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Article ; Online: Comprehensive Analysis of Soluble Mediator Profiles in Congenital CMV Infection Using an MCMV Model.

Karner, Dubravka / Kvestak, Daria / Lisnic, Berislav / Cokaric Brdovcak, Maja / Juranic Lisnic, Vanda / Kucan Brlic, Paola / Hasan, Milena / Lenac Rovis, Tihana

Viruses

2024 Volume 16, Issue 2

Abstract: Congenital human cytomegalovirus (HCMV) infection may cause life-threatening disease and permanent damage to the central nervous system. The mouse model of CMV infection is most commonly used to study mechanisms of infection and pathogenesis. While ... ...

Abstract	Congenital human cytomegalovirus (HCMV) infection may cause life-threatening disease and permanent damage to the central nervous system. The mouse model of CMV infection is most commonly used to study mechanisms of infection and pathogenesis. While essential to limit mouse CMV (MCMV) replication, the inflammatory responses, particularly IFNγ and TNFα, cause neurodevelopmental abnormalities. Other soluble mediators of the immune response in most tissues remain largely unexplored. To address this gap, we quantified 48 soluble mediators of the immune response, including 32 cytokines, 10 chemokines, 3 growth factors/regulators, and 3 soluble receptors in the spleen, liver, lungs, and brain at 9 and 14 days postinfection (dpi). Our analysis found 25 induced molecules in the brain at 9 dpi, with an additional 8 showing statistically elevated responses at 14 dpi. Specifically, all analyzed CCL group cytokines (CCL2, CCL3, CCL4, CCL5, CCL7, and CCL11) were upregulated at 14 dpi in the brain. Furthermore, data revealed differentially regulated analytes across tissues, such as CCL11, CXCL5, and IL-10 in the brain, IL-33/IL-33R in the liver, and VEGF-a and IL-5 in the lungs. Overall, this study provides an overview of the immune dynamics of soluble mediators in congenital CMV.
MeSH term(s)	Animals ; Humans ; Mice ; Cytomegalovirus Infections ; Cytokines ; Brain ; Tumor Necrosis Factor-alpha ; Muromegalovirus
Chemical Substances	Cytokines ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16020208
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Article ; Online: Decoding murine cytomegalovirus.

Lodha, Manivel / Muchsin, Ihsan / Jürges, Christopher / Juranic Lisnic, Vanda / L'Hernault, Anne / Rutkowski, Andrzej J / Prusty, Bhupesh K / Grothey, Arnhild / Milic, Andrea / Hennig, Thomas / Jonjic, Stipan / Friedel, Caroline C / Erhard, Florian / Dölken, Lars

PLoS pathogens

2023 Volume 19, Issue 5, Page(s) e1010992

Abstract: The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics ... ...

Abstract	The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include >200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model.
MeSH term(s)	Animals ; Mice ; Humans ; Muromegalovirus ; Cytomegalovirus/genetics ; Cytomegalovirus/metabolism ; Base Sequence ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Open Reading Frames
Chemical Substances	Viral Proteins
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010992
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Article ; Online: Rodent Models of Congenital Cytomegalovirus Infection.

Lisnić, Berislav / Tomac, Jelena / Cekinović, Djurdjica / Jonjić, Stipan / Juranić Lisnić, Vanda

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2244, Page(s) 365–401

Abstract: Human cytomegalovirus (HCMV) is a leading viral cause of congenital infections in the central nervous system (CNS) and may result in severe long-term sequelae. High rates of sequelae following congenital HCMV infection and insufficient antiviral therapy ... ...

Abstract	Human cytomegalovirus (HCMV) is a leading viral cause of congenital infections in the central nervous system (CNS) and may result in severe long-term sequelae. High rates of sequelae following congenital HCMV infection and insufficient antiviral therapy in the perinatal period makes the development of an HCMV-specific vaccine a high priority of modern medicine. Due to the species specificity of HCMV, animal models are frequently used to study CMV pathogenesis. Studies of murine cytomegalovirus (MCMV) infections of adult mice have played a significant role as a model of CMV biology and pathogenesis, while MCMV infection of newborn mice has been successfully used as a model of perinatal CMV infection. Newborn mice infected with MCMV have high levels of viremia during which the virus establishes a productive infection in most organs, coupled with a robust inflammatory response. Productive infection in the brain parenchyma during early postnatal period leads to an extensive nonnecrotizing multifocal widespread encephalitis characterized by infiltration of components of both innate and adaptive immunity. As a result, impairment in postnatal development of mouse cerebellum leads to long-term motor and sensor disabilities. This chapter summarizes current findings of rodent models of perinatal CMV infection and describes methods for analysis of perinatal MCMV infection in newborn mice.
MeSH term(s)	Animals ; Animals, Newborn ; Brain/immunology ; Central Nervous System/virology ; Cytomegalovirus/immunology ; Cytomegalovirus/metabolism ; Cytomegalovirus/pathogenicity ; Cytomegalovirus Infections/immunology ; Disease Models, Animal ; Encephalitis ; Fetal Diseases ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Muromegalovirus/immunology ; Primary Cell Culture
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1111-1_18
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Article ; Online: nanoString evaluation of murine Cytomegalovirus transcription in vivo and in vitro.

