Oligomerisierung und supramolekulare Organisation membranassoziierter RNA-Polymerase der Picornaviren
Final Report Abstract
Varicella zoster virus (VZV) is a human neurotropic alphaherpesvirus that causes varicella (chickenpox) during primary infection, establishes latency in sensory ganglia and may reactivate to cause herpes zoster (shingles). In Prof. Ann Arvins laboratory, an experimental model for the study of VZV pathogenesis has been established that uses human tissue xenografts in mice with severe combined immunodeficiency (SCID) to analyze VZV tropisms in human dorsal root ganglia (DRG) and skin within the typical tissue microenvironment. Using correlative immunofluorescence/ electron microscopy (IF-EM), I revealed a role for satellite cells as well as neurons during productive VZV infection in human DRG xenografts. Furthermore, syncytium (polykaryon) formation in VZV infected DRG by fusion of neurons and satellite cells was demonstrated for the first time, leading to a better understanding of VZV neuropathogenesis and viral spread in human DRG. The development of a novel strategy to study the VZV replication cycle in vitro, based on differential labeling of VZV infected inoculums cells, allowed for a more accurate characterization of the onset VZV genome replication and nucleocapsid assembly and envelopment. This strategy ultimately lead to the discovery of a distinct class of PML nuclear bodies that did not colocalize with VZV replication compartments but sequestered newly assembled VZV nucleocapsids late in the VZV replication cycle in intranuclear PML cages. Similar PML cages where found in VZV infected human DRG and skin xenografts. The PML IV isoform was identified as an intrinsic antiviral host factor that specifically promotes VZV capsid sequestration in nuclear PML cages and inhibits the production of infectious VZ virions.
Publications
- Aberrant infection and persistence of varicella-zoster virus in human dorsal root ganglia in vivo in the absence of glycoprotein I. Proc Natl Acad Sci USA. 2007 Aug 28;104(35):14086-91
Zerboni L, Reichelt M, Jones CD, Zehnder JL, Ito H, Arvin AM
- Mechanisms of varicella-zoster virus neuropathogenesis in human dorsal root ganglia. J Virol. 2008 Apr;82(8):3971- 83. Epub 2008 Feb 6
Reichelt M, Zerboni L, Arvin AM
- The replication cycle of varicella-zoster virus: analysis of the kinetics of viral protein expression, genome synthesis, and virion assembly at the single-cell level. J Virol. 2009 Apr;83(8):3904-18. Epub 2009 Feb 4
Reichelt M, Brady J, Arvin AM
