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M. J. Reddehase
Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany

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Review
Published: 03 August 2021 in Viruses
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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.

ACS Style

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 Style

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 (8):1530.

Chicago/Turabian Style

Matthias 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.

Journal article
Published: 29 July 2021 in Pathogens
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CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

ACS Style

Kirsten Freitag; Sara Hamdan; Matthias Reddehase; Rafaela Holtappels. Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells. Pathogens 2021, 10, 956 .

AMA Style

Kirsten Freitag, Sara Hamdan, Matthias Reddehase, Rafaela Holtappels. Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells. Pathogens. 2021; 10 (8):956.

Chicago/Turabian Style

Kirsten Freitag; Sara Hamdan; Matthias Reddehase; Rafaela Holtappels. 2021. "Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells." Pathogens 10, no. 8: 956.

Brief report
Published: 10 June 2021 in Pathogens
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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+CD127CD62L. 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.

ACS Style

Niels Lemmermann; Matthias Reddehase. Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection. Pathogens 2021, 10, 731 .

AMA Style

Niels Lemmermann, Matthias Reddehase. Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection. Pathogens. 2021; 10 (6):731.

Chicago/Turabian Style

Niels Lemmermann; Matthias Reddehase. 2021. "Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection." Pathogens 10, no. 6: 731.

Journal article
Published: 22 July 2020 in Vaccines
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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.

ACS Style

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 Style

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 (3):402.

Chicago/Turabian Style

Rafaela 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.

Brief research report article
Published: 21 April 2020 in Frontiers in Cellular and Infection Microbiology
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Angelique 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.

Original research article
Published: 15 April 2020 in Frontiers in Cellular and Infection Microbiology
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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.

ACS Style

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 Style

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.

Chicago/Turabian Style

Rafaela 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.

Editorial
Published: 25 May 2019 in Medical Microbiology and Immunology
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ACS Style

Matthias J. Reddehase. ‘Checks and balances’ in cytomegalovirus-host cohabitation. Medical Microbiology and Immunology 2019, 208, 259 -261.

AMA Style

Matthias J. Reddehase. ‘Checks and balances’ in cytomegalovirus-host cohabitation. Medical Microbiology and Immunology. 2019; 208 (3-4):259-261.

Chicago/Turabian Style

Matthias J. Reddehase. 2019. "‘Checks and balances’ in cytomegalovirus-host cohabitation." Medical Microbiology and Immunology 208, no. 3-4: 259-261.

Review
Published: 10 May 2019 in Medical Microbiology and Immunology
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Cytomegalovirus (CMV) infection has a profound impact on the host’s immune system. Immunological imprinting by CMV is not restricted to immunity against CMV itself, but can affect immunity against other viral or non-viral infectious agents and also immunopathological responses. One category is heterologous immunity based on molecular mimicry, where antigen recognition receptors specific for a CMV antigen with broad avidity distribution also bind with some avidity to unrelated antigens and exert effector functions against target structures other than those linked to CMV. Another category is induction of cytokines by CMV infection that inhibit or drive immune responses to bystander antigens unrelated to CMV, and a third category is the activation of antigen-presenting cells by CMV from which unrelated antigens profit as “stowaways”. A striking example of the “stowaway” category, actually one that is of medical importance, has been published recently and will be discussed here for the more general reader. Specifically, in a murine model, CMV airway infection and inhaled environmental antigen of poor intrinsic allergenic potential were found to sensitize for allergic airway disease (AAD) only when combined. As to the mechanism, viral activation of CD11b+ conventional dendritic cells (CD11b+ cDC) that localize to airway mucosa facilitates uptake and processing of inhaled antigen. Thus, CMV serves as a “door opener” for otherwise harmless environmental antigens that have no intrinsic property to activate DC. Antigen-laden CD11b+ cDC migrate selectively to the airway draining lymph nodes, where they prime type-2 CD4+ T helper (Th-2) cells. Upon airway re-exposure to the inhaled antigen, Th-2 cells secrete interleukins (IL-4, IL-5, IL-9, and IL-25) known to induce goblet cell metaplasia, the lead histopathological manifestation of AAD that is characterized by thickening of airway epithelia and increased numbers of mucus-producing goblet cells, resulting in enhanced mucus secretion and airflow obstruction.

ACS Style

Matthias J. Reddehase. Adverse immunological imprinting by cytomegalovirus sensitizing for allergic airway disease. Medical Microbiology and Immunology 2019, 208, 469 -473.

