Globoside and the mucosal pH mediate parvovirus B19 entry through the epithelial barrier

Abstract

Parvovirus B19 (B19V) is transmitted primarily via the respiratory route, however, the mechanism involved remains unknown. B19V targets a restricted receptor expressed in erythroid progenitor cells in the bone marrow. However, B19V shifts the receptor under acidic conditions and targets the widely expressed globoside. The pH-dependent interaction with globoside may allow virus entry through the naturally acidic nasal mucosa. To test this hypothesis, MDCK II cells and well-differentiated human airway epithelial cell (hAEC) cultures were grown on porous membranes and used as models to study the interaction of B19V with the epithelial barrier. Globoside expression was detected in polarized MDCK II cells and the ciliated cell population of well-differentiated hAEC cultures. Under the acidic conditions of the nasal mucosa, virus attachment and transcytosis occurred without productive infection. Neither virus attachment nor transcytosis was observed under neutral pH conditions or in globoside knockout cells, demonstrating the concerted role of globoside and acidic pH in the transcellular transport of B19V. Globoside-dependent virus uptake involved VP2 and occurred by a clathrin-independent pathway that is cholesterol and dynamin-dependent. This study provides mechanistic insight into the transmission of B19V through the respiratory route and reveals novel vulnerability factors of the epithelial barrier to viruses.

Globoside is an essential intracellular factor required for parvovirus B19 endosomal escape in erythroid progenitor cells

“…However, acidic niches in the body, such as the nasal mucosa, can become potential targets for B19V. In line with this, we demonstrated that the upper respiratory epithelium expresses globoside and allows virus attachment and transcytosis across the airways exclusively under the acidic pH of the nasal mucosa [23].…”

“…Consistent with this notion, in a previous study we found that binding of B19V to globoside expressed on airway epithelial cells exposed to acidic conditions was required and sufficient to induce membrane invagination leading to virus internalization [23].…”

“…Therefore, it is plausible that binding of globoside to the 5-fold symmetry axis initiates a similar membrane invagination process, facilitating endosomal escape without causing membrane disruption. Consistent with this notion, in a previous study we found that binding of B19V to globoside expressed on airway epithelial cells exposed to acidic conditions was required and sufficient to induce membrane invagination leading to virus internalization [23].…”

“…Entry through the airway epithelium is mediated by the interaction of B19V with the glycosphingolipid globoside, which is expressed in the ciliated population of the epithelium. This interaction occurs exclusively under the natural acidic conditions of the upper respiratory tract, resulting in virus transcytosis and release at the basolateral side where the pH is neutral [23]. After penetrating the airway epithelium, B19V targets and productively replicates in erythroid progenitor cells (EPCs) in the bone marrow.…”