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1.
J Infect Dis ; 227(4): 543-553, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36408607

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused widespread morbidity and mortality since its onset in late 2019. Here, we demonstrate that prior infection with human cytomegalovirus (HCMV) substantially increases infection with SARS-CoV-2 in vitro. HCMV is a common herpesvirus carried by 40%-100% of the population, which can reactivate in the lung under inflammatory conditions, such as those resulting from SARS-CoV-2 infection. We show in both endothelial and epithelial cell types that HCMV infection upregulates ACE2, the SARS-CoV-2 cell entry receptor. These observations suggest that HCMV reactivation events in the lung of healthy HCMV carriers could exacerbate SARS-CoV-2 infection and subsequent COVID-19 symptoms. This effect could contribute to the disparity of disease severity seen in ethnic minorities and those with lower socioeconomic status, due to their higher CMV seroprevalence. Our results warrant further clinical investigation as to whether HCMV infection influences the pathogenesis of SARS-CoV-2.


Subject(s)
COVID-19 , Cytomegalovirus Infections , Superinfection , Humans , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2 , Seroepidemiologic Studies , Peptidyl-Dipeptidase A , Epithelial Cells/metabolism
2.
Nat Commun ; 12(1): 4436, 2021 07 21.
Article in English | MEDLINE | ID: mdl-34290252

ABSTRACT

Latent human cytomegalovirus (HCMV) infection is characterized by limited gene expression, making latent HCMV infections refractory to current treatments targeting viral replication. However, reactivation of latent HCMV in immunosuppressed solid organ and stem cell transplant patients often results in morbidity. Here, we report the killing of latently infected cells via a virus-specific nanobody (VUN100bv) that partially inhibits signaling of the viral receptor US28. VUN100bv reactivates immediate early gene expression in latently infected cells without inducing virus production. This allows recognition and killing of latently infected monocytes by autologous cytotoxic T lymphocytes from HCMV-seropositive individuals, which could serve as a therapy to reduce the HCMV latent reservoir of transplant patients.


Subject(s)
Cytomegalovirus/drug effects , Single-Domain Antibodies/pharmacology , T-Lymphocytes, Cytotoxic/immunology , Virus Latency/drug effects , Cells, Cultured , Cytomegalovirus/immunology , Cytomegalovirus Infections/virology , Gene Expression/drug effects , Genes, Immediate-Early/genetics , Humans , Lipopolysaccharide Receptors/metabolism , Monocytes/drug effects , Monocytes/metabolism , Monocytes/virology , Receptors, Chemokine/metabolism , Signal Transduction/drug effects , Single-Domain Antibodies/metabolism , Viral Proteins/metabolism , Virus Activation/drug effects
3.
J Gen Virol ; 102(5)2021 05.
Article in English | MEDLINE | ID: mdl-34042564

ABSTRACT

Viral latency is an active process during which the host cell environment is optimized for latent carriage and reactivation. This requires control of both viral and host gene promoters and enhancers often at the level of chromatin, and several viruses co-opt the chromatin organiser CTCF to control gene expression during latency. While CTCF has a role in the latencies of alpha- and gamma-herpesviruses, it was not known whether CTCF played a role in the latency of the beta-herpesvirus human cytomegalovirus (HCMV). Here, we show that HCMV latency is associated with increased CTCF expression and CTCF binding to the viral major lytic promoter, the major immediate early promoter (MIEP). This increase in CTCF binding is dependent on the virally encoded G protein coupled receptor, US28, and contributes to suppression of MIEP-driven transcription, a hallmark of latency. Furthermore, we show that latency-associated upregulation of CTCF represses expression of the neutrophil chemoattractants S100A8 and S100A9 which we have previously shown are downregulated during HCMV latency. As with downregulation of the MIEP, CTCF binding to the enhancer region of S100A8/A9 drives their suppression, again in a US28-dependent manner. Taken together, we identify CTCF upregulation as an important mechanism for optimizing latent carriage of HCMV at both the levels of viral and cellular gene expression.


