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Title

Identification of a Novel PARP Pathway for Antiviral Defense

Date of Award

Summer 8-15-2013

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Influenza viruses, a negative-sense, single-stranded, segmented RNA genome orthomyxovirus, is one of the leading cause of hospitalizations in the U.S. each year. There are three genera of Influenza, termed A, B, and C. Among these three, type A viruses are the most virulent and cause the most severe disease. Despite there have been a number of Influenza A pandemics in the last decade, there are limitations in the ability to develop efficacious vaccines. We therefore sought to discover novel molecules function in viral control and understanding the working mechanism of these molecules. IFN signaling is critical for host defense against respiratory viruses, serving as a first line of defense against viral infections through the induction of numerous IFN-stimulated genes (ISGs). Microarray analyses comparing seasonal H1N1 infected and uninfected human airway epithelial cells (hAECs) generated in vitro showed differences in the poly (ADP-ribose) polymerase family member 12 (PARP12), one of PARP family members, gene expression pattern. The effect of PARP12 on viral control was assessed in hAECs by loss-of-function approach, PARP12 shRNA lentivirus transduction. Surprisingly, viral titers were decreased in PARP12 knockdown cells compared with control cells generated by lentiviral transduction of a non-mammalian shRNA control plasmid. This enhanced virus resistance by PARP12 gene knockdown was not consequence of viral induced cell death or increase of IFN release level. Following studies revealed that improvement of viral resistance is due to inhibition of a viral induced STAT1 protein decrease, which is not from viral transcriptional regulation. Mice lacking functional Parp12 protein were generated using ZFN technology. Less viral loads were observed in Parp12 deficient mice. Clearly, Parp12 deficient mice were less susceptible to influenza A virus and thereby decreased virus associated mortality.

Language

English (en)

Chair and Committee

Michael J Holtzman

Committee Members

Gaya K Amarasinghe, John P Atkinson, Thomas J Brett, Deborah J Lenschow, Robert M Senior

Comments

Permanent URL: https://doi.org/10.7936/K7M61H5Q

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