• Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.

      Bonifacius, Agnes; Goldmann, Oliver; Floess, Stefan; Holtfreter, Silva; Robert, Philippe A; Nordengrün, Maria; Kruse, Friederike; Lochner, Matthias; Falk, Christine S; Schmitz, Ingo; et al. (Frontiers, 2020-08-07)
      Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
    • Assortative mating by population of origin in a mechanistic model of admixture

      Goldberg, Amy; Rastogi, Ananya; Rosenberg, Noah A.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (Elsevier BV, 2020-04-07)
      Populations whose mating pairs have levels of similarity in phenotypes or genotypes that differ systematically from the level expected under random mating are described as experiencing assortative mating. Excess similarity in mating pairs is termed positive assortative mating, and excess dissimilarity is negative assortative mating. In humans, empirical studies suggest that mating pairs from various admixed populations-whose ancestry derives from two or more source populations-possess correlated ancestry components that indicate the occurrence of positive assortative mating on the basis of ancestry. Generalizing a two-sex mechanistic admixture model, we devise a model of one form of ancestry-assortative mating that occurs through preferential mating based on source population. Under the model, we study the moments of the admixture fraction distribution for different assumptions about mating preferences, including both positive and negative assortative mating by population. We demonstrate that whereas the mean admixture under assortative mating is equivalent to that of a corresponding randomly mating population, the variance of admixture depends on the level and direction of assortative mating. We consider two special cases of assortative mating by population: first, a single admixture event, and second, constant contributions to the admixed population over time In contrast to standard settings in which positive assortment increases variation within a population, certain assortative mating scenarios allow the variance of admixture to decrease relative to a corresponding randomly mating population: with the three populations we consider, the variance-increasing effect of positive assortative mating within a population might be overwhelmed by a variance-decreasing effect emerging from mating preferences involving other pairs of populations. The effect of assortative mating is smaller on the X chromosome than on the autosomes because inheritance of the X in males depends only on the mother's ancestry, not on the mating pair. Because the variance of admixture is informative about the timing of admixture and possibly about sex-biased admixture contributions, the effects of assortative mating are important to consider in inferring features of population history from distributions of admixture values. Our model provides a framework to quantitatively study assortative mating under flexible scenarios of admixture over time.
    • On the Immunological Consequences of Conventionally Fractionated Radiotherapy.

      Alfonso, Juan Carlos L; Papaxenopoulou, Lito A; Mascheroni, Pietro; Meyer-Hermann, Michael; Hatzikirou, Haralampos; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier/Cell Press, 2020-02-11)
      Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests that radiotherapy success depends on the functional tumor vascularity extent and reveals that the pre-treatment tumor size is not a consistent determinant of treatment outcomes. The one-size-fits-all approach of conventionally fractionated radiotherapy is predicted to result in some overtreated patients. In addition, model simulations also suggest that an arbitrary increase in treatment duration does not necessarily result in better tumor control. This study highlights the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential of radiotherapy.
    • Graph-based description of tertiary lymphoid organs at single-cell level.

      Schaadt, Nadine S; Schönmeyer, Ralf; Forestier, Germain; Brieu, Nicolas; Braubach, Peter; Nekolla, Katharina; Meyer-Hermann, Michael; Feuerhake, Friedrich; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (PLOS, 2020-02-01)
      Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions.
    • Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.

      Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier, 2019-10-29)
      Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
    • Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy

      Enderling, Heiko; Alfonso, Juan Carlos López; Moros, Eduardo; Caudell, Jimmy J.; Harrison, Louis B.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier(Cell Press), 2019-08-01)
      In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).
    • Regulatory roles of IL-10-producing human follicular T cells.

      Cañete, Pablo F; Sweet, Rebecca A; Gonzalez-Figueroa, Paula; Papa, Ilenia; Ohkura, Naganari; Bolton, Holly; Roco, Jonathan A; Cuenca, Marta; Bassett, Katharine J; Sayin, Ismail; et al. (Rockefeller University Press, 2019-06-17)
      Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell-derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell-derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10-producing TF cells but not with total T reg cells, TFR, or IL-10-producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.
    • Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy.

      Alfonso, J C L; Berk, L; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (BioMed Central (BMC), 2019-05-30)
      Standard radiobiology theory of radiation response assumes a uniform innate radiosensitivity of tumors. However, experimental data show that there is significant intratumoral heterogeneity of radiosensitivity. Therefore, a model with heterogeneity was developed and tested using existing experimental data to show the potential effects from the presence of an intratumoral distribution of radiosensitivity on radiation therapy response over a protracted radiation therapy treatment course.
    • On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas.

      Mascheroni, Pietro; López Alfonso, Juan Carlos; Kalli, Maria; Stylianopoulos, Triantafyllos; Meyer-Hermann, Michael; Hatzikirou, Haralampos; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (MPDI, 2019-05-24)
      Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes. View Full-Text
    • Postprandial Metabolic Effects of Fiber Mixes Revealed by in vivo Stable Isotope Labeling in Humans.