Subject(s)
CCCTC-Binding Factor/metabolism , Cytomegalovirus Infections/virology , Cytomegalovirus/physiology , Receptors, Chemokine/metabolism , Viral Proteins/metabolism , Virus Latency , CCCTC-Binding Factor/genetics , Calgranulin A/genetics , Calgranulin B/genetics , Enhancer Elements, Genetic , Gene Expression Regulation , Genes, Immediate-Early/genetics , Host-Pathogen Interactions , Humans , Monocytes/virology , Promoter Regions, Genetic
4.
Pharmacol Rev ; 73(2): 828-846, 2021 04.
Article in English | MEDLINE | ID: mdl-33692148

ABSTRACT

Herpesviruses are ubiquitous pathogens that establish lifelong, latent infections in their host. Spontaneous reactivation of herpesviruses is often asymptomatic or clinically manageable in healthy individuals, but reactivation events in immunocompromised or immunosuppressed individuals can lead to severe morbidity and mortality. Moreover, herpesvirus infections have been associated with multiple proliferative cardiovascular and post-transplant diseases. Herpesviruses encode viral G protein-coupled receptors (vGPCRs) that alter the host cell by hijacking cellular pathways and play important roles in the viral life cycle and these different disease settings. In this review, we discuss the pharmacological and signaling properties of these vGPCRs, their role in the viral life cycle, and their contribution in different diseases. Because of their prominent role, vGPCRs have emerged as promising drug targets, and the potential of vGPCR-targeting therapeutics is being explored. Overall, these vGPCRs can be considered as attractive targets moving forward in the development of antiviral, cancer, and/or cardiovascular disease treatments. SIGNIFICANCE STATEMENT: In the last decade, herpesvirus-encoded G protein-coupled receptors (GPCRs) have emerged as interesting drug targets with the growing understanding of their critical role in the viral life cycle and in different disease settings. This review presents the pharmacological properties of these viral receptors, their role in the viral life cycle and different diseases, and the emergence of therapeutics targeting viral GPCRs.


Subject(s)
Herpesviridae Infections , Herpesviridae , Humans , Receptors, G-Protein-Coupled , Signal Transduction
5.
mBio ; 10(6)2019 12 03.
Article in English | MEDLINE | ID: mdl-31796538

ABSTRACT

Human cytomegalovirus (HCMV) latency is an active process which remodels the latently infected cell to optimize latent carriage and reactivation. This is achieved, in part, through the expression of viral genes, including the G-protein-coupled receptor US28. Here, we use an unbiased proteomic screen to assess changes in host proteins induced by US28, revealing that interferon-inducible genes are downregulated by US28. We validate that major histocompatibility complex (MHC) class II and two pyrin and HIN domain (PYHIN) proteins, myeloid cell nuclear differentiation antigen (MNDA) and IFI16, are downregulated during experimental latency in primary human CD14+ monocytes. We find that IFI16 is targeted rapidly during the establishment of latency in a US28-dependent manner but only in undifferentiated myeloid cells, a natural site of latent carriage. Finally, by overexpressing IFI16, we show that IFI16 can activate the viral major immediate early promoter and immediate early gene expression during latency via NF-κB, a function which explains why downregulation of IFI16 during latency is advantageous for the virus.IMPORTANCE Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV latency and reactivation could provide insights into potential ways to target the latent viral reservoir in at-risk patient populations.


Subject(s)
Cytomegalovirus Infections/genetics , Cytomegalovirus/immunology , Interferons/genetics , Virus Latency/genetics , Cell Differentiation/genetics , Cell Differentiation/immunology , Cell Line , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , Down-Regulation/genetics , Down-Regulation/immunology , Gene Expression/genetics , Gene Expression/immunology , Gene Expression Regulation, Viral/genetics , Gene Expression Regulation, Viral/immunology , HEK293 Cells , Humans , Interferons/immunology , Monocytes/immunology , Monocytes/virology , Myeloid Cells/immunology , Myeloid Cells/virology , NF-kappa B/genetics , NF-kappa B/immunology , Promoter Regions, Genetic/genetics , Promoter Regions, Genetic/immunology , Proteomics/methods , Receptors, G-Protein-Coupled/immunology , THP-1 Cells , Viral Proteins/genetics , Viral Proteins/immunology , Virus Activation/genetics , Virus Activation/immunology , Virus Latency/immunology
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