Human Cytomegalovirus Us17 Locus Fine-Tunes Innate And Intrinsic Immune Responses

Author

Stephen James Gurczynski, Wayne State UniversityFollow

Access Type

Open Access Dissertation

Date of Award

January 2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Immunology and Microbiology

First Advisor

Philip E. Pellett

Abstract

HCMV employs numerous strategies to combat, subvert, or co-opt host immunity. One evolutionary strategy for this involves "capture" of a host gene and then its successive duplication and divergence, forming a gene family, many of which have immunomodulatory activities. The HCMV US12 family consists of ten tandemly arranged sequence-related genes in the unique short region of the HCMV genome (US12-US21). Each gene encodes a protein possessing seven predicted transmembrane domains, and patches of sequence similarity with cellular GPCRs and the bax inhibitor-1 family of anti-apoptotic proteins. We show that one member, US17, plays an important role during virion maturation. Microarray analysis of cells infected with a recombinant HCMV deleted for US17 (ΔUS17) revealed blunted host innate and interferon responses at early times after infection (12 hpi), a pattern opposite that previously seen in the absence of the immunomodulatory tegument protein pp65 (pUL83). Although ΔUS17 produced equal numbers of infectious particles in fibroblasts compared to parental virus, at equal multiplicities of infection, it produced >3-fold more genome-containing non-infectious viral particles, and delivered increased amounts of pp65 to newly infected cells. These results suggest that US17 has evolved to control virion composition, so as to elicit an appropriately balanced host immune response. At later time points (96 hpi) ΔUS17 infected cells displayed aberrant expression of several host ER stress response genes and chaperones, some of which are important for the final stages of virion assembly and egress. Our results suggest that US17 modulates host pathways to enable production of virions that elicit an appropriately balanced host immune response.

Recommended Citation

Gurczynski, Stephen James, "Human Cytomegalovirus Us17 Locus Fine-Tunes Innate And Intrinsic Immune Responses" (2013). Wayne State University Dissertations. 840.
https://digitalcommons.wayne.edu/oa_dissertations/840