Comprehensive Analysis of Human Cytomegalovirus- and HIV-Mediated Plasma Membrane Remodeling in Macrophages

Businger, Ramona; Kivimäki, Saima; Simeonov, Stefan; Syrigos, Georgios Vavouras; Pohlmann, Justus; Bolz, Michael; Müller, Patrick; Codrea, Marius Cosmin; Templin, Corinna; Messerle, Martin; Hamprecht, Klaus; Schäffer, Tilman E.; Nahnsen, Sven; Schindler, Michael

doi:10.1128/mbio.01770-21

Cited by 7 publications

(9 citation statements)

References 75 publications

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“…Apart from that, it is noteworthy, that apparently from 332 surface receptors included in our screen, only seven were significantly lower in HCV-expressing cells ( Figure 1A ), which is in contrast to other viruses i.e. HCMV and HIV ( Hsu et al., 2015 ; Sugden et al., 2016 ; Businger et al., 2021 ), that heavily dysregulate the plasma membrane of infected cells for evasion of antiviral immune responses. This indicates that HCV, for efficient persistent and chronic infection adopts a “stealth” mode in infected cells, instead of blunting adaptive and humoral cellular immune responses by cell surface receptor dysregulation.…”

Section: Discussionmentioning

confidence: 82%

“…48 h later, cells were detached and washed, before they were ntibody stained (5x10 4 -2x10 5 cells per well). The staining and fixing procedure, as well as data analysis was performed as described previously ( Businger et al., 2021 ), except that measurement of the samples was conducted with a BD FACS Canto II with high-throughput sampler. The complete measured mean fluorescence intensities (MFIs) and calculations of three biological replicate screens are summarized in Supplementary Table 1 ( Table S1 ).…”

Section: Methodsmentioning

confidence: 99%

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CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells

Bunz,

Eisele,

et al. 2024

Front. Cell. Infect. Microbiol.

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The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout in hepatoma cells. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as a regulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might be relevant for viral persistence and chronic infection.

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells

Bunz,

Eisele,

et al. 2024

Front. Cell. Infect. Microbiol.

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“…48 h later, cells were detached and washed, before they were ntibody stained (5×10 4 -2×10 5 cells per well). The staining and fixing procedure was performed as described previously (27).…”

Section: Methodsmentioning

confidence: 99%

CD81 represses NF-κB in HCV-expressing hepatoma cells

Bunz,

Eisele,

et al. 2023

Preprint

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The tetraspanin CD81 is one of the main entry receptors for Hepatitis C virus, which is a major causative agent to develop liver cirrhosis and hepatocellular carcinoma (HCC). Here, we identify CD81 as one of few surface proteins that are downregulated in HCV expressing hepatoma cells, discovering a functional role of CD81 beyond mediating HCV entry. CD81 was downregulated at the mRNA level in hepatoma cells that replicate HCV. Kinetics of HCV protein expression were increased in CD81-knockout cells and accompanied by enhanced cellular growth. Furthermore, loss of CD81 compensated for inhibition of pro-survival TBK1-signaling in HCV expressing cells. Analysis of functional phenotypes that could be associated with pro-survival signaling revealed that CD81 is a negative regulator of NF-κB. Interaction of the NF-κB subunits p50 and p65 was increased in cells lacking CD81. Similarly, we witnessed an overall increase in the total levels of phosphorylated and cellular p65 upon CD81-knockout. Finally, translocation of p65 in CD81-negative hepatoma cells was markedly induced upon stimulation with TNFα or PMA. Altogether, CD81 emerges as aregulator of pro-survival NF-κB signaling. Considering the important and established role of NF-κB for HCV replication and tumorigenesis, the downregulation of CD81 by HCV and the associated increase in NF-κB signaling might serve as viral mechanism to maintain persistent infection, ultimately causing chronic inflammation and HCC.

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“…Before NCI-60 cells were used for flow cytometric analyses they were cultured from nitrogen stocks and allowed to grow for at least 2 weeks (four to five passages at maximum). Cells were detached by Accutase treatment and stained with the LegendScreen Human PE kit (BioLegend) using 332 PE-conjugated antibodies essentially as described before [ 15 , 16 ]. Cell surface expression of the 332 receptors was measured via flow cytometry using the MACSQuant VYB Analyzer (Miltenyi Biotec).…”

Section: Methodsmentioning

confidence: 99%

Multiomics surface receptor profiling of the NCI-60 tumor cell panel uncovers novel theranostics for cancer immunotherapy

et al. 2022

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Background Immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized cancer therapy. However, therapeutic targeting of inhibitory T cell receptors such as PD-1 not only initiates a broad immune response against tumors, but also causes severe adverse effects. An ideal future stratified immunotherapy would interfere with cancer-specific cell surface receptors only. Methods To identify such candidates, we profiled the surface receptors of the NCI-60 tumor cell panel via flow cytometry. The resulting surface receptor expression data were integrated into proteomic and transcriptomic NCI-60 datasets applying a sophisticated multiomics multiple co-inertia analysis (MCIA). This allowed us to identify surface profiles for skin, brain, colon, kidney, and bone marrow derived cell lines and cancer entity-specific cell surface receptor biomarkers for colon and renal cancer. Results For colon cancer, identified biomarkers are CD15, CD104, CD324, CD326, CD49f, and for renal cancer, CD24, CD26, CD106 (VCAM1), EGFR, SSEA-3 (B3GALT5), SSEA-4 (TMCC1), TIM1 (HAVCR1), and TRA-1-60R (PODXL). Further data mining revealed that CD106 (VCAM1) in particular is a promising novel immunotherapeutic target for the treatment of renal cancer. Conclusion Altogether, our innovative multiomics analysis of the NCI-60 panel represents a highly valuable resource for uncovering surface receptors that could be further exploited for diagnostic and therapeutic purposes in the context of cancer immunotherapy.

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Comprehensive Analysis of Human Cytomegalovirus- and HIV-Mediated Plasma Membrane Remodeling in Macrophages

Abstract: The PM is a key component that viruses have to cope with. It is a barrier for infection and egress and is critically involved in antiviral immune signaling.

Cited by 7 publications

References 75 publications

CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells

CD81 suppresses NF-κB signaling and is downregulated in hepatitis C virus expressing cells

CD81 represses NF-κB in HCV-expressing hepatoma cells

Multiomics surface receptor profiling of the NCI-60 tumor cell panel uncovers novel theranostics for cancer immunotherapy

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