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Hematopoietic cell (HC) transplantation (HCT) is the last resort to cure hematopoietic malignancies that are refractory to standard therapies. Hematoablative treatment aims at wiping out tumor cells as completely as possible to avoid leukemia/lymphoma relapse. This treatment inevitably co-depletes cells of hematopoietic cell lineages, including differentiated cells that constitute the immune system. HCT reconstitutes hematopoiesis and thus, eventually, also antiviral effector cells. In cases of an unrelated donor, that is, in allogeneic HCT, HLA-matching is performed to minimize the risk of graft-versus-host reaction and disease (GvHR/D), but a mismatch in minor histocompatibility antigens (minor HAg) is unavoidable. The transient immunodeficiency in the period between hematoablative treatment and reconstitution by HCT gives latent cytomegalovirus (CMV) the chance to reactivate from latently infected donor HC or from latently infected organs of the recipient, or from both. Clinical experience shows that HLA and/or minor-HAg mismatches increase the risk of complications from CMV. Recent results challenge the widespread, though never proven, view of a mechanistic link between GvHR/D and CMV. Instead, new evidence suggests that histoincompatibility promotes CMV disease by inducing non-cognate transplantation tolerance that inhibits an efficient reconstitution of high-avidity CD8+ T cells capable of recognizing and resolving cytopathogenic tissue infection.
Matthias Reddehase; Rafaela Holtappels; Niels Lemmermann. Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm. Viruses 2021, 13, 1530 .
AMA StyleMatthias Reddehase, Rafaela Holtappels, Niels Lemmermann. Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm. Viruses. 2021; 13 (8):1530.
Chicago/Turabian StyleMatthias Reddehase; Rafaela Holtappels; Niels Lemmermann. 2021. "Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm." Viruses 13, no. 8: 1530.
Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment of a latent infection, referred to as “latency.” CMV latency is associated with an increase in the number of cells specific for certain viral epitopes over time. The inflationary subset was identified as effector-memory T cells (iTEM) characterized by the cell surface phenotype KLRG1+CD127−CD62L−. As we have shown recently, latent viral genomes are not transcriptionally silent. Rather, viral genes are sporadically desilenced in a stochastic fashion. The current hypothesis proposes MI to be driven by presented viral antigenic peptides encoded by the corresponding, stochastically expressed viral genes. Although this mechanism suggests itself, independent evidence for antigen presentation during viral latency is pending. Here we fill this gap by showing that T cell-receptor transgenic OT-I cells that are specific for peptide SIINFEKL proliferate upon adoptive cell transfer in C57BL/6 recipients latently infected with murine CMV encoding SIINFEKL (mCMV-SIINFEKL), but not in those latently infected with mCMV-SIINFEKA, in which antigenicity is lost by mutation L8A of the C-terminal amino acid residue.
Niels Lemmermann; Matthias Reddehase. Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection. Pathogens 2021, 10, 731 .
AMA StyleNiels Lemmermann, Matthias Reddehase. Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection. Pathogens. 2021; 10 (6):731.
Chicago/Turabian StyleNiels Lemmermann; Matthias Reddehase. 2021. "Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection." Pathogens 10, no. 6: 731.
Cytomegalovirus (CMV) is widespread in humans and has been implicated in glioblastoma (GBM) and other tumors. However, the role of CMV in GBM remains poorly understood and the mechanisms involved are not well-defined. The goal of this study was to identify candidate pathways relevant to GBM that may be modulated by CMV. Analysis of RNAseq data after CMV infection of patient-derived GBM cells showed significant upregulation of GBM-associated transcripts including the MET oncogene, which is known to play a role in a subset of GBM patients. These findings were validated in vitro in both mouse and human GBM cells. Using immunostaining and RT-PCR in vivo, we confirmed c-MET upregulation in a mouse model of CMV-driven GBM progression and in human GBM. siRNA knockdown showed that MET upregulation was dependent on CMV-induced upregulation of NF-κB signaling. Finally, proneural GBM xenografts overexpressing c-MET grew much faster in vivo than controls, suggesting a mechanism by which CMV infection of tumor cells could induce a more aggressive mesenchymal phenotype. These studies implicate the CMV-induced upregulation of c-MET as a potential mechanism involved in the effects of CMV on GBM growth.
Harald Krenzlin; Mykola Zdioruk; Michal O. Nowicki; Tomer Finkelberg; Naureen Keric; Niels Lemmermann; Magdalena Skubal; E. Antonio Chiocca; Charles H. Cook; Sean E. Lawler. Cytomegalovirus infection of glioblastoma cells leads to NF-κB dependent upregulation of the c-MET oncogenic tyrosine kinase. Cancer Letters 2021, 513, 26 -35.
AMA StyleHarald Krenzlin, Mykola Zdioruk, Michal O. Nowicki, Tomer Finkelberg, Naureen Keric, Niels Lemmermann, Magdalena Skubal, E. Antonio Chiocca, Charles H. Cook, Sean E. Lawler. Cytomegalovirus infection of glioblastoma cells leads to NF-κB dependent upregulation of the c-MET oncogenic tyrosine kinase. Cancer Letters. 2021; 513 ():26-35.
Chicago/Turabian StyleHarald Krenzlin; Mykola Zdioruk; Michal O. Nowicki; Tomer Finkelberg; Naureen Keric; Niels Lemmermann; Magdalena Skubal; E. Antonio Chiocca; Charles H. Cook; Sean E. Lawler. 2021. "Cytomegalovirus infection of glioblastoma cells leads to NF-κB dependent upregulation of the c-MET oncogenic tyrosine kinase." Cancer Letters 513, no. : 26-35.