Griessl, Marion / Gutknecht, Michael / Juranić-Lisnić, Vanda / Cook, Charles H

Journal of virological methods

2021 Volume 301, Page(s) 114436

Abstract: Background: Next Generation Sequencing allows for deep analysis of transcriptional activity in cells and tissues, however it is still a cost intensive method that demands well versed data handling. Reverse transcription quantitative PCR (RT-qPCR) is the ...

Abstract	Background: Next Generation Sequencing allows for deep analysis of transcriptional activity in cells and tissues, however it is still a cost intensive method that demands well versed data handling. Reverse transcription quantitative PCR (RT-qPCR) is the most commonly used method to measure gene expression levels, however the information gathered is quite small in comparison to NGS. A newer method called nanoString allows for highly multiplexed gene expression analysis by detecting mRNAs without the use of enzymes for reverse transcription or amplification even for single cells or low input material. The method can be done in 1.5 days and data are quickly analyzed by the accompanied user friendly software. Our aim was to investigate this new method and compare it to the existing alternatives, while investigating murine Cytomegalovirus (mCMV) infection and latency. Methods: mCMV infected murine embryonic fibroblasts (MEF), lung and salivary glands from BALB/c mice were evaluated at different stages of infection. A set of 30 custom designed nanoString probes were tested, 20 probes specific for mCMV genes, 6 probes for host genes known to be influenced by viral infection and 4 reference gene specific probes. nanoString counts were compared to published RNA-Seq RPKM. Results: We found that nanoString can be used for analysis of cytomegalovirus gene expression during acute infection in vitro and in vivo, both for virus specific and host genes. Although some transcripts show different expression rates in comparison to NGS data, the most abundant transcripts are comparable. When tissues are infected, there are significantly fewer transcripts than in MEFs, and consistent with previous work there are significant differences in relevant abundance between MEF and tissues. We were unable to detect our viral transcripts of interest in latently infected tissue. Conclusions: For viruses with annotated transcriptomes, nanoString allows simultaneous quantitation of multiple virus and host genes. One huge advantage of the platform is rapid turnaround and simplicity of analysis. It should prove to be very useful to explore host virus interactions during acute infection, but it is unclear if it has adequate sensitivity for analysis during latency in immunocompetent mice.
MeSH term(s)	Animals ; Cytomegalovirus/genetics ; Cytomegalovirus Infections ; Mice ; Mice, Inbred BALB C ; Muromegalovirus/genetics ; Transcriptome
Language	English
Publishing date	2021-12-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2021.114436
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Article ; Online: Two murine cytomegalovirus microRNAs target the major viral immediate early 3 gene.

Herb, Stefanie / Zeleznjak, Jelena / Hennig, Thomas / L'Hernault, Anne / Lodha, Manivel / Jürges, Christopher / Trsan, Tihana / Juranic Lisnic, Vanda / Jonjic, Stipan / Erhard, Florian / Krmpotic, Astrid / Dölken, Lars

The Journal of general virology

2022 Volume 103, Issue 11

Abstract: Human cytomegalovirus is responsible for morbidity and mortality in immune compromised patients and is the leading viral cause of congenital infection. Virus-encoded microRNAs (miRNAs) represent interesting targets for novel antiviral agents. While many ... ...