AMA Style

Matthias J. Reddehase. Adverse immunological imprinting by cytomegalovirus sensitizing for allergic airway disease. Medical Microbiology and Immunology. 2019; 208 (3):469-473.

Chicago/Turabian Style

Matthias J. Reddehase. 2019. "Adverse immunological imprinting by cytomegalovirus sensitizing for allergic airway disease." Medical Microbiology and Immunology 208, no. 3: 469-473.

Review
Published: 06 May 2019 in Medical Microbiology and Immunology
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The establishment of a lifelong latent infection after resolution of primary infection is a hallmark of cytomegalovirus (CMV) biology. Primary infection with human CMV is possible any time in life, but most frequently, virus transmission occurs already perinatally or in early childhood. Many years or even decades later, severe clinical problems can result from recurrence of infectious virus by reactivation from latency in individuals who undergo immunocompromising medical treatment, for instance, transplant recipients, but also in septic patients without canonical immunosuppression, and in elderly people with a weakened immune system. The diversity of disease manifestations, such as retinitis, pneumonia, hepatitis, gastrointestinal disease, and others, has remained an enigma. In clinical routine, seropositivity for IgG antibodies against human CMV is taken to indicate latent infection and thus to define a qualitative risk of recurrence, but it is insufficient as a predictor for the quantitative risk of recurrence. Early experimental studies in the mouse model, comparing primary infection of neonatal and adult mice, led to the hypothesis that high load of latent viral genomes is a better predictor for the quantitative risk. A prolonged period of virus multiplication in the immunologically immature neonatally infected host increased the risk of virus recurrence by an enhanced copy number of latent virus genomes from which reactivation can initiate. In extension of this hypothesis, one would predict today that a higher incidence of reactivation events will also fuel the expansion of virus-specific T cells observed in the elderly, a phenomenon known as “memory inflation”. Notably, the mouse model also indicated a stochastic nature of reactivation, thus offering an explanation for the diversity and organ selectivity of disease manifestations observed in patients. As the infection history is mostly undefined in humans, such predictions from the mouse model are difficult to verify by clinical investigation, and moreover, such questions were actually rarely addressed. Here, we have surveyed the existing literature for reports that may help to retrospectively relate the individual infection history to the risk of virus recurrence and recrudescent organ disease.

ACS Style

Stuart P. Adler; Matthias J. Reddehase. Pediatric roots of cytomegalovirus recurrence and memory inflation in the elderly. Medical Microbiology and Immunology 2019, 208, 323 -328.

AMA Style

Stuart P. Adler, Matthias J. Reddehase. Pediatric roots of cytomegalovirus recurrence and memory inflation in the elderly. Medical Microbiology and Immunology. 2019; 208 (3-4):323-328.

Chicago/Turabian Style

Stuart P. Adler; Matthias J. Reddehase. 2019. "Pediatric roots of cytomegalovirus recurrence and memory inflation in the elderly." Medical Microbiology and Immunology 208, no. 3-4: 323-328.

Review
Published: 22 April 2019 in Medical Microbiology and Immunology
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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.

ACS Style

Matthias J. Reddehase; Niels A. W. Lemmermann. Cellular reservoirs of latent cytomegaloviruses. Medical Microbiology and Immunology 2019, 208, 391 -403.

AMA Style

Matthias J. Reddehase, Niels A. W. Lemmermann. Cellular reservoirs of latent cytomegaloviruses. Medical Microbiology and Immunology. 2019; 208 (3-4):391-403.

Chicago/Turabian Style

Matthias J. Reddehase; Niels A. W. Lemmermann. 2019. "Cellular reservoirs of latent cytomegaloviruses." Medical Microbiology and Immunology 208, no. 3-4: 391-403.

Original investigation
Published: 19 April 2019 in Medical Microbiology and Immunology
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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.

ACS Style

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 Style

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 (3-4):531-542.

Chicago/Turabian Style

Annette 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.