Acute infection with murine cytomegalovirus (mCMV) is controlled by CD8+ T cells and develops into a state of latent infection, referred to as latency, which is defined by lifelong maintenance of viral genomes but absence of infectious virus in latently infected cell types. Latency is associated with an increase in numbers of viral epitope-specific CD8+ T cells over time, a phenomenon known as “memory inflation” (MI). The “inflationary” subset of CD8+ T cells has been phenotyped as KLRG1+CD62L- effector-memory T cells (iTEM). It is agreed upon that proliferation of iTEM requires repeated episodes of antigen presentation, which implies that antigen-encoding viral genes must be transcribed during latency. Evidence for this has been provided previously for the genes encoding the MI-driving antigenic peptides IE1-YPHFMPTNL and m164-AGPPRYSRI of mCMV in the H-2d haplotype. There exist two competing hypotheses for explaining MI-driving viral transcription. The “reactivation hypothesis” proposes frequent events of productive virus reactivation from latency. Reactivation involves a coordinated gene expression cascade from immediate-early (IE) to early (E) and late phase (L) transcripts, eventually leading to assembly and release of infectious virus. In contrast, the “stochastic transcription hypothesis” proposes that viral genes become transiently de-silenced in latent viral genomes in a stochastic fashion, not following the canonical IE-E-L temporal cascade of reactivation. The reactivation hypothesis, however, is incompatible with the finding that productive virus reactivation is exceedingly rare in immunocompetent mice and observed only under conditions of compromised immunity. In addition, the reactivation hypothesis fails to explain why immune evasion genes, which are regularly expressed during reactivation in the same cells in which epitope-encoding genes are expressed, do not prevent antigen presentation and thus MI. Here we show that IE, E, and L genes are transcribed during latency, though stochastically, not following the IE-E-L temporal cascade. Importantly, transcripts that encode MI-driving antigenic peptides rarely coincide with those that encode immune evasion proteins. As immune evasion can operate only in cis, that is, in a cell that simultaneously expresses antigenic peptides, the stochastic transcription hypothesis explains why immune evasion is not operative in latently infected cells and, therefore, does not interfere with MI.
Marion Griessl; Angelique Renzaho; Kirsten Freitag; Christof K. Seckert; Matthias J. Reddehase; Niels A. W. Lemmermann. Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion. Frontiers in Immunology 2021, 12, 1 .
AMA StyleMarion Griessl, Angelique Renzaho, Kirsten Freitag, Christof K. Seckert, Matthias J. Reddehase, Niels A. W. Lemmermann. Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion. Frontiers in Immunology. 2021; 12 ():1.
Chicago/Turabian StyleMarion Griessl; Angelique Renzaho; Kirsten Freitag; Christof K. Seckert; Matthias J. Reddehase; Niels A. W. Lemmermann. 2021. "Stochastic Episodes of Latent Cytomegalovirus Transcription Drive CD8 T-Cell “Memory Inflation” and Avoid Immune Evasion." Frontiers in Immunology 12, no. : 1.
Several rapid antigen tests (RATs) for the detection of SARS-CoV-2 were evaluated recently. However, reliable performance data for laboratory-based, high-throughput antigen tests are lacking. Therefore and in response to a short-term shortage of PCR reagents, we evaluated DiaSorin's LIAISON SARS-CoV-2 antigen test in comparison to RT-qPCR, and concerning the application of screening non-COVID-19 patients on hospital admission. Applying the manufacturer-recommended cut-off of 200 arbitrary units (AU/mL) the specificity of the LIAISON Test was 100%, the overall analytical sensitivity 40.2%. Lowering the cut-off to 100 AU/mL increased the sensitivity to 49.7% and decreased the specificity to 98.3%. Confining the analysis to samples with an RT-qPCR result < 25 Ct resulted in a sensitivity of 91.2%. The quality of the LIAISON test is very similar to that of good RATs described in the literature with the advantage of high throughput and the disadvantage of relatively long analysis time. It passes the WHO quality criteria for rapid antigen tests and is characterized by particularly high specificity. The LIAISON test can therefore be used for the same applications as recommended for RATs by the WHO. Due to limited sensitivity, the LIAISON test should only be used for screening, if PCR-based assays are not available.
Friederike Häuser; Martin F. Sprinzl; Kim J. Dreis; Angelique Renzaho; Simon Youhanen; Wolfgang M. Kremer; Jürgen Podlech; Peter R. Galle; Karl J. Lackner; Heidi Rossmann; Niels A. Lemmermann. Evaluation of a laboratory-based high-throughput SARS-CoV-2 antigen assay for non-COVID-19 patient screening at hospital admission. Medical Microbiology and Immunology 2021, 1 -7.
AMA StyleFriederike Häuser, Martin F. Sprinzl, Kim J. Dreis, Angelique Renzaho, Simon Youhanen, Wolfgang M. Kremer, Jürgen Podlech, Peter R. Galle, Karl J. Lackner, Heidi Rossmann, Niels A. Lemmermann. Evaluation of a laboratory-based high-throughput SARS-CoV-2 antigen assay for non-COVID-19 patient screening at hospital admission. Medical Microbiology and Immunology. 2021; ():1-7.
Chicago/Turabian StyleFriederike Häuser; Martin F. Sprinzl; Kim J. Dreis; Angelique Renzaho; Simon Youhanen; Wolfgang M. Kremer; Jürgen Podlech; Peter R. Galle; Karl J. Lackner; Heidi Rossmann; Niels A. Lemmermann. 2021. "Evaluation of a laboratory-based high-throughput SARS-CoV-2 antigen assay for non-COVID-19 patient screening at hospital admission." Medical Microbiology and Immunology , no. : 1-7.
While establishing a regional SARS-Cov-2 variant surveillance by genome sequencing, we have identified three infected individuals in a clinical setting (two long-term hospitalized patients and a nurse) that shared the spike N501Y mutation within a genotype background distinct from the current viral variants of concern. We suggest that the adaptive N501Y mutation, known to increase SARS-CoV-2 transmissibility, arose by convergent evolution around December in Mainz, Germany. Hospitalized patients with a compromised immune system may be a potential source of novel viral variants, which calls for monitoring viral evolution by genome sequencing in clinical settings.
Na Lemmermann; B Lieb; T Laufs; A Renzaho; S Runkel; W Kohnen; M Linke; S Gerber; S Schweiger; A Michel; S-E Bikar; B Plachter; T Hankeln. SARS-CoV-2 genome surveillance in Mainz, Germany, reveals convergent origin of the N501Y spike mutation in a hospital setting. 2021, 1 .
