The innate immune system is our first line of defense against pathogenic challenge. These responses include cell-intrinsic mechanisms to combat these invaders in infected cells. Autophagy, the mechanism by which cells engulf cytoplasmic components, has been shown to have antimicrobial properties against intracellular bacteria. This process leads to the destruction of these cytoplasmic microorganisms. It has been proposed that such a mechanism may play an important role in controlling viral infection. Our preliminary data support this in that loss of this conserved pathway leads to an increase in viral replication in Drosophila. This suggests that autophagy plays an important antiviral role. In this proposal we seek to establish the mechanism by which the autophagic pathway affects viral propagation and pathogenesis, and the mechanisms whereby this process is activated to clear the viral invader. By taking advantage of the powerful tools available in this model system, including genetics and functional genomics, to investigate these questions in a variety of contexts we will be uniquely situated to identify conserved intrinsic mechanisms by which all organisms fight viruses. The identification of new host factors amenable to inhibition may lead to targets for much-needed antiviral therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074951-05
Application #
8089397
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Leitner, Wolfgang W
Project Start
2007-07-01
Project End
2012-08-14
Budget Start
2011-07-01
Budget End
2012-08-14
Support Year
5
Fiscal Year
2011
Total Cost
$364,276
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Molleston, Jerome M; Cherry, Sara (2017) Attacked from All Sides: RNA Decay in Antiviral Defense. Viruses 9:
Rausch, Keiko; Hackett, Brent A; Weinbren, Nathan L et al. (2017) Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus. Cell Rep 18:804-815
Aguado, Lauren C; Schmid, Sonja; May, Jared et al. (2017) RNase III nucleases from diverse kingdoms serve as antiviral effectors. Nature 547:114-117
Bayer, Avraham; Lennemann, Nicholas J; Ouyang, Yingshi et al. (2016) Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection. Cell Host Microbe 19:705-12
Molleston, Jerome M; Sabin, Leah R; Moy, Ryan H et al. (2016) A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev 30:1658-70
Zhang, Rong; Miner, Jonathan J; Gorman, Matthew J et al. (2016) A CRISPR screen defines a signal peptide processing pathway required by flaviviruses. Nature 535:164-8
Ramage, Holly; Cherry, Sara (2015) Virus-Host Interactions: From Unbiased Genetic Screens to Function. Annu Rev Virol 2:497-524
Panda, Debasis; Cherry, Sara (2015) A genome-wide RNAi screening method to discover novel genes involved in virus infection. Methods 91:75-81
Hopkins, Kaycie C; Tartell, Michael A; Herrmann, Christin et al. (2015) Virus-induced translational arrest through 4EBP1/2-dependent decay of 5'-TOP mRNAs restricts viral infection. Proc Natl Acad Sci U S A 112:E2920-9
Harris, Katharine G; Morosky, Stefanie A; Drummond, Coyne G et al. (2015) RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells. Cell Host Microbe 18:221-32

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