publications of the junior research group immunomodulation (VIMM)
http://hdl.handle.net/10033/621050
2024-03-28T14:36:59ZUNC93B1 Is Widely Expressed in the Murine CNS and Is Required for Neuroinflammation and Neuronal Injury Induced by MicroRNA .
http://hdl.handle.net/10033/623098
UNC93B1 Is Widely Expressed in the Murine CNS and Is Required for Neuroinflammation and Neuronal Injury Induced by MicroRNA .
Klammer, Markus G; Dzaye, Omar; Wallach, Thomas; Krüger, Christina; Gaessler, Dorothea; Buonfiglioli, Alice; Derkow, Katja; Kettenmann, Helmut; Brinkmann, Melanie M; Lehnardt, Seija
The chaperone protein Unc-93 homolog B1 (UNC93B1) regulates internalization, trafficking, and stabilization of nucleic acid-sensing Toll-like receptors (TLR) in peripheral immune cells. We sought to determine UNC93B1 expression and its functional relevance in inflammatory and injurious processes in the central nervous system (CNS). We found that UNC93B1 is expressed in various CNS cells including microglia, astrocytes, oligodendrocytes, and neurons, as assessed by PCR, immunocyto-/histochemistry, and flow cytometry. UNC93B1 expression in the murine brain increased during development. Exposure to the microRNA let-7b, a recently discovered endogenous TLR7 activator, but also to TLR3 and TLR4 agonists, led to increased UNC93B1 expression in microglia and neurons. Microglial activation by extracellular let-7b required functional UNC93B1, as assessed by TNF ELISA. Neuronal injury induced by extracellular let-7b was dependent on UNC93B1, as UNC93B1-deficient neurons were unaffected by the microRNA's neurotoxicity in vitro. Intrathecal application of let-7b triggered neurodegeneration in wild-type mice, whereas mice deficient for UNC93B1 were protected against injurious effects on neurons and axons. In summary, our data demonstrate broad UNC93B1 expression in the murine brain and establish this chaperone as a modulator of neuroinflammation and neuronal injury triggered by extracellular microRNA and subsequent induction of TLR signaling.
2021-09-13T00:00:00ZCall for a pan-European COVID-19 response must be comprehensive - Authors' reply.
http://hdl.handle.net/10033/622924
Call for a pan-European COVID-19 response must be comprehensive - Authors' reply.
Priesemann, Viola; Brinkmann, Melanie M; Ciesek, Sandra; Cuschieri, Sarah; Czypionka, Thomas; Giordano, Giulia; Hanson, Claudia; Hens, Niel; Iftekhar, Emil; Klimek, Peter; Kretzschmar, Mirjam; Peichl, Andreas; Perc, Matjaž; Sannino, Francesco; Schernhammer, Eva; Schmidt, Alexander; Staines, Anthony; Szczurek, Ewa
No abstract available
2021-04-22T00:00:00ZThe Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral / Transcripts.
http://hdl.handle.net/10033/622916
The Zinc Finger Antiviral Protein ZAP Restricts Human Cytomegalovirus and Selectively Binds and Destabilizes Viral / Transcripts.
Gonzalez-Perez, Ana Cristina; Stempel, Markus; Wyler, Emanuel; Urban, Christian; Piras, Antonio; Hennig, Thomas; Ganskih, Sabina; Wei, Yuanjie; Heim, Albert; Landthaler, Markus; Pichlmair, Andreas; Dölken, Lars; Munschauer, Mathias; Erhard, Florian; Brinkmann, Melanie M
Interferon-stimulated gene products (ISGs) play a crucial role in early infection control. The ISG zinc finger CCCH-type antiviral protein 1 (ZAP/ZC3HAV1) antagonizes several RNA viruses by binding to CG-rich RNA sequences, whereas its effect on DNA viruses is less well understood. Here, we decipher the role of ZAP in the context of human cytomegalovirus (HCMV) infection, a β-herpesvirus that is associated with high morbidity in immunosuppressed individuals and newborns. We show that expression of the two major isoforms of ZAP, ZAP-S and ZAP-L, is induced during HCMV infection and that both negatively affect HCMV replication. Transcriptome and proteome analyses demonstrated that the expression of ZAP results in reduced viral mRNA and protein levels and decelerates the progression of HCMV infection. Metabolic RNA labeling combined with high-throughput sequencing (SLAM-seq) revealed that most of the gene expression changes late in infection result from the general attenuation of HCMV. Furthermore, at early stages of infection, ZAP restricts HCMV by destabilizing a distinct subset of viral mRNAs, particularly those from the previously uncharacterized UL4-UL6 HCMV gene locus. Through enhanced cross-linking immunoprecipitation and sequencing analysis (eCLIP-seq), we identified the transcripts expressed from this HCMV locus as the direct targets of ZAP. Moreover, our data show that ZAP preferentially recognizes not only CG, but also other cytosine-rich sequences, thereby expanding its target specificity. In summary, this report is the first to reveal direct targets of ZAP during HCMV infection, which strongly indicates that transcripts from the UL4-UL6 locus may play an important role for HCMV replication.IMPORTANCE Viral infections have a large impact on society, leading to major human and economic losses and even global instability. So far, many viral infections, including human cytomegalovirus (HCMV) infection, are treated with a small repertoire of drugs, often accompanied by the occurrence of resistant mutants. There is no licensed HCMV vaccine in sight to protect those most at risk, particularly immunocompromised individuals or pregnant women who might otherwise transmit the virus to the fetus. Thus, the identification of novel intervention strategies is urgently required. In this study, we show that ZAP decelerates the viral gene expression cascade, presumably by selectively handpicking a distinct set of viral transcripts for degradation. Our study illustrates the potent role of ZAP as an HCMV restriction factor and sheds light on a possible role for UL4 and/or UL5 early during infection, paving a new avenue for the exploration of potential targets for novel therapies.
2021-05-04T00:00:00ZCalling for pan-European commitment for rapid and sustained reduction in SARS-CoV-2 infections.
http://hdl.handle.net/10033/622689
Calling for pan-European commitment for rapid and sustained reduction in SARS-CoV-2 infections.
Priesemann, Viola; Brinkmann, Melanie M; Ciesek, Sandra; Cuschieri, Sarah; Czypionka, Thomas; Giordano, Giulia; Gurdasani, Deepti; Hanson, Claudia; Hens, Niel; Iftekhar, Emil; Kelly-Irving, Michelle; Klimek, Peter; Kretzschmar, Mirjam; Peichl, Andreas; Perc, Matjaž; Sannino, Francesco; Schernhammer, Eva; Schmidt, Alexander; Staines, Anthony; Szczurek, Ewa
[No abstract available]
2020-12-18T00:00:00Z