Neal A. DeLuca, PhD

Professor


Dr. DeLuca

Contact

412-648-9947
Fax: 412-624-1401

514 Bridgeside Point II

450 Technology Drive

Pittsburgh, PA 15219-3143

Education

PhD in Biophysics, Pennsylvania State University

Research Summary

The pathogenic and cytotoxic effects of viruses are largely due to the expression of viral gene products. Therefore, the determinants of these outcomes are the mechanisms underlying the expression of viral genes. The hallmark of herpes simplex virus gene expression is the sequential and coordinately regulated expression of the approximately 80 viral genes. This regulation occurs largely through modulation of RNA polymerase II transcription. Two viral proteins, VP16 and ICP4, function to activate transcription of the five immediate early genes, and the remainder of the HSV genome, respectively. ICP4 is a large and structurally complex molecule. Previous studies from our lab have provided insight into how this molecule regulates transcription. Considerable effort has been placed on the mechanisms by which the major regulatory protein of HSV, ICP4, affects the pol II transcriptional apparatus of the cell resulting in the regulation of HSV genes. This involves structure/function studies of ICP4 using viral mutants in the context of infection and reconstituted in vitro transcription studies aimed at determining the molecular mechanism of ICP4 function. 

In addition to the modification of polII transcription by ICP4, many other cellular nuclear processes are modified by viral gene products to support productive infection.  Many of these processes function on the viral genome.  The viral genome is the only component of the virus present throughout its productive life cycle.  However, the viral and cellular proteins that bind to, and the processes that occur on the genome change as the life cycle progresses from entry to the packaging of viral genomes into nascent virions.  We have developed approaches to determine in a nonbiased way, the viral and cellular proteins that associate with the genome throughout infection, from the initial sensing of the genome to its packaging, and to image these genomes relative to cellular structures and proteins.

HSV gene expression during lytic infection is contrasted by the ability to establish latency in PNS neurons. During latency, viral lytic gene expression does not occur, and the genome persists as an episomal element packaged in chromatin. Reactivation from latency presumably involves activation of the genome in the absence of VP16. One IE protein, ICP0, has been shown to be involved in the process of reactivation from latency in several model systems. ICP0 has also been shown to facilitate lytic viral gene expression. While its mechanism of action is unknown, it has been shown to interact with a ubiquitin proteinase and function as a ubiquitin E3 ligase. The use of mutants deficient in subsets of the IE proteins provides the means to examine viral gene expression and genome persistence in the absence of lytic gene expression in tissue culture. Mutants that do not express any of the five IE proteins, are completely nontoxic, and establishes a long-term relationship with the cell. Gene expression from the persisting genomes is repressed by repressive chromatin, and interferon signaling is induced. Both processes can be reversed by the addition of ICP0. Therefore, some of the events occurring in d109-infected tissue culture cells are similar to those that may occur with latent genomes in vivo. We study the interplay between genome repression, activation, and the cellular antiviral response.

 

Research Lab Affiliation

Publications

Fox HL, Dembowski JA and DeLuca NA. (2017) A Herpesviral Immediate Early Protein Promotes Transcription Elongation of Viral Transcripts. MBio. 8: e00745-17. |  View Abstract

Dembowski JA; Dremel SE and DeLuca NA. (2017) Replication-Coupled Recruitment of Viral and Cellular Factors to Herpes Simplex Virus Type 1 Replication Forks for the Maintenance and Expression of Viral Genomes. PLoS Pathogen. 13: e1006166. |  View Abstract

Colgrove RC; Liu X; Griffiths A; Raja P; DeLuca NA; Newman RM; Coen DM and Knipe DM. (2016) History and genomic sequence analysis of the herpes simplex virus 1 KOS and KOS1.1 sub-strains. Virology. 487: 215-221. |  View Abstract

Taylor TJ, Diaz F, Colgrove RC, Bernard KA, DeLuca NA, Whelan SPJ and Knipe DM. (2016) Production of immunogenic West Nile virus-like particles using a herpes simplex virus 1 recombinant vector. Virology. 496: 186-193. |  View Abstract

Dembowski JA and DeLuca NA. (2015) Selective recruitment of nuclear factors to productively replicating herpes simplex virus genomes. PLoS Pathog. 11: e1004939. |  View Abstract

Harkness JM, Kader M and DeLuca NA. (2014) Transcription of the herpes simplex virus 1 genome during productive and quiescent infection of neuronal and nonneuronal cells. J Virol. 88: 6847-6861. |  View Abstract

Wagner LM and DeLuca NA. (2013) Temporal association of herpes simplex virus ICP4 with cellular complexes functioning at multiple steps in PolII transcription. PLoS One. 8: e78242. |  View Abstract