The Tiers and Dimensions of Evasion of the Type I Interferon Response by Human Cytomegalovirus

Human cytomegalovirus (HCMV), the human beta-herpesvirus, can cause severe syndromes among both immunocompromised adult patients and newborns. Type I interferon (IFN-I) exerts an important effect to resist infections caused by viruses such as HCMV, while IFN evasion may serve as a key determining factor for viral dissemination and disease occurrence within hosts. In this study, UL23, a tegument protein of HCMV, was confirmed to be a key factor for negatively regulating the type I IFN immune response. A detailed analysis indicated that the viral UL23 protein increases the IFN-I antiviral resistance during HCMV infections. Furthermore, UL23 was shown to significantly reduce the levels of IFN-stimulated genes (ISGs) and promoter activity of IFN-I-stimulated response element. Mechanically, UL23 was discovered to impair the signal transducer and activator of transcription 1 (STAT1) phosphorylation, although it was not found to affect phosphorylation and expression of STAT2, Janus activated kinase 1, or tyrosine kinase 2, which are associated with IFN-I signal transduction pathway. Additionally, a significantly reduced nuclear expression of STAT1 but not of IFN regulatory factor 9 or STAT2 was observed. Findings of this study indicate that HCMV UL23 is a viral antagonist that acts against the cellular innate immunity and reveal a possible novel effect of UL23 on IFN-I signaling.

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The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response

Frontiers in Microbiology ◽

10.3389/fmicb.2021.675112 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yueyan Liao ◽

Xiangyu Ke ◽

Tianyi Deng ◽

Qingsong Qin

Keyword(s):

Human Cytomegalovirus ◽

Viral Entry ◽

Nuclear Export ◽

Second Generation ◽

Type I Interferon ◽

Opportunistic Pathogen ◽

Interferon Response ◽

Type I ◽

Dependent Manner ◽

Hcmv Replication

Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.

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Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus

PLoS Pathogens ◽

10.1371/journal.ppat.1004785 ◽

2015 ◽

Vol 11 (3) ◽

pp. e1004785 ◽

Cited By ~ 41

Author(s):

Young-Eui Kim ◽

Jin-Hyun Ahn

Keyword(s):

Human Cytomegalovirus ◽

Type I Interferon ◽

Promyelocytic Leukemia ◽

Interferon Response ◽

Type I ◽

Positive Role ◽

Promyelocytic Leukemia Protein

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Faculty Opinions recommendation of Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104493.560531 ◽

2008 ◽

Author(s):

Ann Hill

Keyword(s):

B Cells ◽

Type I Interferon ◽

Interferon Response ◽

Type I

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Faculty Opinions recommendation of USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726829800.793527398 ◽

2017 ◽

Author(s):

Benedict Michael ◽

Mark Ellul

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Viral Invasion and Type I Interferon Response Characterize the Immunophenotypes during COVID-19 Infection

SSRN Electronic Journal ◽

10.2139/ssrn.3555695 ◽

2020 ◽

Cited By ~ 8

Author(s):

Lai Wei ◽

Siqi Ming ◽

Bin Zou ◽

Yongjian Wu ◽

Zhongsi Hong ◽

...

Keyword(s):

Type I Interferon ◽

Interferon Response ◽

Type I

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Positive natural selection in primate genes of the type I interferon response

BMC Ecology and Evolution ◽

10.1186/s12862-021-01783-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Elena N. Judd ◽

Alison R. Gilchrist ◽

Nicholas R. Meyerson ◽

Sara L. Sawyer

Keyword(s):

Natural Selection ◽

Positive Selection ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Sequence Alignments ◽

Multiple Sequence ◽

Multiple Sequence Alignments ◽

Interferon Stimulated Genes ◽

Interferon Induction

Abstract Background The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one. Results We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, “induction” genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid. Conclusion Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.

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