A long-standing dilemma that has puzzled researchers of varicella zoster virus (VZV), the causative agent of chickenpox (varicella) and shingles (zoster), is how airborne virions that emerge from skin lesions are able to readily transmit to new hosts, yet when grown in vitro, the virus is highly cell-associated and very few infectious virions are released. A new study published in Cell resolves this issue and implicates a host protein — the mannose 6-phosphate receptor (MPR) — as being a key molecule in both processes.

Cell association of VZV has been attributed to the diversion of newly assembled virions to late endosomes where they are degraded prior to exocytosis. As previous work has shown that VZV is able to interact with cation-independent MPRs via its envelope glycoproteins, Michael Gershon and colleagues speculated that the presence of MPRs in the membrane of vesicles used to transport the newly enveloped virions could be responsible for their re-routing to late endosomes. Furthermore, previous research also demonstrated that mannose 6-phosphate, the ligand of MPRs, inhibits the infection of host cells by free VZV particles, indicating that MPRs have a role in the infection of new cells. The goal of this study was to test the hypothesis that the intracellular trafficking of newly assembled VZV and the infection of target cells by free virions are MPR-dependent.

To this end, the authors generated five human cell lines deficient in MPRs using antisense cDNA technology. Analysis of these cell lines revealed that all were resistant to infection by cell-free VZV, although the cells could be infected by cell-associated VZV. Once infected, the authors were able to demonstrate that the mutant cell lines could secrete infectious virions, thus supporting the hypothesis that both infection of naive cells by the free virus and diversion of newly assembled VZV to late endosomes require the participation of MPRs.

Further investigation of VZV infection in human epidermis revealed that the intracellular pathway of virus in superficial epidermal cells resembled that observed with the MPR-deficient cell lines. These results support the contention that, as MPR expression is lost in maturing superficial epidermal cells of the skin and VZV is not diverted to late endosomes, the virus can be secreted in a form able to propagate infection to new hosts in a controlled manner.