AMA StyleNa Lemmermann, B Lieb, T Laufs, A Renzaho, S Runkel, W Kohnen, M Linke, S Gerber, S Schweiger, A Michel, S-E Bikar, B Plachter, T Hankeln. SARS-CoV-2 genome surveillance in Mainz, Germany, reveals convergent origin of the N501Y spike mutation in a hospital setting. . 2021; ():1.
Chicago/Turabian StyleNa Lemmermann; B Lieb; T Laufs; A Renzaho; S Runkel; W Kohnen; M Linke; S Gerber; S Schweiger; A Michel; S-E Bikar; B Plachter; T Hankeln. 2021. "SARS-CoV-2 genome surveillance in Mainz, Germany, reveals convergent origin of the N501Y spike mutation in a hospital setting." , no. : 1.
Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Results: COVID-19 patients (n = 65) were investigated, 19 with uncomplicated, 29 with complicated, and 17 with critical course; nine (13.8%) died. Seven patients showed overt DIC according to the ISTH criteria. The fibrinogen levels dropped significantly in these patients, although not below 100 mg/dl. Hallmarks of TMA, such as thrombocytopenia and microangiopathic haemolytic anaemia, were not detected in any of our COVID-19 patients. ADAMTS13 activity was mildly to moderately reduced in 4/22 patients, all having strongly elevated procalcitonin levels. Conclusion: DIC occurred in 7/65 COVID-19 patients but fibrinogen and platelet consumption were compensated in almost all. ADAMTS13 assays excluded TTP and hallmarks of classic TMA were absent in all investigated patients. We hypothesize that the lacking erythrocyte fragmentation and only mild platelet consumption in severe COVID-19 are due to a microangiopathy predominantly localized to the alveolar microcirculation with a low blood pressure gradient.
Tanja Falter; Heidi Rossmann; Philipp Menge; Jan Goetje; Steffen Groenwoldt; Arndt Weinmann; Visvakanth Sivanathan; Andreas Schulz; Niels Lemmermann; Sven Danckwardt; Karl Lackner; Peter Galle; Inge Scharrer; Bernhard Lämmle; Martin Sprinzl. No Evidence for Classic Thrombotic Microangiopathy in COVID-19. Journal of Clinical Medicine 2021, 10, 671 .
AMA StyleTanja Falter, Heidi Rossmann, Philipp Menge, Jan Goetje, Steffen Groenwoldt, Arndt Weinmann, Visvakanth Sivanathan, Andreas Schulz, Niels Lemmermann, Sven Danckwardt, Karl Lackner, Peter Galle, Inge Scharrer, Bernhard Lämmle, Martin Sprinzl. No Evidence for Classic Thrombotic Microangiopathy in COVID-19. Journal of Clinical Medicine. 2021; 10 (4):671.
Chicago/Turabian StyleTanja Falter; Heidi Rossmann; Philipp Menge; Jan Goetje; Steffen Groenwoldt; Arndt Weinmann; Visvakanth Sivanathan; Andreas Schulz; Niels Lemmermann; Sven Danckwardt; Karl Lackner; Peter Galle; Inge Scharrer; Bernhard Lämmle; Martin Sprinzl. 2021. "No Evidence for Classic Thrombotic Microangiopathy in COVID-19." Journal of Clinical Medicine 10, no. 4: 671.
Murine cytomegalovirus (mCMV) codes for MHC class-I trafficking modulators m04/gp34, m06/gp48, and m152/gp40. By interacting with the MHC class-Iα chain, these proteins disconnect peptide-loaded MHC class-I (pMHC-I) complexes from the constitutive vesicular flow to the cell surface. Based on the assumption that all three inhibit antigen presentation, and thus the recognition of infected cells by CD8 T cells, they were referred to as “immunoevasins.” Improved antigen presentation mediated by m04 in the presence of m152 after infection with deletion mutant mCMV-Δm06W, compared to mCMV-Δm04m06 expressing only m152, led us to propose renaming these molecules “viral regulators of antigen presentation” (vRAP) to account for both negative and positive functions. In accordance with a positive function, m04-pMHC-I complexes were found to be displayed on the cell surface, where they are primarily known as ligands for Ly49 family natural killer (NK) cell receptors. Besides the established role of m04 in NK cell silencing or activation, an anti-immunoevasive function by activation of CD8 T cells is conceivable, because the binding site of m04 to MHC class-Iα appears not to mask the peptide binding site for T-cell receptor recognition. However, functional evidence was based on mCMV-Δm06W, a virus of recently doubted authenticity. Here we show that mCMV-Δm06W actually represents a mixture of an authentic m06 deletion mutant and a mutant with an accidental additional deletion of a genome region encompassing also gene m152. Reanalysis of previously published experiments for the authentic mutant in the mixture confirms the previously concluded positive vRAP function of m04.
Sara Becker; Annette Fink; Jürgen Podlech; Irina Giese; Julia K. Schmiedeke; Thomas Bukur; Matthias J. Reddehase; Niels A. Lemmermann. Positive Role of the MHC Class-I Antigen Presentation Regulator m04/gp34 of Murine Cytomegalovirus in Antiviral Protection by CD8 T Cells. Frontiers in Cellular and Infection Microbiology 2020, 10, 1 .
AMA StyleSara Becker, Annette Fink, Jürgen Podlech, Irina Giese, Julia K. Schmiedeke, Thomas Bukur, Matthias J. Reddehase, Niels A. Lemmermann. Positive Role of the MHC Class-I Antigen Presentation Regulator m04/gp34 of Murine Cytomegalovirus in Antiviral Protection by CD8 T Cells. Frontiers in Cellular and Infection Microbiology. 2020; 10 ():1.