Review
Published: 28 March 2019 in Medical Microbiology and Immunology
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Cytomegaloviruses (CMVs) are highly prevalent herpesviruses, characterized by strict species specificity and the ability to establish non-productive latent infection from which reactivation can occur. Reactivation of latent human CMV (HCMV) represents one of the most important clinical challenges in transplant recipients secondary to the strong immunosuppression. In addition, HCMV is the major viral cause of congenital infection with severe sequelae including brain damage. The accumulated evidence clearly shows that cellular immunity plays a major role in the control of primary CMV infection as well as establishment and maintenance of latency. However, the efficiency of antiviral antibodies in virus control, particularly in prevention of congenital infection and virus reactivation from latency in immunosuppressed hosts, is much less understood. Because of a strict species specificity of HCMV, the role of antibodies in controlling CMV disease has been addressed using murine CMV (MCMV) as a model. Here, we review and discuss the role played by the antiviral antibody response during CMV infections with emphasis on latency and reactivation not only in the MCMV model, but also in relevant clinical settings. We provide evidence to conclude that antiviral antibodies do not prevent the initiating molecular event of virus reactivation from latency but operate by preventing intra-organ spread and inter-organ dissemination of recurrent virus.

ACS Style

Astrid Krmpotic; Jürgen Podlech; Matthias J. Reddehase; William J. Britt; Stipan Jonjić. Role of antibodies in confining cytomegalovirus after reactivation from latency: three decades’ résumé. Medical Microbiology and Immunology 2019, 208, 415 -429.

AMA Style

Astrid Krmpotic, Jürgen Podlech, Matthias J. Reddehase, William J. Britt, Stipan Jonjić. Role of antibodies in confining cytomegalovirus after reactivation from latency: three decades’ résumé. Medical Microbiology and Immunology. 2019; 208 (3):415-429.

Chicago/Turabian Style

Astrid Krmpotic; Jürgen Podlech; Matthias J. Reddehase; William J. Britt; Stipan Jonjić. 2019. "Role of antibodies in confining cytomegalovirus after reactivation from latency: three decades’ résumé." Medical Microbiology and Immunology 208, no. 3: 415-429.

Research article
Published: 07 March 2019 in PLOS Pathogens
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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.

ACS Style

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 Style

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 (3):e1007595.

Chicago/Turabian Style

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. 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.

Review
Published: 06 December 2018 in Viruses
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Human Cytomegalovirus (hCMV), which is the prototype member of the β-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised period before hematopoietic reconstitution restores antiviral immunity. Clinical investigation of pathomechanisms and of strategies for an immune intervention aimed at restoring antiviral immunity earlier than by hematopoietic reconstitution are limited in patients to observational studies mainly because of ethical issues including the imperative medical indication for chemotherapy with antivirals. Aimed experimental studies into mechanisms, thus, require animal models that match the human disease as close as possible. Any model for hCMV disease is, however, constrained by the strict host-species specificity of CMVs that prevents the study of hCMV in any animal model including non-human primates. During eons of co-speciation, CMVs each have evolved a set of “private genes” in adaptation to their specific mammalian host including genes that have no homolog in the CMV virus species of any other host species. With a focus on the mouse model of CD8 T cell-based immunotherapy of CMV disease after experimental HCT and infection with murine CMV (mCMV), we review data in support of the phenomenon of “biological convergence” in virus-host adaptation. This includes shared fundamental principles of immune control and immune evasion, which allows us to at least make reasoned predictions from the animal model as an experimental “proof of concept.” The aim of a model primarily is to define questions to be addressed by clinical investigation for verification, falsification, or modification and the results can then give feedback to refine the experimental model for research from “bedside to bench”.

ACS Style

Matthias J. Reddehase; Niels A. W. Lemmermann. Mouse Model of Cytomegalovirus Disease and Immunotherapy in the Immunocompromised Host: Predictions for Medical Translation that Survived the “Test of Time”. Viruses 2018, 10, 693 .

AMA Style

Matthias J. Reddehase, Niels A. W. Lemmermann. Mouse Model of Cytomegalovirus Disease and Immunotherapy in the Immunocompromised Host: Predictions for Medical Translation that Survived the “Test of Time”. Viruses. 2018; 10 (12):693.

Chicago/Turabian Style

Matthias J. Reddehase; Niels A. W. Lemmermann. 2018. "Mouse Model of Cytomegalovirus Disease and Immunotherapy in the Immunocompromised Host: Predictions for Medical Translation that Survived the “Test of Time”." Viruses 10, no. 12: 693.

Editorial
Published: 17 October 2018 in Medical Microbiology and Immunology
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Matthias J. Reddehase. From basic molecular biology to curative antiviral therapy: the success story of Hepatitis C virology. Medical Microbiology and Immunology 2018, 208, 1 -2.

AMA Style

Matthias J. Reddehase. From basic molecular biology to curative antiviral therapy: the success story of Hepatitis C virology. Medical Microbiology and Immunology. 2018; 208 (1):1-2.

