scholarly journals The Ends Dictate the Means: Promoter Switching in Herpesvirus Gene Expression

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Andrew E. Hale ◽  
Nathaniel J. Moorman
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Annual Review ◽  
Publication Date ◽  
Alternative Promoters ◽  
Contextual Cues ◽  
Viral Genes ◽  
Functional Consequences ◽  
Post Transcriptional Regulation

Herpesvirus gene expression is dynamic and complex, with distinct complements of viral genes expressed at specific times in different infection contexts. These complex patterns of viral gene expression arise in part from the integration of multiple cellular and viral signals that affect the transcription of viral genes. The use of alternative promoters provides an increased level of control, allowing different promoters to direct the transcription of the same gene in response to distinct temporal and contextual cues. While once considered rare, herpesvirus alternative promoter usage was recently found to be far more pervasive and impactful than previously thought. Here we review several examples of promoter switching in herpesviruses and discuss the functional consequences on the transcriptional and post-transcriptional regulation of viral gene expression. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Targeted Restriction of Viral Gene Expression and Replication by the ZAP Antiviral System

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Mattia Ficarelli ◽  
Stuart J.D. Neil ◽  
Chad M. Swanson
Keyword(s):  
Gene Expression ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Annual Review ◽  
Publication Date ◽  
Messenger Rnas ◽  
Antiviral Protein ◽  
Dna Viruses ◽  
Cpg Dinucleotides ◽  
Viral Vaccine

The zinc finger antiviral protein (ZAP) restricts the replication of a broad range of RNA and DNA viruses. ZAP directly binds viral RNA, targeting it for degradation and inhibiting its translation. While the full scope of RNA determinants involved in mediating selective ZAP activity are unclear, ZAP binds CpG dinucleotides, dictating at least part of its target specificity. ZAP interacts with many cellular proteins, although only a few have been demonstrated to be essential for its antiviral activity, including the 3′–5′ exoribonuclease exosome complex, TRIM25, and KHNYN. In addition to inhibiting viral gene expression, ZAP also directly and indirectly targets a subset of cellular messenger RNAs to regulate the innate immune response. Overall, ZAP protects a cell from viral infection by restricting viral replication and regulating cellular gene expression. Further understanding of the ZAP antiviral system may allow for novel viral vaccine and anticancer therapy development. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Global Analysis of Baculovirus Autographa californica Multiple Nucleopolyhedrovirus Gene Expression in the Midgut of the Lepidopteran HostTrichoplusia ni

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Anita Shrestha ◽  
Kan Bao ◽  
Yun-Ru Chen ◽  
Wenbo Chen ◽  
Ping Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Line ◽  
Trichoplusia Ni ◽  
Cultured Cells ◽  
Expression Profiles ◽  
Secondary Infection ◽  
Expression Patterns ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Viral Genes

ABSTRACTThe baculovirusAutographa californica multiple nucleopolyhedrovirus(AcMNPV) is a large double-stranded DNA (dsDNA) virus that encodes approximately 156 genes and is highly pathogenic to a variety of larval lepidopteran insects in nature. Oral infection of larval midgut cells is initiated by the occlusion-derived virus (ODV), while secondary infection of other tissues is mediated by the budded virus (BV). Global viral gene expression has been studied in detail in BV-infected cell cultures, but studies of ODV infection in the larval midgut are limited. In this study, we examined expression of the ∼156 AcMNPV genes inTrichoplusia nimidgut tissue using a transcriptomic approach. We analyzed expression profiles of viral genes in the midgut and compared them with profiles from aT. nicell line (Tnms42). Several viral genes (p6.9,orf76,orf75,pp31,Ac-bro,odv-e25, andodv-ec27) had high expression levels in the midgut throughout the infection. Also, the expression of genes associated with occlusion bodies (polhandp10) appeared to be delayed in the midgut in comparison with the cell line. Comparisons of viral gene expression profiles revealed remarkable similarities between the midgut and cell line for most genes, although substantial differences were observed for some viral genes. These included genes associated with high level BV production (fp-25k), acceleration of systemic infection (v-fgf), and enhancement of viral movement (arif-1/orf20). These differential expression patterns appear to represent specific adaptations for virus infection and transmission through the polarized cells of the lepidopteran midgut.IMPORTANCEBaculoviruses such as AcMNPV are pathogens that are natural regulators of certain insect populations. Baculovirus infections are biphasic, with a primary phase initiated by oral infection of midgut epithelial cells by occlusion-derived virus (ODV) virions and a secondary phase in which other tissues are infected by budded-virus (BV) virions. While AcMNPV infections in cultured cells have been studied extensively, comparatively little is known regarding primary infection in the midgut. In these studies, we identified gene expression patterns associated with ODV-mediated infection of the midgut inTrichoplusia niand compared those results with prior results from BV-infected cultured cells, which simulate secondary infection. These studies provide a detailed analysis of viral gene expression patterns in the midgut, which likely represent specific viral strategies to (i) overcome or avoid host defenses in the gut and (ii) rapidly move infection from the midgut, into the hemocoel to facilitate systemic infection.