Chicago/Turabian StyleSara Becker; Annette Fink; Jürgen Podlech; Irina Giese; Julia K. Schmiedeke; Thomas Bukur; Matthias J. Reddehase; Niels A. Lemmermann. 2020. "Positive Role of the MHC Class-I Antigen Presentation Regulator m04/gp34 of Murine Cytomegalovirus in Antiviral Protection by CD8 T Cells." Frontiers in Cellular and Infection Microbiology 10, no. : 1.
Mast cells (MC) represent “inbetweeners” of the immune system in that they are part of innate immunity by acting as first-line sentinels for environmental antigens but also provide a link to adaptive immunity by secretion of chemokines that recruit CD8 T cells to organ sites of infection. An interrelationship between MC and cytomegalovirus (CMV) has been a blank area in science until recently when the murine model revealed a role for MC in the resolution of pulmonary infection by murine CMV (mCMV). As to the mechanism, MC were identified as a target cell type of mCMV. Infected MC degranulate and synthesize the CC-chemokine ligand-5 (CCL-5), which is released to attract protective virus-specific CD8 T cells to infected host tissue for confining and eventually resolving the productive, cytopathogenic infection. In a step forward in our understanding of how mCMV infection of MC triggers their degranulation, we document here a critical role for the mCMV m38.5 gene product, a mitochondria-localized inhibitor of apoptosis (vMIA). We show an involvement of mCMV vMIA-m38.5 in MC degranulation by two reciprocal approaches: first, by enhanced degranulation after m38.5 gene transfection of bone marrow-derived cell culture-grown MC (BMMC) and, second, by reduced degranulation of MC in peritoneal exudate cell populations infected ex corpore or in corpore with mutant virus mCMV-Δm38.5. These studies thus reveal a so far unknown function of mCMV vMIA-m38.5 and offer a previously unconsidered but biologically relevant cell system for further analyzing functional analogies between vMIAs of different CMV species.
Julia K. Schmiedeke; Ann-Kathrin Hartmann; Teresa Ruckenbrod; Michael Stassen; Matthias J. Reddehase; Niels A. Lemmermann. The Anti-apoptotic Murine Cytomegalovirus Protein vMIA-m38.5 Induces Mast Cell Degranulation. Frontiers in Cellular and Infection Microbiology 2020, 10, 1 .
AMA StyleJulia K. Schmiedeke, Ann-Kathrin Hartmann, Teresa Ruckenbrod, Michael Stassen, Matthias J. Reddehase, Niels A. Lemmermann. The Anti-apoptotic Murine Cytomegalovirus Protein vMIA-m38.5 Induces Mast Cell Degranulation. Frontiers in Cellular and Infection Microbiology. 2020; 10 ():1.
Chicago/Turabian StyleJulia K. Schmiedeke; Ann-Kathrin Hartmann; Teresa Ruckenbrod; Michael Stassen; Matthias J. Reddehase; Niels A. Lemmermann. 2020. "The Anti-apoptotic Murine Cytomegalovirus Protein vMIA-m38.5 Induces Mast Cell Degranulation." Frontiers in Cellular and Infection Microbiology 10, no. : 1.
Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive ‘latent’ infection. This phenomenon, known as ‘memory inflation’ (MI), was found to be based on inflationary KLRG1+CD62L− effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1−CD62L+ central memory T cells (TCM) and conventional KLRG1−CD62L− effector memory T cells (cTEM) were found to expand, associated with ‘avidity maturation’, whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.
Rafaela Holtappels; Kirsten Freitag; Angelique Renzaho; Sara Becker; Niels A.W. Lemmermann; Matthias J. Reddehase. Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors. Vaccines 2020, 8, 402 .
AMA StyleRafaela Holtappels, Kirsten Freitag, Angelique Renzaho, Sara Becker, Niels A.W. Lemmermann, Matthias J. Reddehase. Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors. Vaccines. 2020; 8 (3):402.
Chicago/Turabian StyleRafaela Holtappels; Kirsten Freitag; Angelique Renzaho; Sara Becker; Niels A.W. Lemmermann; Matthias J. Reddehase. 2020. "Revisiting CD8 T-cell ‘Memory Inflation’: New Insights with Implications for Cytomegaloviruses as Vaccine Vectors." Vaccines 8, no. 3: 402.
Hematoablative treatment followed by hematopoietic cell transplantation (HCT) for reconstituting the co-ablated immune system is a therapeutic option to cure aggressive forms of hematopoietic malignancies. In cases of family donors or unrelated donors, immunogenetic mismatches in major histocompatibility complex (MHC) and/or minor histocompatibility (minor-H) loci are unavoidable and bear a risk of graft-vs.-host reaction and disease (GvHR/D). Transient immunodeficiency inherent to the HCT protocol favors a productive reactivation of latent cytomegalovirus (CMV) that can result in multiple-organ CMV disease. In addition, there exists evidence from a mouse model of MHC class-I-mismatched GvH-HCT to propose that mismatches interfere with an efficient reconstitution of antiviral immunity. Here we used a mouse model of MHC-matched HCT with C57BL/6 donors and MHC-congenic BALB.B recipients that only differ in polymorphic autosomal background genes, including minor-H loci coding for minor-H antigens (minor-HAg). Minor-HAg mismatch is found to promote lethal CMV disease in absence of a detectable GvH response to an immunodominant minor-HAg, the H60 locus-encoded antigenic peptide LYL8. Lethality of infection correlates with inefficient reconstitution of viral epitope-specific CD8+ T cells. Notably, lethality is prevented and control of cytopathogenic infection is restored when viral antigen presentation is enhanced by deletion of immune evasion genes from the infecting virus. We hypothesize that any kind of mismatch in GvH-HCT can induce “non-cognate transplantation tolerance” that dampens not only a mismatch-specific GvH response, which is beneficial, but adversely affects also responses to mismatch-unrelated antigens, such as CMV antigens in the specific case, with the consequence of lethal CMV disease.
Emin Gezinir; Jürgen Podlech; Kerstin M. Gergely; Sara Becker; Matthias J. Reddehase; Niels Lemmermann. Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation. Frontiers in Cellular and Infection Microbiology 2020, 10, 279 .