Chicago/Turabian Style

Matthias J. Reddehase. 2018. "From basic molecular biology to curative antiviral therapy: the success story of Hepatitis C virology." Medical Microbiology and Immunology 208, no. 1: 1-2.

Conference proceedings
Published: 01 June 2017 in GeroScience
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Human cytomegalovirus (CMV) is one of the largest viruses known to cause human diseases. Chronic CMV infection, as defined by anti-CMV IgG serology, increases with age and is highly prevalent in older adults. It has complex biology with significant immunologic and health consequences. This article aims to summarize research findings presented at the 6th International Workshop on CMV and Immunosenescence that relate to advances in the areas of CMV tropism, latency, CMV manipulation of cell metabolism, and T cell memory inflation, as well as novel diagnostic evaluation and translational research of chronic CMV infection in older adults. Information summarized here represents the current state of knowledge in these important fields. Investigators have also identified a number of areas that deserve further and more in-depth investigation, including building more precise parallels between mouse CMV (mCMV) and human CMV (HCMV) research. It is hoped that this article will also stimulate engaging discussion on strategies and direction to advance the science to the next level.

ACS Style

Sean X. Leng; Jeremy Kamil; John Purdy; Niels Lemmermann; Matthias Reddehase; Felicia D. Goodrum. Recent advances in CMV tropism, latency, and diagnosis during aging. GeroScience 2017, 39, 251 -259.

AMA Style

Sean X. Leng, Jeremy Kamil, John Purdy, Niels Lemmermann, Matthias Reddehase, Felicia D. Goodrum. Recent advances in CMV tropism, latency, and diagnosis during aging. GeroScience. 2017; 39 (3):251-259.

Chicago/Turabian Style

Sean X. Leng; Jeremy Kamil; John Purdy; Niels Lemmermann; Matthias Reddehase; Felicia D. Goodrum. 2017. "Recent advances in CMV tropism, latency, and diagnosis during aging." GeroScience 39, no. 3: 251-259.

Research article
Published: 25 May 2017 in PLOS Pathogens
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The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNβ promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNβ transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host. The herpesvirus cytomegalovirus can cause severe morbidity in immunosuppressed people and poses a much greater global problem in the context of congenital infections than the Zika virus. To establish infection, cytomegalovirus needs to modulate the antiviral immune response of its host. One of the first lines of defense against viral infections is the type I interferon response which is activated by cellular sensors called pattern recognition receptors. These receptors sense viral entry and rapidly induce the transcription of type I interferons, which are instrumental for the induction of an antiviral state in infected and surrounding cells. We have identified the first viral protein encoded by murine cytomegalovirus, the M35 protein, that counteracts type I interferon transcription downstream of multiple pattern recognition receptors. We found that this viral countermeasure occurs shortly after viral entry into the host cell, as M35 is delivered with the viral particle. M35 then localizes to the nucleus where it modulates NF-κB-mediated transcription. In vivo, murine cytomegalovirus deficient of the M35 protein replicates to lower levels in spleen and liver and cannot establish a productive infection in the salivary glands, which is a key site of viral transmission, highlighting the important role of M35 for the establishment of infection. Our study provides novel insights into the complex interaction between cytomegalovirus and the innate immune response of its host.

ACS Style

Baca Chan; Vladimir Gonçalves Magalhães; Niels A. W. Lemmermann; Vanda Juranić Lisnić; Markus Stempel; Kendra A. Bussey; Elisa Reimer; Jürgen Podlech; Stefan Lienenklaus; Matthias Reddehase; Stipan Jonjic; Melanie M. Brinkmann. The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. PLOS Pathogens 2017, 13, e1006382 .

AMA Style

Baca Chan, Vladimir Gonçalves Magalhães, Niels A. W. Lemmermann, Vanda Juranić Lisnić, Markus Stempel, Kendra A. Bussey, Elisa Reimer, Jürgen Podlech, Stefan Lienenklaus, Matthias Reddehase, Stipan Jonjic, Melanie M. Brinkmann. The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. PLOS Pathogens. 2017; 13 (5):e1006382.

Chicago/Turabian Style

Baca Chan; Vladimir Gonçalves Magalhães; Niels A. W. Lemmermann; Vanda Juranić Lisnić; Markus Stempel; Kendra A. Bussey; Elisa Reimer; Jürgen Podlech; Stefan Lienenklaus; Matthias Reddehase; Stipan Jonjic; Melanie M. Brinkmann. 2017. "The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription." PLOS Pathogens 13, no. 5: e1006382.

