Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells

Abstract

Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4), infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells.

Author Summary

We detect invading viruses with dendritic cells and eliminate them with lymphocytes. A key interaction is lymphocyte activation by dendritic cells presenting viral antigens. Not all viruses can be eliminated, and some that persist deliberately colonize lymphocytes and dendritic cells, such that parasitism and host defence co-exist within the same sites. Once established, these infections are very hard to eliminate. Therefore to vaccinate against them we must determine how infection first occurs. Here we show that a gamma-herpesvirus relation of the Kaposi's Sarcoma-associated Herpesvirus and Epstein-Barr virus - B cell-tropic human pathogens that cause cancers - uses dendritic cells to reach and infect B lymphocytes. Dendritic cells were infected before B cells; viruses marked genetically in dendritic cells were recovered from B cells; and a virus unable to replicate in dendritic cells infected B cells poorly. Thus dendritic cells not only present viral antigens to lymphocytes, but can be exploited by evasive viruses to infect lymphocytes. Therefore targeting dendritic cell infection could be an effective means of vaccine-primed host defence.