This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interferon regulatory factor 3 (IRF3) is critical in the induction phase of the IFN response. Its role, however, in the control of replication of certain viruses, including HSV-1, is enigmatic. A number of HSV genes interfere with the localization and function of IRF-3 in vitro, suggesting that IRF-3 is critical for controlling HSV replication. The deficiency ofIRF-3 would therefore be predicted to preclude the function of early recognition pathways and thereby impact HSV-1 replication. Paradoxically,IRF-3 deficient mice (IRF3-/-) show no increased susceptibility to HSV-1,and no changes in HSV replication in primary IRF-3-/- MEFs have been observed. In agreement with this, we have shown that primary MEFs do not exert such control. Other recent preliminary data, however, showed significantly increased growth of HSV in IRF3-/- dendritic cells, suggesting that cells derived from the immune system exert IRF-3 dependent control over HSV replication. We reasoned that there were two possible hypotheses to explain these observations. First, that HSV controls IRF-3 activity so completely that, in certain cells, IRF-3 is rendered redundant. Second, that there is a tissue-specificity to the control of HSV replication in vitro and in vivo, and virulence in vivo by IRF-3- dependent mechanisms. The over-arching goal of this proposal is therefore, to test these hypotheses and distinguish between them.
Specific aim 1 : To measure and assess the impact of IRF-3- dependent mechanisms upon the replication of HSV in primary cells derived from the immune system in vitro.
Specific aim 2 : To measure and assess the impact of IRF-3- dependent mechanisms upon the replication and virulence of HSV in mouse models of HSV pathogenesis and latency in vivo.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR016437-10
Application #
8168325
Study Section
Special Emphasis Panel (ZRR1-RI-8 (01))
Project Start
2010-07-01
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
10
Fiscal Year
2010
Total Cost
$199,867
Indirect Cost
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Parker, Zachary M; Pasieka, Tracy Jo; Parker, George A et al. (2016) Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure. J Virol 90:10789-10799
Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res 76:6253-6265
Rosato, Pamela C; Katzenell, Sarah; Pesola, Jean M et al. (2016) Neuronal IFN signaling is dispensable for the establishment of HSV-1 latency. Virology 497:323-327
O'Connor, Megan A; Vella, Jennifer L; Green, William R (2016) Reciprocal relationship of T regulatory cells and monocytic myeloid-derived suppressor cells in LP-BM5 murine retrovirus-induced immunodeficiency. J Gen Virol 97:509-22
Yeager, Mark P; Pioli, Patricia A; Collins, Jane et al. (2016) Glucocorticoids enhance the in vivo migratory response of human monocytes. Brain Behav Immun 54:86-94
Ball, Michael S; Shipman, Emilie P; Kim, Hyunjung et al. (2016) CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages. PLoS One 11:e0149600
Katzenell, Sarah; Leib, David A (2016) Herpes Simplex Virus and Interferon Signaling Induce Novel Autophagic Clusters in Sensory Neurons. J Virol 90:4706-4719
Patankar, Yash R; Mabaera, Rodwell; Berwin, Brent (2015) Differential ASC requirements reveal a key role for neutrophils and a noncanonical IL-1? response to Pseudomonas aeruginosa. Am J Physiol Lung Cell Mol Physiol 309:L902-13
Parker, Zachary M; Murphy, Aisling A; Leib, David A (2015) Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1. J Virol 89:11080-91
Rosato, Pamela C; Leib, David A (2015) Neuronal Interferon Signaling Is Required for Protection against Herpes Simplex Virus Replication and Pathogenesis. PLoS Pathog 11:e1005028

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