AMA StyleEmin Gezinir, Jürgen Podlech, Kerstin M. Gergely, Sara Becker, Matthias J. Reddehase, Niels Lemmermann. Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation. Frontiers in Cellular and Infection Microbiology. 2020; 10 ():279.
Chicago/Turabian StyleEmin Gezinir; Jürgen Podlech; Kerstin M. Gergely; Sara Becker; Matthias J. Reddehase; Niels Lemmermann. 2020. "Enhancement of Antigen Presentation by Deletion of Viral Immune Evasion Genes Prevents Lethal Cytomegalovirus Disease in Minor Histocompatibility Antigen-Mismatched Hematopoietic Cell Transplantation." Frontiers in Cellular and Infection Microbiology 10, no. : 279.
Reactivation of latent cytomegalovirus (CMV) in recipients of hematopoietic cell transplantation (HCT) not only results in severe organ manifestations, but can also cause “graft failure” resulting in bone marrow (BM) aplasia. This inhibition of hematopoietic stem and progenitor cell engraftment is a manifestation of CMV infection that is long known in clinical hematology as “myelosuppression.” Previous studies in a murine model of sex-chromosome mismatched but otherwise syngeneic HCT and infection with murine CMV have shown that transplanted hematopoietic cells (HC) initially home to the BM stroma of recipients but then fail to further divide and differentiate. Data from this model were in line with the hypothesis that infection of stromal cells, which constitute “hematopoietic niches” where hematopoiesis takes place, causes a local deficiency in essential hematopoietins. Based on this understanding, one must postulate that preventing infection of stromal cells should restore the stroma's capacity to support hematopoiesis. Adoptively-transferred antiviral CD8+ T cells prevent lethal CMV disease by controlling viral spread and histopathology in vital organs, such as liver and lungs. It remained to be tested, however, if they can also prevent infection of the BM stroma and thus allow for successful HC engraftment. Here we demonstrate that antiviral CD8+ T cells control stromal infection. By tracking male donor-derived sry+ HC in the BM of infected female sry− recipients, we show the CD8+ T cells allow for successful donor HC engraftment and thereby prevent CMV-associated BM aplasia. These data provide a further argument for cytoimmunotherapy of CMV infection after HCT.
Angelique Renzaho; Jürgen Podlech; Birgit Kühnapfel; Franziska Blaum; Matthias J. Reddehase; Niels A. W. Lemmermann. Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells. Frontiers in Cellular and Infection Microbiology 2020, 10, 138 .
AMA StyleAngelique Renzaho, Jürgen Podlech, Birgit Kühnapfel, Franziska Blaum, Matthias J. Reddehase, Niels A. W. Lemmermann. Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells. Frontiers in Cellular and Infection Microbiology. 2020; 10 ():138.
Chicago/Turabian StyleAngelique Renzaho; Jürgen Podlech; Birgit Kühnapfel; Franziska Blaum; Matthias J. Reddehase; Niels A. W. Lemmermann. 2020. "Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells." Frontiers in Cellular and Infection Microbiology 10, no. : 138.
Reactivation of latent cytomegalovirus (CMV) poses a clinical problem in transiently immunocompromised recipients of hematopoietic cell (HC) transplantation (HCT) by viral histopathology that results in multiple organ manifestations. Compared to autologous HCT and to syngeneic HCT performed with identical twins as HC donor and recipient, lethal outcome of CMV infection is more frequent in allogeneic HCT with MHC/HLA or minor histocompatibility loci mismatch between donor and recipient. It is an open question if a graft-vs.-host (GvH) reaction exacerbates CMV disease, or if CMV exacerbates GvH disease (GvHD), or if interference is mutual. Here we have used a mouse model of experimental HCT and murine CMV (mCMV) infection with an MHC class-I mismatch by gene deletion, so that either HCT donor or recipient lack a single MHC class-I molecule, specifically H-2 Ld. This particular immunogenetic disparity has the additional advantage that it allows to experimentally separate GvH reaction of donor-derived T cells against recipient's tissues from host-vs.-graft (HvG) reaction of residual recipient-derived T cells against the transplanted HC and their progeny. While in HvG-HCT with Ld-plus donors and Ld-minus recipients almost all infected recipients were found to control the infection and survived, almost all infected recipients died of uncontrolled virus replication and consequent multiple-organ viral histopathology in case of GvH-HCT with Ld-minus donors and Ld-plus recipients. Unexpectedly, although anti-Ld-reactive CD8+ T cells were detected, mortality was not found to be associated with GvHD histopathology. By comparing HvG-HCT and GvH-HCT, investigation into the mechanism revealed an inefficient reconstitution of antiviral high-avidity CD8+ T cells, associated with lack of formation of protective nodular inflammatory foci (NIF) in host tissue, selectively in GvH-HCT. Most notably, mice infected with an immune evasion gene deletion mutant of mCMV survived under otherwise identical GvH-HCT conditions. Survival was associated with enhanced antigen presentation and formation of protective NIF by antiviral CD8+ T cells that control the infection and prevent viral histopathology. This is an impressive example of lethal viral disease in HCT recipients based on a failure of the immune control of CMV infection due to viral immune evasion in concert with an MHC class-I mismatch.
Rafaela Holtappels; Sina I. Schader; Oliver Oettel; Jürgen Podlech; Christof K. Seckert; Matthias J. Reddehase; Niels A. W. Lemmermann. Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation. Frontiers in Cellular and Infection Microbiology 2020, 10, 157 .
AMA StyleRafaela Holtappels, Sina I. Schader, Oliver Oettel, Jürgen Podlech, Christof K. Seckert, Matthias J. Reddehase, Niels A. W. Lemmermann. Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation. Frontiers in Cellular and Infection Microbiology. 2020; 10 ():157.
Chicago/Turabian StyleRafaela Holtappels; Sina I. Schader; Oliver Oettel; Jürgen Podlech; Christof K. Seckert; Matthias J. Reddehase; Niels A. W. Lemmermann. 2020. "Insufficient Antigen Presentation Due to Viral Immune Evasion Explains Lethal Cytomegalovirus Organ Disease After Allogeneic Hematopoietic Cell Transplantation." Frontiers in Cellular and Infection Microbiology 10, no. : 157.