scholarly journals Mechanisms of pathogenesis of emerging adenoviruses

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 90 ◽  
Author(s):  
James Cook ◽  
Jay Radke
Keyword(s):  
Gene Expression ◽  
Human Population ◽  
Viral Gene Expression ◽  
Critical Threshold ◽  
Severe Illness ◽  
Viral Gene ◽  
Altered Expression ◽  
Biological Studies ◽  
Viral Genes

Periodic outbreaks of human adenovirus infections can cause severe illness in people with no known predisposing conditions. The reasons for this increased viral pathogenicity are uncertain. Adenoviruses are constantly undergoing mutation during circulation in the human population, but related phenotypic changes of the viruses are rarely detected because of the infrequency of such outbreaks and the limited biological studies of the emergent strains. Mutations and genetic recombinations have been identified in these new strains. However, the linkage between these genetic changes and increased pathogenicity is poorly understood. It has been observed recently that differences in virus-induced immunopathogenesis can be associated with altered expression of non-mutant viral genes associated with changes in viral modulation of the host innate immune response. Initial small animal studies indicate that these changes in viral gene expression can be associated with enhanced immunopathogenesisin vivo. Available evidence suggests the hypothesis that there is a critical threshold of expression of certain viral genes that determines both the sustainability of viral transmission in the human population and the enhancement of immunopathogenesis. Studies of this possibility will require extension of the analysis of outbreak viral strains from a sequencing-based focus to biological studies of relationships between viral gene expression and pathogenic responses. Advances in this area will require increased coordination among public health organizations, diagnostic microbiology laboratories, and research laboratories to identify, catalog, and systematically study differences between prototype and emergent viral strains that explain the increased pathogenicity that can occur during clinical outbreaks.

scholarly journals Rat Cytomegalovirus Gene Expression in Cardiac Allograft Recipients Is Tissue Specific and Does Not Parallel the Profiles Detected In Vitro

2007 ◽  
Vol 81 (8) ◽  
pp. 3816-3826 ◽  
Author(s):  
Daniel N. Streblow ◽  
Koen W. R. van Cleef ◽  
Craig N. Kreklywich ◽  
Christine Meyer ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rat Heart ◽  
Cultured Cells ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Viral Mrna ◽  
Tissue Specific ◽  
Viral Genes

