Grant: $505,770 - National Institutes of Health - Jun. 18, 2009
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Award Description: DESCRIPTION (provided by applicant): Varicella zoster virus (VZV) causes varicella during primary infection, persists in sensory ganglia and may reactivate from latency to cause zoster. VZV pathogenesis depends upon its tropisms for T cells, skin and sensory ganglia. VZV vaccines to prevent varicella and to reduce zoster morbidity in the elderly are very effective. However, VZV control could be improved with a 2nd generation recombinant vaccine that has attenuated replication in skin, but limited infectivity for T cells and ganglia. VZV infection of sensory ganglia ensures its survival in the human population through reactivations from latency that result in zoster. We have developed a model for studying VZV neuropathogenesis by making xenografts of human dorsal root ganglia (DRG) in mice with severe combined immunodeficiency (SCID). Our analyses of VZV tegument/regulatory proteins will be extended to examine their functions in VZV neurotropism. We will focus on IE63, an important immediate early regulatory protein encoded by ORF63, and the ORF66 kinase protein using VZV recombinants that have targeted mutations in these genes. The SCIDhu DRG model also offers unique opportunities to investigate how cell transactivators that modulate viral gene promoters may control VZV neurotropism and to identify what perturbations of persistently infected neurons may trigger VZV reactivation. The roles of IE63 and ORF66 at early and late stages of VZV infection of ganglia will be examined in SCIDhu DRG. Experiments will address four general hypotheses: 1) initial VZV replication is required for, or influences the level of persistent VZV DNA copies in neurons; 2) VZ virions must be made and released efficiently; 3) VZV proteins that inhibit neural cell apoptosis facilitate persistence; 4) VZV infection of DRG reflects an equilibrium with innate cellular responses, mediated by interferons (IFN), which optimizes persistence. VZV gene promoters, like those of all herpesviruses, have elements that are recognized by ubiquitous host cell regulatory proteins. Our hypothesis is that cellular proteins regulate transcription from the critical ORF63 promoter during initial infection and are needed for the transition to latency in sensory neurons. Experiments to understand what cellular stressors may induce VZV reactivation from persistently infected DRG will examine heat, chemical agents, histone deacetylase inhibitors, interference with nerve growth factor signaling and other triggers known to enhance herpes simplex virus reactivation. This work is expected to yield new information about the molecular mechanisms of VZV neuropathogenesis in differentiated peripheral neurons and satellite cells within human sensory ganglia and to identify options for designing a 2nd generation VZV vaccine with genetic changes that have been proved to reduce virulence in the SCIDhu DRG model in vivo. PUBLIC HEALTH RELEVANCE: Chickenpox and herpes zoster (shingles) are caused by varicella-zoster virus (VZV). These infections remain an important public health problem in the United States. The licensed VZV vaccines induce protection in most children and elderly adults but complications can occur in healthy vaccine recipients and in those who have diseases that impair their immune systems. Our goal is to identify strategies for creating better vaccines to prevent VZV infections in healthy and high risk people.
Project Description: As defined in the Award Description field
Jobs Summary: Faculty, Research Assistant, Research Associate, Scientist, Postdoctorial Fellow (Total jobs reported: 3)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 18, 2009. Help expand these official descriptions using the wiki below.
Funds from this award have been disbursed to sub-grantees. Click here to see a list of sub-grantees.
|UNIVERSITY OF IOWA, THE (INC)||$31,500||IOWA CITY||IA|
|RESEARCH FOUNDATION OF STATE UNIVERSITY OF NEW YORK, THE||$36,455||BUFFALO||NY|