The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.
Inga Kavazović; Hongya Han; Giulia Balzaretti; Erik Slinger; Niels A. W. Lemmermann; Anja Ten Brinke; Doron Merkler; Jan Koster; Yenan T. Bryceson; Niek De Vries; Stipan Jonjić; Paul L. Klarenbeek; Bojan Polić; Eric Eldering; Felix M. Wensveen. Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity. PLoS Biology 2020, 18, e3000648 .
AMA StyleInga Kavazović, Hongya Han, Giulia Balzaretti, Erik Slinger, Niels A. W. Lemmermann, Anja Ten Brinke, Doron Merkler, Jan Koster, Yenan T. Bryceson, Niek De Vries, Stipan Jonjić, Paul L. Klarenbeek, Bojan Polić, Eric Eldering, Felix M. Wensveen. Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity. PLoS Biology. 2020; 18 (3):e3000648.
Chicago/Turabian StyleInga Kavazović; Hongya Han; Giulia Balzaretti; Erik Slinger; Niels A. W. Lemmermann; Anja Ten Brinke; Doron Merkler; Jan Koster; Yenan T. Bryceson; Niek De Vries; Stipan Jonjić; Paul L. Klarenbeek; Bojan Polić; Eric Eldering; Felix M. Wensveen. 2020. "Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity." PLoS Biology 18, no. 3: e3000648.
Cytomegalovirus (CMV) is one of the largest and most ubiquitous latent persistent viruses. Most humans are infected with CMV early in life, and all immunocompetent humans spend several decades living with CMV. In the vast majority of the hosts, CMV does not cause manifest disease, and CMV therefore can be considered part of normal aging for 50–90% of the human population worldwide. Experimental, clinical, and epidemiological studies suggest that CMV carriage can have nuanced outcomes, including both potentially harmful and potentially beneficial impacts on the host. We here present a summary of the 7th International Workshop on CMV and Immunosenescence, covering various aspects of the interplay between CMV and its mammalian hosts in the context of virus spread, immune evasion, antiviral immunity, as well as the impact on health span and aging.
Janko Nikolich-Žugich; Luka Čicin-Šain; Donna Collins-McMillen; Sarah Elizabeth Jackson; Annette Oxenius; John Sinclair; Christopher Snyder; Mark Wills; Niels Lemmermann. Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging. GeroScience 2020, 42, 495 -504.
AMA StyleJanko Nikolich-Žugich, Luka Čicin-Šain, Donna Collins-McMillen, Sarah Elizabeth Jackson, Annette Oxenius, John Sinclair, Christopher Snyder, Mark Wills, Niels Lemmermann. Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging. GeroScience. 2020; 42 (2):495-504.
Chicago/Turabian StyleJanko Nikolich-Žugich; Luka Čicin-Šain; Donna Collins-McMillen; Sarah Elizabeth Jackson; Annette Oxenius; John Sinclair; Christopher Snyder; Mark Wills; Niels Lemmermann. 2020. "Advances in cytomegalovirus (CMV) biology and its relationship to health, diseases, and aging." GeroScience 42, no. 2: 495-504.
Cytomegaloviruses (CMVs), members of the β-subfamily of the herpesvirus family, have co-speciated with their respective mammalian hosts resulting in a mutual virus–host adaptation reflected by sets of ‘private’ viral genes that a particular CMV species does not share with other CMVs and that define the host-species specificity of CMVs. Nonetheless, based on “biological convergence” in evolution, fundamental rules in viral pathogenesis and immune control are functionally analogous between different virus–host pairs. Therefore, the mouse model of infection with murine CMV (mCMV) has revealed generally valid principles of CMV–host interactions. Specifically, the mouse model has paved the way to cellular immunotherapy of CMV disease in immunocompromised recipients of hematopoietic cell transplantation (HCT). Precisely in the context of HCT, however, current view assumes that there exists a major difference between hCMV and mCMV regarding “latent virus reservoirs” in that only hCMV establishes latency in hematopoietic lineage cells (HLCs), whereas mCMV establishes latency in endothelial cells. This would imply that only hCMV can reactivate from transplanted HLCs of a latently infected donor. In addition, as viral transcriptional activity during latency is discussed as a driver of clonal T-cell expansion over lifetime, a phenomenon known as “memory inflation”, it is important to know if hCMV and mCMV establish latency in the same cell type(s) for imprinting the immune system. Here, we review the currently available evidence to propose that the alleged difference in latent virus reservoirs between hCMV and mCMV may rather relate to a difference in the focus of research. While studies on hCMV latency in HLCs likely described a non-canonical, transient type-2 latency, studies in the mouse model focussed on canonical, lifelong type-1 latency.
Matthias J. Reddehase; Niels A. W. Lemmermann. Cellular reservoirs of latent cytomegaloviruses. Medical Microbiology and Immunology 2019, 208, 391 -403.
AMA StyleMatthias J. Reddehase, Niels A. W. Lemmermann. Cellular reservoirs of latent cytomegaloviruses. Medical Microbiology and Immunology. 2019; 208 (3-4):391-403.
Chicago/Turabian StyleMatthias J. Reddehase; Niels A. W. Lemmermann. 2019. "Cellular reservoirs of latent cytomegaloviruses." Medical Microbiology and Immunology 208, no. 3-4: 391-403.
