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HCMV virus produced in different cell types induces different transcriptional responses

ABSTRACT: Human cytomegalovirus infects multiple cell types, including fi- broblasts and epithelial cells. It penetrates fibroblasts by fusion at the cell surface but is endocytosed into epithelial cells. In this report, we demonstrate by electron microscopy that the virus uses two different routes to enter retinal pigmented epithelial cells, depending on the cell type in which the infecting virus was produced. Virus produced in epithelial cells preferentially fuses with the plasma membrane, whereas fibroblast-derived virus mostly enters by receptor-mediated endocytosis. Treatment of epithelial cells with agents that block endosome acidification inhibited infection by virus produced in fibroblasts but had only a modest effect on infection by virus from epithelial cells. Epithelial cell-generated virions had higher intrinsic ‘‘fusion-from-without’’ activity than fibroblast-generated particles, and the two virus preparations triggered different cellular signaling responses, as evidenced by markedly different transcriptional profiles. We propose that the cell type in which a human cytomegalovirus particle is produced likely influences its subsequent spread and its contribution to pathogenesis. Keywords: cell type comparison, viral infection, cell tropism, viral entry

ORGANISM(S): Homo sapiens

PROVIDER: GSE9578 | GEO | 2007/11/10

SECONDARY ACCESSION(S): PRJNA103407

REPOSITORIES: GEO

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Project description:Human cytomegalovirus (HCMV) replication requires host metabolism. Infection alters the activity in multiple metabolic pathways, including increasing fatty acid elongation and lipid synthesis. The virus-host interactions regulating the metabolic changes associated with replication are essential to infection. While multiple host factors, including kinases and transcription factors, have been identified to be important to metabolic changes that occurr following HCMV infection, little is known about the viral factors required to alter metabolism. The HCMV UL37x1 protein (pUL37x1) localizes to the mitochondria and ER and controls Ca2+ flux from the ER to the cytosol which may influence metabolism. In this study, we tested the hypothesis that pUL37x1 is important to the metabolic remodeling that is necessary for HCMV replication by using a combination of metabolomics, lipidomics, and metabolic tracers to measure fatty acid elongation. We observed that fibroblast cells infected with wild-type (WT) HCMV had similar levels of metabolites as those infected with a mutant virus lacking the UL37x1 gene, subUL37x1. However, we found that subUL37x1-infected cells had reduced levels of two host proteins that were previously demonstrated to be important for lipid metabolism during HCMV infection—fatty acid elongase 7 (ELOVL7) and ER-stress related kinase PERK—relative to WT-infected cells. Moreover, we observed that HCMV infection results in an increase in phospholipids with very long-chain fatty acid tails (PL-VLCFAs) that contain 26 or more carbons in one of their two tails. The levels of many PL-VLCFAs were lower in subUL37x1-infected cells compared to WT-infected cells. We also show that uninfected cells expressing a high-level of pUL37x1 have a greater amount of lipids relative to control cells. Overall, we conclude that although pUL37x1 is not necessary for network-wide metabolic changes occurring during infection, it is important to the remodeling of lipid metabolic pathways during HCMV infection.

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HCMV virus produced in different cell types induces different transcriptional responses

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