Abstract	Human cytomegalovirus is responsible for morbidity and mortality in immune compromised patients and is the leading viral cause of congenital infection. Virus-encoded microRNAs (miRNAs) represent interesting targets for novel antiviral agents. While many cellular targets that augment productive infection have been identified in recent years, regulation of viral genes such as the major viral immediate early protein 72 (IE72) by hcmv-miR-UL112-1 may contribute to both the establishment and the maintenance of latent infection. We employed photoactivated ribonucleotide-enhanced individual nucleotide resolution crosslinking (PAR-iCLIP) to identify murine cytomegalovirus (MCMV) miRNA targets during lytic infection. While the PAR-iCLIP data were of insufficient quality to obtain a comprehensive list of cellular and viral miRNA targets, the most prominent PAR-iCLIP peak in the MCMV genome mapped to the 3' untranslated region of the major viral immediate early 3 (
MeSH term(s)	Humans ; Mice ; Animals ; Muromegalovirus/genetics ; Genes, Immediate-Early ; CD8-Positive T-Lymphocytes/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Cytomegalovirus/genetics ; 3' Untranslated Regions
Chemical Substances	MicroRNAs ; 3' Untranslated Regions ; microRNA-UL112, human cytomegalovirus
Language	English
Publishing date	2022-11-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	219316-4
ISSN	1465-2099 ; 0022-1317
ISSN (online)	1465-2099
ISSN	0022-1317
DOI	10.1099/jgv.0.001804
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Article ; Online: Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells.

Rožmanić, Carmen / Lisnić, Berislav / Pribanić Matešić, Marina / Mihalić, Andrea / Hiršl, Lea / Park, Eugene / Lesac Brizić, Ana / Indenbirken, Daniela / Viduka, Ina / Šantić, Marina / Adler, Barbara / Yokoyama, Wayne M / Krmpotić, Astrid / Juranić Lisnić, Vanda / Jonjić, Stipan / Brizić, Ilija

Nature communications

2023 Volume 14, Issue 1, Page(s) 6412

Abstract: Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection ... ...

Abstract	Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA Ifng-as1 expression. Moreover, the bone marrow's capacity to efficiently generate new NK cells is reduced, explaining the prolonged negative effects of perinatal infection on NK cells. This study demonstrates that viral infections in early life can profoundly impact NK cell biology, including long-lasting impairment in NK cell functionality.
MeSH term(s)	Mice ; Animals ; Killer Cells, Natural ; Cytomegalovirus Infections/genetics ; Muromegalovirus
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42182-w
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Article ; Online: Decoding murine cytomegalovirus.

Manivel Lodha / Ihsan Muchsin / Christopher Jürges / Vanda Juranic Lisnic / Anne L'Hernault / Andrzej J Rutkowski / Bhupesh K Prusty / Arnhild Grothey / Andrea Milic / Thomas Hennig / Stipan Jonjic / Caroline C Friedel / Florian Erhard / Lars Dölken

PLoS Pathogens, Vol 19, Iss 5, p e

2023 Volume 1010992

Abstract	The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include >200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: nanoString evaluation of murine Cytomegalovirus transcription in vivo and in vitro

Griessl, Marion / Gutknecht, Michael / Juranić-Lisnić, Vanda / Cook, Charles H.

Journal of Virological Methods. 2022 Mar., v. 301 p.114436-

2022

Abstract: Next Generation Sequencing allows for deep analysis of transcriptional activity in cells and tissues, however it is still a cost intensive method that demands well versed data handling. Reverse transcription quantitative PCR (RT-qPCR) is the most ... ...

Abstract	Next Generation Sequencing allows for deep analysis of transcriptional activity in cells and tissues, however it is still a cost intensive method that demands well versed data handling. Reverse transcription quantitative PCR (RT-qPCR) is the most commonly used method to measure gene expression levels, however the information gathered is quite small in comparison to NGS. A newer method called nanoString allows for highly multiplexed gene expression analysis by detecting mRNAs without the use of enzymes for reverse transcription or amplification even for single cells or low input material. The method can be done in 1.5 days and data are quickly analyzed by the accompanied user friendly software. Our aim was to investigate this new method and compare it to the existing alternatives, while investigating murine Cytomegalovirus (mCMV) infection and latency. mCMV infected murine embryonic fibroblasts (MEF), lung and salivary glands from BALB/c mice were evaluated at different stages of infection. A set of 30 custom designed nanoString probes were tested, 20 probes specific for mCMV genes, 6 probes for host genes known to be influenced by viral infection and 4 reference gene specific probes. nanoString counts were compared to published RNA-Seq RPKM. We found that nanoString can be used for analysis of cytomegalovirus gene expression during acute infection in vitro and in vivo, both for virus specific and host genes. Although some transcripts show different expression rates in comparison to NGS data, the most abundant transcripts are comparable. When tissues are infected, there are significantly fewer transcripts than in MEFs, and consistent with previous work there are significant differences in relevant abundance between MEF and tissues. We were unable to detect our viral transcripts of interest in latently infected tissue. For viruses with annotated transcriptomes, nanoString allows simultaneous quantitation of multiple virus and host genes. One huge advantage of the platform is rapid turnaround and simplicity of analysis. It should prove to be very useful to explore host virus interactions during acute infection, but it is unclear if it has adequate sensitivity for analysis during latency in immunocompetent mice.
Keywords	Muromegalovirus ; computer software ; fibroblasts ; gene expression ; genes ; lungs ; mice ; reverse transcriptase polymerase chain reaction ; reverse transcription ; sequence analysis ; transcriptome ; viruses ; Murine cytomegalovirus ; nanoString ; Viral transcription
Language	English
Dates of publication	2022-03
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2021.114436
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rat cytomegalovirus efficiently replicates in dendritic cells and induces changes in their transcriptional profile.