As an immune evasion mechanism, cytomegaloviruses (CMVs) have evolved proteins that interfere with cell surface trafficking of MHC class-I (MHC-I) molecules to tone down recognition by antiviral CD8 T cells. This interference can affect the trafficking of recently peptide-loaded MHC-I from the endoplasmic reticulum to the cell surface, thus modulating the presentation of viral peptides, as well as the recycling of pre-existing cell surface MHC-I, resulting in reduction of the level of overall MHC-I cell surface expression. Murine cytomegalovirus (mCMV) was paradigmatic in that it led to the discovery of this immune evasion strategy of CMVs. Members of its m02-m16 gene family code for type-I transmembrane glycoproteins, proven or predicted, most of which carry cargo sorting motifs in their cytoplasmic, C-terminal tail. For the m06 gene product m06 (gp48), the cargo has been identified as being MHC-I, which is linked by m06 to cellular adapter proteins AP-1A and AP-3A through the dileucine motif EPLARLL. Both APs are involved in trans-Golgi network (TGN) cargo sorting and, based on transfection studies, their engagement by the dileucine motif was proposed to be absolutely required to prevent MHC-I exposure at the cell surface. Here, we have tested this prediction in an infection system with the herein newly described recombinant virus mCMV-m06AA, in which the dileucine motif is destroyed by replacing EPLARLL with EPLARAA. This mutation has a phenotype in that the transition of m06-MHC-I complexes from early endosomes (EE) to late endosomes (LE)/lysosomes for degradation is blocked. Consistent with the binding of the MHC-I α-chain to the luminal domain of m06, the m06-mediated disposal of MHC-I did not require the β2m chain of mature MHC-I. Unexpectedly, however, disconnecting MHC-I cargo from AP-1A/3A by the motif mutation in m06 had no notable rescuing impact on overall cell surface MHC-I, though it resulted in some improvement of the presentation of viral antigenic peptides by recently peptide-loaded MHC-I. Thus, the current view on the mechanism by which m06 mediates immune evasion needs to be revised. While the cargo sorting motif is critically involved in the disposal of m06-bound MHC-I in the endosomal/lysosomal pathway at the stage of EE to LE transition, this motif-mediated disposal is not the critical step by which m06 causes immune evasion. We rather propose that engagement of AP-1A/3A by the cargo sorting motif in m06 routes the m06-MHC-I complexes into the endosomal pathway and thereby detracts them from the constitutive cell surface transport.
Annette Fink; Snježana Mikuličić; Franziska Blaum; Matthias J. Reddehase; Luise Florin; Niels A. W. Lemmermann. Function of the cargo sorting dileucine motif in a cytomegalovirus immune evasion protein. Medical Microbiology and Immunology 2019, 208, 531 -542.
AMA StyleAnnette Fink, Snježana Mikuličić, Franziska Blaum, Matthias J. Reddehase, Luise Florin, Niels A. W. Lemmermann. Function of the cargo sorting dileucine motif in a cytomegalovirus immune evasion protein. Medical Microbiology and Immunology. 2019; 208 (3-4):531-542.
Chicago/Turabian StyleAnnette Fink; Snježana Mikuličić; Franziska Blaum; Matthias J. Reddehase; Luise Florin; Niels A. W. Lemmermann. 2019. "Function of the cargo sorting dileucine motif in a cytomegalovirus immune evasion protein." Medical Microbiology and Immunology 208, no. 3-4: 531-542.
Roizman’s definition of herpesviral latency, which applies also to cytomegaloviruses (CMVs), demands maintenance of reactivation-competent viral genomes after clearance of productive infection. It is more recent understanding that failure to complete the productive viral cycle for virus assembly and release does not imply viral gene silencing at all genetic loci and all the time. It rather appears that CMV latency is transcriptionally “noisy” in that silenced viral genes get desilenced from time to time in a stochastic manner, leading to “transcripts expressed in latency” (TELs). If a TEL happens to code for a protein that contains a CD8 T cell epitope, protein processing can lead to the presentation of the antigenic peptide and restimulation of cognate CD8 T cells during latency. This mechanism is discussed as a potential driver of epitope-selective accumulation of CD8 T cells over time, a phenomenon linked to CMV latency and known as “memory inflation” (MI). So far, expression of an epitope-encoding TEL was shown only for the major immediate-early (MIE) gene m123/ie1 of murine cytomegalovirus (mCMV), which codes for the prototypic MI-driving antigenic peptide YPHFMPTNL that is presented by the MHC class-I molecule Ld. The only known second MI-driving antigenic peptide of mCMV in the murine MHC haplotype H-2d is AGPPRYSRI presented by the MHC-I molecule Dd. This peptide is very special in that it is encoded by the early (E) phase gene m164 and by an overlapping immediate-early (IE) transcript governed by a promoter upstream of m164. If MI is driven by presentation of TEL-derived antigenic peptides, as the hypothesis says, one should find corresponding TELs. We show here that E-phase and IE-phase transcripts that code for the MI-driving antigenic peptide AGPPRYSRI are independently and stochastically expressed in latently infected lungs.
Angelique Renzaho; Julia K. Schmiedeke; Marion Griessl; Birgit Kühnapfel; Christof K. Seckert; Niels A. W. Lemmermann. Transcripts expressed in cytomegalovirus latency coding for an antigenic IE/E phase peptide that drives “memory inflation”. Medical Microbiology and Immunology 2019, 208, 439 -446.
AMA StyleAngelique Renzaho, Julia K. Schmiedeke, Marion Griessl, Birgit Kühnapfel, Christof K. Seckert, Niels A. W. Lemmermann. Transcripts expressed in cytomegalovirus latency coding for an antigenic IE/E phase peptide that drives “memory inflation”. Medical Microbiology and Immunology. 2019; 208 (3-4):439-446.
Chicago/Turabian StyleAngelique Renzaho; Julia K. Schmiedeke; Marion Griessl; Birgit Kühnapfel; Christof K. Seckert; Niels A. W. Lemmermann. 2019. "Transcripts expressed in cytomegalovirus latency coding for an antigenic IE/E phase peptide that drives “memory inflation”." Medical Microbiology and Immunology 208, no. 3-4: 439-446.
