Three-dimensional normal human neural progenitor tissue-like assemblies: a model of persistent varicella-zoster virus infection.
Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells.
Disease Modeling/Tissue Analogues Laboratory, NASA Johnson Space Center, Houston, Texas, United States of America. thomas.j.goodwin@nasa.gov
Thomas J
TJ
Goodwin
Maureen
M
McCarthy
Nikolaus
N
Osterrieder
Randall J
RJ
Cohrs
Benedikt B
BB
Kaufer
D045744:Cell Line, Tumor; D002644:Chickenpox / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017781:Genes, Immediate-Early / Q000502:physiology; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D008954:Models, Biological; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000821:virology; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology; D017735:Virus Latency / Q000502:physiology*