Journal article
Published: 08 May 2017 in Cellular & Molecular Immunology
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Interstitial pneumonia is a life-threatening clinical manifestation of human cytomegalovirus (hCMV) infection. In particular, it can be deadly in patients with hematopoietic malignancies who undergo hematopoietic cell transplantation (HCT) in whom a ‘window of risk’, which is defined by transient immunodeficiency, occurs between hematoablative therapeutic treatment and immunological reconstitution.

ACS Style

Niels Lemmermann; Matthias Reddehase. TLR3-independent activation of mast cells by cytomegalovirus contributes to control of pulmonary infection. Cellular & Molecular Immunology 2017, 14, 479 -481.

AMA Style

Niels Lemmermann, Matthias Reddehase. TLR3-independent activation of mast cells by cytomegalovirus contributes to control of pulmonary infection. Cellular & Molecular Immunology. 2017; 14 (6):479-481.

Chicago/Turabian Style

Niels Lemmermann; Matthias Reddehase. 2017. "TLR3-independent activation of mast cells by cytomegalovirus contributes to control of pulmonary infection." Cellular & Molecular Immunology 14, no. 6: 479-481.

Research article
Published: 27 April 2017 in PLOS Pathogens
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Regulatory T (Treg) cells dampen an exaggerated immune response to viral infections in order to avoid immunopathology. Cytomegaloviruses (CMVs) are herpesviruses usually causing asymptomatic infection in immunocompetent hosts and induce strong cellular immunity which provides protection against CMV disease. It remains unclear how these persistent viruses manage to avoid induction of immunopathology not only during the acute infection but also during life-long persistence and virus reactivation. This may be due to numerous viral immunoevasion strategies used to specifically modulate immune responses but also induction of Treg cells by CMV infection. Here we demonstrate that liver Treg cells are strongly induced in mice infected with murine CMV (MCMV). The depletion of Treg cells results in severe hepatitis and liver damage without alterations in the virus load. Moreover, liver Treg cells show a high expression of ST2, a cellular receptor for tissue alarmin IL-33, which is strongly upregulated in the liver of infected mice. We demonstrated that IL-33 signaling is crucial for Treg cell accumulation after MCMV infection and ST2-deficient mice show a more pronounced liver pathology and higher mortality compared to infected control mice. These results illustrate the importance of IL-33 in the suppressive function of liver Treg cells during CMV infection. Treg cells are crucial for immune homeostasis and for dampening immune response to several diseased conditions, including viral infections. Murine cytomegalovirus (MCMV) is a herpesvirus with pathogenic potential, so that early immune mechanisms are essential in controlling virus and protecting from virus-induced pathology. Studies on Foxp3+ Treg cells have revealed their inhibitory role on the early T cell response to MCMV infection and have suggested Treg cells as a target of MCMV’s immunoevasion mechanisms. Here we demonstrate that the number and activation status of liver Treg cells is strongly induced upon MCMV infection in order to protect the host from severe liver damage. They constitutively express high amounts of IL-33 receptor ST2 and their accumulation depends on IL-33, which is released as a tissue alarmin after the cell damage. For the first time, we show an immunoregulatory role of IL-33-dependent Treg cells in the liver of MCMV infected mice and their suppression of MCMV-induced immunopathology.

ACS Style

Branka Popovic; Mijo Golemac; Jürgen Podlech; Jelena Zeleznjak; Lidija Bilic-Zulle; Miodrag Lukic; Luka Cicin-Sain; Matthias Reddehase; Tim Sparwasser; Astrid Krmpotic; Stipan Jonjic. IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection. PLOS Pathogens 2017, 13, e1006345 .

AMA Style

Branka Popovic, Mijo Golemac, Jürgen Podlech, Jelena Zeleznjak, Lidija Bilic-Zulle, Miodrag Lukic, Luka Cicin-Sain, Matthias Reddehase, Tim Sparwasser, Astrid Krmpotic, Stipan Jonjic. IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection. PLOS Pathogens. 2017; 13 (4):e1006345.

Chicago/Turabian Style

Branka Popovic; Mijo Golemac; Jürgen Podlech; Jelena Zeleznjak; Lidija Bilic-Zulle; Miodrag Lukic; Luka Cicin-Sain; Matthias Reddehase; Tim Sparwasser; Astrid Krmpotic; Stipan Jonjic. 2017. "IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection." PLOS Pathogens 13, no. 4: e1006345.