Despite a broad cell-type tropism, cytomegalovirus (CMV) is an evidentially pulmonary pathogen. Predilection for the lungs is of medical relevance in immunocompromised recipients of hematopoietic cell transplantation, in whom interstitial CMV pneumonia is a frequent and, if left untreated, fatal clinical manifestation of human CMV infection. A conceivable contribution of CMV to airway diseases of other etiology is an issue that so far attracted little medical attention. As the route of primary CMV infection upon host-to-host transmission in early childhood involves airway mucosa, coincidence of CMV airway infection and exposure to airborne environmental antigens is almost unavoidable. For investigating possible consequences of such a coincidence, we established a mouse model of airway co-exposure to CMV and ovalbumin (OVA) representing a protein antigen of an inherently low allergenic potential. Accordingly, intratracheal OVA exposure alone failed to sensitize for allergic airway disease (AAD) upon OVA aerosol challenge. In contrast, airway infection at the time of OVA sensitization predisposed for AAD that was characterized by airway inflammation, IgE secretion, thickening of airway epithelia, and goblet cell hyperplasia. This AAD histopathology was associated with a T helper type 2 (Th2) transcription profile in the lungs, including IL-4, IL-5, IL-9, and IL-25, known inducers of Th2-driven AAD. These symptoms were all prevented by a pre-challenge depletion of CD4+ T cells, but not of CD8+ T cells. As to the underlying mechanism, murine CMV activated migratory CD11b+ as well as CD103+ conventional dendritic cells (cDCs), which have been associated with Th2 cytokine-driven AAD and with antigen cross-presentation, respectively. This resulted in an enhanced OVA uptake and recruitment of the OVA-laden cDCs selectively to the draining tracheal lymph nodes for antigen presentation. We thus propose that CMV, through activation of migratory cDCs in the airway mucosa, can enhance the allergenic potential of otherwise poorly allergenic environmental protein antigens. From an epidemiological perspective, natural host-to-host transmission of human CMV mostly occurs in early childhood through saliva from virus-shedding intimate contact persons, such as family members or peers. The oronasal route of transmission involves also the airway mucosa and airway-draining lymph nodes. Almost unavoidably, CMV airway infection coincides with airway exposure to environmental antigens, which include potent classical allergens but also protein antigens that have low-to-no allergenic potential on their own. Ovalbumin (OVA), when administered as a purified protein, can serve as a well-studied model antigen for only poorly allergenic environmental antigens. In a murine model of airway exposure to OVA for allergenic sensitization, we have addressed the question if a simultaneous airway infection with murine CMV (mCMV) can promote allergic airway disease (AAD) elicited by challenge exposure to OVA. As anticipated by the model design, exposure to OVA alone did not sensitize for an allergic response to challenge exposure, nor did mCMV infection alone. Notably, based on viral activation of antigen uptake by DCs, both combined sensitized for a type 2 CD4+ T helper (Th2) cell-driven AAD histopathology. This is a novel aspect in CMV pathobiology with the medical relevance that CMV airway infection enlarges the spectrum of environmental allergens.
Sebastian Reuter; Niels A. W. Lemmermann; Joachim Maxeiner; Jürgen Podlech; Hendrik Beckert; Kirsten Freitag; Daniel Teschner; Frederic Ries; Christian Taube; Roland Buhl; Matthias J. Reddehase; Rafaela Holtappels. Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells. PLOS Pathogens 2019, 15, e1007595 .
AMA StyleSebastian Reuter, Niels A. W. Lemmermann, Joachim Maxeiner, Jürgen Podlech, Hendrik Beckert, Kirsten Freitag, Daniel Teschner, Frederic Ries, Christian Taube, Roland Buhl, Matthias J. Reddehase, Rafaela Holtappels. Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells. PLOS Pathogens. 2019; 15 (3):e1007595.
Chicago/Turabian StyleSebastian Reuter; Niels A. W. Lemmermann; Joachim Maxeiner; Jürgen Podlech; Hendrik Beckert; Kirsten Freitag; Daniel Teschner; Frederic Ries; Christian Taube; Roland Buhl; Matthias J. Reddehase; Rafaela Holtappels. 2019. "Coincident airway exposure to low-potency allergen and cytomegalovirus sensitizes for allergic airway disease by viral activation of migratory dendritic cells." PLOS Pathogens 15, no. 3: e1007595.
Cytomegaloviruses (CMVs) are master manipulators of the host immune response. Here, we reveal that the murine CMV (MCMV) protein m152 specifically targets the type I interferon (IFN) response by binding to stimulator of interferon genes (STING), thereby delaying its trafficking to the Golgi compartment from where STING initiates type I IFN signaling. Infection with an MCMV lacking m152 induced elevated type I IFN responses and this leads to reduced viral transcript levels both in vitro and in vivo. This effect is ameliorated in the absence of STING. Interestingly, while m152 inhibits STING‐mediated IRF signaling, it did not affect STING‐mediated NF‐κB signaling. Analysis of how m152 targets STING translocation reveals that STING activates NF‐κB signaling already from the ER prior to its trafficking to the Golgi. Strikingly, this response is important to promote early MCMV replication. Our results show that MCMV has evolved a mechanism to specifically antagonize the STING‐mediated antiviral IFN response, while preserving its pro‐viral NF‐κB response, providing an advantage in the establishment of an infection.
Markus Stempel; Baca Chan; Vanda Juranić Lisnić; Astrid Krmpotic; Josephine Hartung; Søren R Paludan; Nadia Füllbrunn; Niels Aw Lemmermann; Melanie M Brinkmann. The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection. The EMBO Journal 2019, 38, 1 .
AMA StyleMarkus Stempel, Baca Chan, Vanda Juranić Lisnić, Astrid Krmpotic, Josephine Hartung, Søren R Paludan, Nadia Füllbrunn, Niels Aw Lemmermann, Melanie M Brinkmann. The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection. The EMBO Journal. 2019; 38 (5):1.
Chicago/Turabian StyleMarkus Stempel; Baca Chan; Vanda Juranić Lisnić; Astrid Krmpotic; Josephine Hartung; Søren R Paludan; Nadia Füllbrunn; Niels Aw Lemmermann; Melanie M Brinkmann. 2019. "The herpesviral antagonist m152 reveals differential activation of STING ‐dependent IRF and NF ‐κB signaling and STING 's dual role during MCMV infection." The EMBO Journal 38, no. 5: 1.