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Human cytomegalovirusinduces neuronal geneexpression to promote virionmaturationin macroH2A1-dependent manner

ABSTRACT: Human cytomegalovirus (HCMV) uniquely remodels host cells, generating a cytoplasmic viral-induced assembly compartment (vIAC) and a kidney-bean-shaped nucleus. How these stark morphology changes take place in the context of host gene regulation is still emerging. Here, we discovered that HCMV titers, but not virus particle numbers, were significantly reduced in the absence of the histone variant macroH2A1, indicating that macroH2A1 is essential for producing infectious progeny. Because virion maturation and cellular remodeling are closely linked processes, we used confocal and electron microscopy to define structural changes in the host cell. We uncovered that HCMV-induced reorganization of the host nucleus, cytoskeleton, and endoplasmic reticulum does not occur in the absence of macroH2A1. Furthermore, we discovered using RNA-seq that while all viral genes were highly expressed in the absence of macroH2A1, many HCMV-induced host genes were not. Hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with neuronal synapse formation and vesicle trafficking. Knock-down during infection of several HCMV-induced neuronal genes resulted in malformed vIACs and smaller plaques, establishing their importance to HCMV infection. Together, our findings demonstrate that HCMV manipulates host gene expression to hijack the dormant neuronal secretory pathway for proper virion maturation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272267 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-gamma and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-gamma-responsive promoters. However, neither synthesis nor secretion of IFN-gamma or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity. We used a total of 18 microarrays for analyzing triplicate samples each of IE1-negative control fibroblasts (TetR cells) without induction (3 arrays), fibroblasts containing inducible IE1 (TetR-IE1 cells) without induction (3 arrays), TetR cells induced for 24 h (3 arrays), TetR-IE1 cells induced for 24 h (3 arrays), TetR cells induced for 72 h (3 arrays), and TetR-IE1 cells induced for 72 h (3 arrays)

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Human cytomegalovirusinduces neuronal geneexpression to promote virionmaturationin macroH2A1-dependent manner

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OmicsDI is part of the ELIXIR infrastructure

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Human cytomegalovirusinduces neuronal geneexpression to promote virionmaturationin macroH2A1-dependent manner​

Dataset's files

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OmicsDI is part of the ELIXIR infrastructure

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Human cytomegalovirusinduces neuronal geneexpression to promote virionmaturationin macroH2A1-dependent manner