Madela-Mönchinger, Julia Cecilia / Wolf, Silver Anthony / Wyler, Emanuel / Bauer, Agnieszka / Mischke, Marius / Möller, Lars / Juranić Lisnić, Vanda / Landthaler, Markus / Malyshkina, Anna / Voigt, Sebastian

Frontiers in immunology

2023 Volume 14, Page(s) 1192057

Abstract: Dendritic cells (DC) play a crucial role in generating and maintaining antiviral immunity. While DC are implicated in the antiviral defense by inducing T cell responses, they can also become infected by Cytomegalovirus (CMV). CMV is not only highly ... ...

Abstract	Dendritic cells (DC) play a crucial role in generating and maintaining antiviral immunity. While DC are implicated in the antiviral defense by inducing T cell responses, they can also become infected by Cytomegalovirus (CMV). CMV is not only highly species-specific but also specialized in evading immune protection, and this specialization is in part due to characteristic genes encoded by a given virus. Here, we investigated whether rat CMV can infect XCR1
MeSH term(s)	Rats ; Animals ; Muromegalovirus ; Cytomegalovirus/genetics ; T-Lymphocytes/metabolism ; Cytomegalovirus Infections/metabolism ; Dendritic Cells
Language	English
Publishing date	2023-11-23
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1192057
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Article: Endosomal Phosphatidylinositol-3-Phosphate-Associated Functions Are Dispensable for Establishment of the Cytomegalovirus Pre-Assembly Compartment but Essential for the Virus Growth.

Marcelić, Marina / Lučin, Hana Mahmutefendić / Begonja, Antonija Jurak / Zagorac, Gordana Blagojević / Lisnić, Vanda Juranić / Lučin, Pero

Life (Basel, Switzerland)

2021 Volume 11, Issue 8

Abstract: Murine cytomegalovirus (MCMV) initiates the stepwise establishment of the pre-assembly compartment (pre-AC) in the early phase of infection by the expansion of the early endosome (EE)/endosomal recycling compartment (ERC) interface and relocation of the ... ...

Abstract	Murine cytomegalovirus (MCMV) initiates the stepwise establishment of the pre-assembly compartment (pre-AC) in the early phase of infection by the expansion of the early endosome (EE)/endosomal recycling compartment (ERC) interface and relocation of the Golgi complex. We depleted Vps34-derived phosphatidylinositol-3-phosphate (PI(3)P) at EEs by VPS34-IN1 and inhibited PI(3)P-associated functions by overexpression of 2xFYVE- and p40PX PI(3)P-binding modules to assess the role of PI(3)P-dependent EE domains in the pre-AC biogenesis. We monitored the accumulation of Rab10 and Evectin-2 in the inner pre-AC and the relocation of GM130-positive cis-Golgi organelles to the outer pre-AC by confocal microscopy. Although PI(3)P- and Vps34-positive endosomes build a substantial part of pre-AC, the PI(3)P depletion and the inhibition of PI(3)P-associated functions did not prevent the establishment of infection and progression through the early phase. The PI(3)P depletion in uninfected and MCMV-infected cells rapidly dispersed PI(3)P-bond proteins and reorganized EEs, including ablation of EE-to-ERC transport and relocation of Rab11 endosomes. The PI(3)P depletion one hour before pre-AC initiation and overexpression of 2xFYVE and p40PX domains neither prevented Rab10- and Evectin-2 accumulation, nor Golgi unlinking and relocation. These data demonstrate that PI(3)P-dependent functions, including the Rab11-dependent EE-to-ERC route, are dispensable for pre-AC initiation. Nevertheless, the virus growth was drastically reduced in PI(3)P-depleted cells, indicating that PI(3)P-associated functions are essential for the late phase of infection.
Language	English
Publishing date	2021-08-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life11080859
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