Functions of the unique N-terminal region of glycoprotein E in the pathogenesis of varicella-zoster virus infection.
Varicella-zoster virus (VZV) is an alphaherpesvirus that infects skin, lymphocytes, and sensory ganglia. VZV glycoprotein E (gE) has a unique N-terminal region (aa1-188), which is required for replication and includes domains involved in secondary envelopment, efficient cell-cell spread, and skin infection in vivo. The nonconserved N-terminal region also mediates binding to the insulin-degrading enzyme (IDE), which is proposed to be a VZV receptor. Using viral mutagenesis to make the recombinant rOka-DeltaP27-G90, we showed that amino acids in this region are required for gE/IDE binding in infected cells; this deletion reduced cell-cell spread in vitro and skin infection in vivo. However, a gE point mutation, linker insertions, and partial deletions in the aa27-90 region, and deletion of a large portion of the unique N-terminal region, aa52-187, had similar or more severe effects on VZV replication in vitro and in vivo without disrupting the gE/IDE interaction. VZV replication in T cells in vivo was not impaired by deletion of gE aa27-90, suggesting that these gE residues are not essential for VZV T cell tropism. However, the rOka-DeltaY51-P187 mutant failed to replicate in T cell xenografts as well as skin in vivo. VZV tropism for T cells and skin, which is necessary for its life cycle in the human host, requires this nonconserved region of the N-terminal region of VZV gE.
Berarducci
Barbara
B
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. barbara.berarducci@pasteur.fr
Rajamani
Jaya
J
Zerboni
Leigh
L
Che
Xibing
X
Sommer
Marvin
M
Arvin
Ann M
AM
D000818:Animals; D045744:Cell Line, Tumor; D002644:Chickenpox / Q000378:metabolism / Q000503:physiopathology*; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D012867:Skin / Q000166:cytology / Q000473:pathology / Q000821:virology; D012871:Skin Diseases / Q000473:pathology / Q000821:virology; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014183:Transplantation, Heterologous; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics
D014759:Viral Envelope Proteins; C056913:glycoprotein E, varicella-zoster virus