Research article
Published: 15 December 2016 in PLOS Pathogens
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Cytomegalovirus (CMV) elicits long-term T-cell immunity of unparalleled strength, which has allowed the development of highly protective CMV-based vaccine vectors. Counterintuitively, experimental vaccines encoding a single MHC-I restricted epitope offered better immune protection than those expressing entire proteins, including the same epitope. To clarify this conundrum, we generated recombinant murine CMVs (MCMVs) encoding well-characterized MHC-I epitopes at different positions within viral genes and observed strong immune responses and protection against viruses and tumor growth when the epitopes were expressed at the protein C-terminus. We used the M45-encoded conventional epitope HGIRNASFI to dissect this phenomenon at the molecular level. A recombinant MCMV expressing HGIRNASFI on the C-terminus of M45, in contrast to wild-type MCMV, enabled peptide processing by the constitutive proteasome, direct antigen presentation, and an inflation of antigen-specific effector memory cells. Consequently, our results indicate that constitutive proteasome processing of antigenic epitopes in latently infected cells is required for robust inflationary responses. This insight allows utilizing the epitope positioning in the design of CMV-based vectors as a novel strategy for enhancing their efficacy. Experimental cytomegalovirus (CMV) based vaccine vectors have provided highly encouraging results as innovative vaccine formulations against deadly virus infections, such as Ebola or AIDS. Nevertheless, it has remained incompletely understood why CMV is so efficient at stimulating T-lymphocytes, the immune cells that recognize pathogens within infected cells. We have generated an array of CMV mutants expressing the same antigen in different genes or in different parts of the same gene. This allowed us to identify that the immediate environment of the antigen, rather than properties of the antigen itself, crucially determine the immune protection conferred by CMV-based vaccines, implying that optimal immunity depends on the ability of host cells to degrade CMV proteins into peptides, short units that are recognized by T-cells. Detailed analysis revealed that strong and sustained T-cell immunity occurs only when their antigenic targets are processed by a primitive cellular machinery that is present in all cells of the body, rather than by its newly-evolved counterpart, which is present only in specialized antigen-presenting cells. Most importantly, our results provide a simple strategy to develop improved CMV vaccines by positioning the antigenic peptides at the right spot in CMV proteins.

ACS Style

Iryna Dekhtiarenko; Robert B. Ratts; Renata Blatnik; Lian N. Lee; Sonja Fischer; Lisa Borkner; Jennifer D. Oduro; Thomas F. Marandu; Stephanie Hoppe; Zsolt Ruzsics; Julia K. Sonnemann; Mandana Mansouri; Christine Meyer; Niels A. W. Lemmermann; Rafaela Holtappels; Ramon Arens; Paul Klenerman; Klaus Früh; Matthias Reddehase; Angelika Riemer; Luka Cicin-Sain. Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. PLOS Pathogens 2016, 12, e1006072 .

AMA Style

Iryna Dekhtiarenko, Robert B. Ratts, Renata Blatnik, Lian N. Lee, Sonja Fischer, Lisa Borkner, Jennifer D. Oduro, Thomas F. Marandu, Stephanie Hoppe, Zsolt Ruzsics, Julia K. Sonnemann, Mandana Mansouri, Christine Meyer, Niels A. W. Lemmermann, Rafaela Holtappels, Ramon Arens, Paul Klenerman, Klaus Früh, Matthias Reddehase, Angelika Riemer, Luka Cicin-Sain. Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors. PLOS Pathogens. 2016; 12 (12):e1006072.

Chicago/Turabian Style

Iryna Dekhtiarenko; Robert B. Ratts; Renata Blatnik; Lian N. Lee; Sonja Fischer; Lisa Borkner; Jennifer D. Oduro; Thomas F. Marandu; Stephanie Hoppe; Zsolt Ruzsics; Julia K. Sonnemann; Mandana Mansouri; Christine Meyer; Niels A. W. Lemmermann; Rafaela Holtappels; Ramon Arens; Paul Klenerman; Klaus Früh; Matthias Reddehase; Angelika Riemer; Luka Cicin-Sain. 2016. "Peptide Processing Is Critical for T-Cell Memory Inflation and May Be Optimized to Improve Immune Protection by CMV-Based Vaccine Vectors." PLOS Pathogens 12, no. 12: e1006072.