, 227 different cell types belonging to the heterogenous group of marrow-derived circulating angiogenic cells (CACs) with similarities to the erythroid and endothelial lineage, to be targets for B19 infection [2]. B19V directly induces apoptosis of CAC through the viral proteins NS1, VP1 [2], and the small 11kDa protein and impairs their trafficking [4]
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