ABSTRACT Rat cytomegalovirus (RCMV) is a β-herpesvirus with a 230-kbp genome containing over 167 open reading frames (ORFs). RCMV gene expression is tightly regulated in cultured cells, occurring in three distinct kinetic classes (immediate early, early, and late). However, the extent of viral-gene expression in vivo and its relationship to the in vitro expression are unknown. In this study, we used RCMV-specific DNA microarrays to investigate the viral transcriptional profiles in cultured, RCMV-infected endothelial cells, fibroblasts, and aortic smooth muscle cells and to compare these profiles to those found in tissues from RCMV-infected rat heart transplant recipients. In cultured cells, RCMV expresses approximately 95% of the known viral ORFs with few differences between cell types. By contrast, in vivo viral-gene expression in tissues from rat heart allograft recipients is highly restricted. In the tissues studied, a total of 80 viral genes expressing levels twice above background (5,000 to 10,000 copies per μg total RNA) were detected. In each tissue type, there were a number of genes expressed exclusively in that tissue. Although viral mRNA and genomic DNA levels were lower in the spleen than in submandibular glands, the number of individual viral genes expressed was higher in the spleen (60 versus 41). This finding suggests that the number of viral genes expressed is specific to a given tissue and is not dependent upon the viral load or viral mRNA levels. Our results demonstrate that the profiles, as well as the amplitude, of viral-gene expression are tissue specific and are dramatically different from those in infected cultured cells, indicating that RCMV gene expression in vitro does not reflect viral-gene expression in vivo.

Viral gene expression during the establishment of human cytomegalovirus latent infection in myeloid progenitor cells

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3691-3699 ◽  
Author(s):  
Allen K. L. Cheung ◽  
Allison Abendroth ◽  
Anthony L. Cunningham ◽  
Barry Slobedman
Keyword(s):  
Gene Expression ◽  
Viral Genome ◽  
Latent Infection ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Time Points ◽  
Myeloid Progenitor ◽  
Viral Genes ◽  
Myeloid Progenitor Cells ◽  
Establishment Phase

AbstractHuman cytomegalovirus (HCMV) establishes and maintains a latent infection in myeloid cells and can reactivate to cause serious disease in allograft recipients. To better understand the molecular events associated with the establishment of latency, we tracked the virus following infection of primary human myeloid progenitor cells at days 1, 2, 3, 5, and 11. At all time points, the viral genome was maintained in most cells at approximately 10 copies. Infectious virus was not detected, but virus could be reactivated by extended fibroblast coculture. In contrast to wild-type HCMV, the viral genome was rapidly lost from myeloid progenitors infected with ultraviolet (UV)–inactivated virus, suggesting viral gene expression was required for efficient establishment of latency. To identify viral genes associated with the establishment phase, RNA from each time point was interrogated using custom-made HCMV gene microarrays. Using this approach, we detected expression of viral RNAs at all time points. The pattern of expression differed from that which occurs during productive infection, and decreased over time. This study provides evidence that a molecular pathway into latency is associated with expression of a unique subset of viral transcripts. Viral genes expressed during the establishment phase may serve as targets for therapies to interrupt this process.

scholarly journals Alternative promoters drive human cytomegalovirus reactivation from latency

2019 ◽  
Vol 116 (35) ◽  
pp. 17492-17497 ◽  
Author(s):  
Donna Collins-McMillen ◽  
Mike Rak ◽  
Jason C. Buehler ◽  
Suzu Igarashi-Hayes ◽  
Jeremy P. Kamil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Viral Gene Expression ◽  
Lytic Cycle ◽  
Immediate Early ◽  
Viral Gene ◽  
Genome Replication ◽  
Alternative Promoters ◽  
Cytomegalovirus Reactivation ◽  
Context Specific

Reactivation from latency requires reinitiation of viral gene expression and culminates in the production of infectious progeny. The major immediate early promoter (MIEP) of human cytomegalovirus (HCMV) drives the expression of crucial lytic cycle transactivators but is silenced during latency in hematopoietic progenitor cells (HPCs). Because the MIEP has poor activity in HPCs, it is unclear how viral transactivators are expressed during reactivation. It has been presumed that viral gene expression is reinitiated via de-repression of the MIEP. We demonstrate that immediate early transcripts arising from reactivation originate predominantly from alternative promoters within the canonical major immediate early locus. Disruption of these intronic promoters results in striking defects in re-expression of viral genes and viral genome replication in the THP-1 latency model. Furthermore, we show that these promoters are necessary for efficient reactivation in primary CD34+ HPCs. Our findings shift the paradigm for HCMV reactivation by demonstrating that promoter switching governs reactivation from viral latency in a context-specific manner.

scholarly journals Single-Cell Virus Sequencing of Influenza Infections That Trigger Innate Immunity

