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Title: The Role of Aryl Hydrocarbon Receptor Signaling in Human Cytomegalovirus Infection
Advisors: Shenk, Thomas E
Contributors: Molecular Biology Department
Keywords: Aryl Hydrocarbon Receptor
Cell Cycle
Cell Cycle Arrest
Human Cytomegalovirus
Subjects: Virology
Molecular biology
Cellular biology
Issue Date: 2019
Publisher: Princeton, NJ : Princeton University
Abstract: Human Cytomegalovirus (HCMV) is a ubiquitous beta-herpesvirus, which causes life-threatening disease in immunocompromised patients and severe birth defects in newborn infants. It is not, however, definitively associated with significant pathology in immunocompetent adults. The virus extensively reprograms host cell metabolism and gene expression upon infection. To efficiently complete an infectious cycle, HCMV must both block the replication of host cell DNA and counteract the cellular innate immune responses. The latter involves the production of interferons and subsequent induction of interferon-stimulated genes (ISGs). Indoleamine 2,3-dioxygenase (IDO1), specifically, is recognized as an important effector ISG in the antiviral innate immune response. It catalyzes the first reaction in Tryptophan (TRP) catabolism, i.e., the conversion of tryptophan to kynurenine (KYN). Activation of IDO1 is believed to restrict HCMV replication by depriving the infected cells of TRP, an essential amino acid. Consequently, the regulation of IDO1 expression and activity by HCMV infection has been the subject of several studies. Notably, KYN and its biological effect on HCMV replication, on the other hand, have received less attention. KYN is an endogenous ligand for the Aryl hydrocarbon Receptor (AhR), a ligand-activated transcription factor. Our group has shown that intracellular KYN levels are elevated during HCMV replication. Moreover, high plasma KYN levels have been correlated with HCMV reactivation in renal transplant recipients, and the exogenous activation of AhR has been shown to enhance viral replication. Therefore, I aimed my graduate studies at determining the molecular mechanisms by which endogenous AhR signaling modulates HCMV infection. Herein, I will discuss how I discovered: (i) HCMV infection of primary human fibroblasts triggers the persistent induction of AhR transcriptional activity; (ii) sustained AhR activity is associated with tightly balanced IDO1 activity; (iii) AhR signaling is required for the efficient replication of virus; (iv) HCMV{induced G1/S cell cycle arrest depends on AhR activity; and (v) the virus exploits AhR signaling to counteract the innate antiviral immune response, in a negative feedback loop containing IDO1-KYN-AhR.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog:
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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