Antibody-Mediated Enhancement of Parvovirus B19 Uptake into Endothelial Cells Mediated by a Receptor for Complement Factor C1q

Despite its strong host tropism for erythroid progenitor cells, human parvovirus B19 (B19V) can also infect a variety of additional cell types. Acute and chronic inflammatory cardiomyopathies have been associated with a high prevalence of B19V DNA in endothelial cells of the myocardium. To elucidate the mechanisms of B19V uptake into endothelium, we first analyzed the surface expression of the well-characterized primary B19V receptor P antigen and the putative co-receptors α 5 s 1 integrins and Ku80 antigen on primary and persistent endothelial cells. The receptor expression pattern and also the primary attachment levels were similar as in the UT7/Epo-S1 cell line regarded as functional for B19V entry, but internalization of the virus was strongly reduced. As an alternative B19V uptake mechanism in endothelial cells we could demonstrate antibody dependent enhancement (ADE) with an up to 4000-fold increase in B19V uptake in the presence of B19V-specific human antibodies. ADE was mediated almost exclusively at the level of virus internalization with efficient B19V translocation to the nucleus. In contrast to monocytes, where ADE of B19V has been described before, enhancement does not rely on interaction of the virus-antibody complexes with Fc receptors (FcR), but rather involves an alternative mechanism mediated by the heat-sensitive complement factor C1q and its receptor CD93. Our results suggest that ADE represents the predominant mechanism of endothelial B19V infection and it is tempting to speculate that it may play a role in the pathogenicity of cardiac B19V infection. Importance Both efficient entry and productive infection of human parvovirus B19 (B19V) seem to be limited to erythroid progenitor cells. However, in vivo the viral DNA can be also be detected in additional cell types such as endothelial cells of the myocardium, where its presence has been associated with acute and chronic inflammatory cardiomyopathies. In this study we could demonstrate that uptake of B19V into endothelial cells most probably does not rely on the classical receptor mediated route via the primary B19V receptor P antigen and co-receptors such as α 5 s 1 integrins, but rather on antibody-dependent mechanisms. Since the strong antibody-dependent enhancement (ADE) of B19V entry requires the CD93 surface protein, it very likely involves bridging of the B19V-antibody complexes to this receptor by the complement factor C1q, leading to an enhanced endocytosis of the virus.