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

Abstract

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 coreceptors ␣ 5 ␤ 1 integrins and Ku80 antigen on primary and permanent endothelial cells. The receptor expression pattern and also the primary attachment levels were similar to those 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 demonstrated antibody-dependent enhancement (ADE), with up to a 4,000-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 previously, enhancement does not rely on interaction of the virus-antibody complexes with Fc receptors (FcRs), 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. IMPORTANCEBoth 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 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 demonstrated 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 coreceptors, such as ␣ 5 ␤ 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 enhanced endocytosis of the virus.

Неугодная Иммунология

“…У взрослых пациентов поражения кожи менее распространены, но встречаются случаи острой и хро-нической кардиомиопатии с высоким содержанием ДНК парвовируса B19V в эндотелиальных клетках мио-карда, что находится в противоречии с результатами опытов, выполненных в условиях in vitro, показавших невозможность такой инфекции. K. Kietzell et al [64] установили, что в основе поглощения эндотелиальны-ми клетками B19V лежит механизм, использующий ан-тителозависимое усиление инфекции. Специфические к B19V антитела, образуя комплекс с вирусом и взаи-модействуя с поверхностным гликопротеином эндоте-лия CD93, -рецептором температурочувствительного фактора комплемента C1q, увеличивают его поглоще-ние эндотелиальными клетками миокарда почти в 4000 раз.…”

“…Показана связь ADE с антителами к гликопротеину Е вируса C-ADE Феномен ADE увеличивает тропность вируса к другим тканям, в частности к эндо-телию сосудов миокарда, что приводит к развитию миокардита [64] Корь…”

Human Parvovirus B19: a Mechanistic Overview of Infection and DNA Replication

“…Globoside is also present in red blood cells and some nonerythroid cells, such as fetal myocytes, placenta, megakaryocytes and some endothelial cells [57–60], which might explain the diverse clinical manifestations in different tissues. Besides the primary receptor globoside, integrin α5β1 and Ku80 were proposed to be coreceptors for B19V [61,62]; however, cell surface expression of Ku80 was shown to be very low in ex vivo -expanded CD36 + hEPCs (<5%) and other B19V-permissive cells [45,63]. Therefore, the erythroid tropism of B19V cannot be simply explained by the presence of the receptor/coreceptors.…”

“…A few other nonerythroid lineage cells have been reported to support B19V infection [63,67–68]. B19V infection has been suggested to be associated with myocarditis and acute and chronic inflammatory cardiomyopathies, since B19V DNA was frequently detected in patients who have these symptoms [67,69–71].…”

“…A recent study by Kietzell et al identified a new route for the B19V infection of myocardial endothelial cells [63]. There are no major differences in surface expression of B19V receptor/coreceptors among UT7/Epo-S1 and primary endothelial cells, which are isolated from the pulmonary arteria (human pulmonary artery cells [HPAEC]), the umbilical vein (human umbilical vein endothelial cells [HUVEC]) and the aorta (human aortic endothelial cells [HAoEC]).…”