2019 ◽  
Vol 93 (14) ◽  
Author(s):  
Alistair B. Russell ◽  
Elizaveta Elshina ◽  
Jacob R. Kowalsky ◽  
Aartjan J. W. te Velthuis ◽  
Jesse D. Bloom
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Genetic Variation ◽  
Immune Activation ◽  
Single Cells ◽  
Viral Gene Expression ◽  
Innate Immune ◽  
Viral Gene ◽  
Viral Genes ◽  
Infected Cells

ABSTRACTInfluenza virus-infected cells vary widely in their expression of viral genes and only occasionally activate innate immunity. Here, we develop a new method to assess how the genetic variation in viral populations contributes to this heterogeneity. We do this by determining the transcriptome and full-length sequences of all viral genes in single cells infected with a nominally “pure” stock of influenza virus. Most cells are infected by virions with defects, some of which increase the frequency of innate-immune activation. These immunostimulatory defects are diverse and include mutations that perturb the function of the viral polymerase protein PB1, large internal deletions in viral genes, and failure to express the virus’s interferon antagonist NS1. However, immune activation remains stochastic in cells infected by virions with these defects and occasionally is triggered even by virions that express unmutated copies of all genes. Our work shows that the diverse spectrum of defects in influenza virus populations contributes to—but does not completely explain—the heterogeneity in viral gene expression and immune activation in single infected cells.IMPORTANCEBecause influenza virus has a high mutation rate, many cells are infected by mutated virions. But so far, it has been impossible to fully characterize the sequence of the virion infecting any given cell, since conventional techniques such as flow cytometry and single-cell transcriptome sequencing (scRNA-seq) only detect if a protein or transcript is present, not its sequence. Here we develop a new approach that uses long-read PacBio sequencing to determine the sequences of virions infecting single cells. We show that viral genetic variation explains some but not all of the cell-to-cell variability in viral gene expression and innate immune induction. Overall, our study provides the first complete picture of how viral mutations affect the course of infection in single cells.

scholarly journals Nuclear Lamina binds the EBV genome during latency and regulates viral gene expression

2021 ◽  
Author(s):  
Lisa Beatrice Caruso ◽  
Rui Guo ◽  
Sarah Boyle ◽  
Kelsey Keith ◽  
Jozef Madzo ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Latent Infection ◽  
Viral Gene Expression ◽  
Nuclear Lamina ◽  
Viral Gene ◽  
Lamin A ◽  
Knock Out ◽  
Ebv Infection ◽  
Viral Genes

The Epstein Barr virus (EBV) establishes a persistent latent infection in almost 90% of the population worldwide. EBV latent infection is associated with several malignancies of epithelial and lymphoid origin. In latently infected cells, the EBV genome persists as a chromatinized episome that expresses a limited set of viral genes. Latent genes are expressed in different patterns that are referred to as latency types. Latency types coincide with varying stages of EBV infection and various malignancies. Our previous work demonstrated that latency types correlate with differences in the composition and structure of the EBV episome. Several cellular factors, including nuclear lamina, regulate chromatin composition and chromatin architecture. The interaction with nuclear lamina has already been studied in the context of EBV lytic reactivation. Still, the role of nuclear lamina in controlling EBV latency has not been investigated. Here, we reported that nuclear lamina is also another essential epigenetic regulator of the EBV episome. First, we observed that in B cells, EBV infection affects the composition of nuclear lamina by inducing the expression of Lamin A/C, and Lamin A/C is present only in EBV+ B cells expressing the Type III latency program. By ChIP-seq, we determined that lamins, Lamin B1 and Lamin A/C, bind the EBV genome, and their binding correlates with deposition of the histone repressive mark H3K9me2. By RNA-seq, we observed that the knock-out of Lamin A/C alters EBV gene expression in B cells and decreases H3K9me2 levels across the viral genome. Our data indicate that the interaction between lamins and the EBV episome contributes to the epigenetic control of viral genes expression during latency, suggesting a restrictive function of the nuclear lamina in the host response against the intrusion of viral DNA into the nucleus.

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