      Schlicker, Lisa; Boers, Hanny M; Dudek, Christian-Alexander; Zhao, Gang; Barua, Arnab; Trezzi, Jean-Pierre; Meyer-Hermann, Michael; Jacobs, Doris M; Hiller, Karsten; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MPDI, 2019-05-07)
      Food supplementation with a fiber mix of guar gum and chickpea flour represents a promising approach to reduce the risk of type 2 diabetes mellitus (T2DM) by attenuating postprandial glycemia. To investigate the effects on postprandial metabolic fluxes of glucose-derived metabolites in response to this fiber mix, a randomized, cross-over study was designed. Twelve healthy, male subjects consumed three different flatbreads either supplemented with 2% guar gum or 4% guar gum and 15% chickpea flour or without supplementation (control). The flatbreads were enriched with ~2% of 13C-labeled wheat flour. Blood was collected at 16 intervals over a period of 360 min after bread intake and plasma samples were analyzed by GC-MS based metabolite profiling combined with stable isotope-assisted metabolomics. Although metabolite levels of the downstream metabolites of glucose, specifically lactate and alanine, were not altered in response to the fiber mix, supplementation of 4% guar gum was shown to significantly delay and reduce the exogenous formation of these metabolites. Metabolic modeling and computation of appearance rates revealed that the effects induced by the fiber mix were strongest for glucose and attenuated downstream of glucose. Further investigations to explore the potential of fiber mix supplementation to counteract the development of metabolic diseases are warranted.
    • Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery.

      López Alfonso, Juan Carlos; Poleszczuk, Jan; Walker, Rachel; Kim, Sungjune; Pilon-Thomas, Shari; Conejo-Garcia, Jose J; Soliman, Hatem; Czerniecki, Brian; Harrison, Louis B; Enderling, Heiko; et al. (American Society of Clinical Oncology, 2019-01-01)
      PURPOSE Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and diseasefree survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced antitumor immunity contributing to outcomes. MATERIALS AND METHODS We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus, esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR, RS, and radiotherapy alone in a mathematical model of tumor-immune interactions. RESULTS RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046) and improved DFS for cancers with higher survival (breast: HR = 0.64; P , .001). For rectal cancer, with intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04). Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter combinations. This could create an immune memory that may explain increased DFS after RS for certain cancers. CONCLUSION Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune activation of RS versus SR in controlled clinical studies
    • Synchronous Germinal Center Onset Impacts the Efficiency of Antibody Responses.

      Arulraj, Theinmozhi; Binder, Sebastian C; Robert, Philippe A; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Frontiers, 2019-01-01)
      The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback mechanism termed antibody feedback. By imposing antibody feedback, germinal centers can interact and regulate the output of other germinal centers. Using an agent-based model of the germinal center reaction, we studied the impact of antibody feedback on kinetics and efficiency of a germinal center. Our simulations predict that high feedback of antibodies from germinal centers reduces the production of plasma cells and subsequently the efficiency of the germinal center reaction by promoting earlier termination. Affinity maturation is only weakly improved by increased antibody feedback and ultimately interrupted because of premature termination of the reaction. The model predicts that the asynchronous onset and changes in number of germinal centers could alter the efficiency of antibody response due to changes in feedback by soluble antibodies. Consequently, late initialized germinal centers have a compromised output due to higher antibody feedback from the germinal centers formed earlier. The results demonstrate potential effects of germinal center intercommunication and highlight the importance of understanding germinal center interactions for optimizing the antibody response, in particular, in the elderly and in the context of vaccination.
    • Estimation of the cancer risk induced by therapies targeting stem cell replication and treatment recommendations.

      Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2018-08-06)
      Rejuvenation of stem cell activity might increase life expectancy by prolonging functionality of organs. Higher stem cell replication rates also bear the risk of cancer. The extent of this risk is not known. While it is difficult to evaluate this cancer risk in experiments, it can be estimated using a mathematical model for tissue homeostasis by stem cell replication and associated cancer risk. The model recapitulates the observation that treatments targeting stem cell replication can induce a substantial delay of organ failure. The model predicts that the cancer risk is minor under particular conditions. It depends on the assumed implications for cell damage repair during treatment. The benefit of rejuvenation therapy and its impact on cancer risk depend on the biological age at the time of treatment and on the overall cell turnover rate of the organs. Different organs have to be considered separately in the planning of systemic treatments. In recent years, the transfer of blood from young to old individuals was shown to bear the potential of rejuvenation of stem cell activity. In this context, the model predicts that the treatment schedule is critical for success and that schedules successful in animal experiments are not transferable to humans. Guidelines for successful protocols are proposed. The model presented here may be used as a guidance for the development of stem cell rejuvenation treatment protocols and the identification of critical parameters for cancer risk.
    • F-Actin-Driven CD28-CD80 Localization in the Immune Synapse.

      Siokis, Anastasios; Robert, Philippe A; Demetriou, Philippos; Dustin, Michael L; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier, 2018-07-31)
      During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.
    • PK/PD-based adaptive tailoring of oseltamivir doses to treat within-host influenza viral infections.

      Montaseri, Ghazal; Boianelli, Alessandro; Hernandez-Vargas, Esteban A; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2018-07-19)
      Influenza A virus (IAV) is a latent global threat to human health. In view of the risk of pandemics, prophylactic and curative treatments are essential. Oseltamivir is a neuraminidase inhibitor efficiently supporting recovery from influenza infections. Current common clinical practice is a constant drug dose (75 or 150 mg) administered at regular time intervals twice a day. We aim to use quantitative systems pharmacology to propose an efficient adaptive drug scheduling. We combined the mathematical model for IAV infections validated by murine data, which captures the viral dynamics and the dynamics of the immune host response, with a pharmacokinetic (PK)/pharmacodynamic (PD) model of oseltamivir. Next, we applied an adaptive impulsive feedback control method to systematically calculate the adaptive dose of oseltamivir in dependence on the viral load and the number of immune effectors at the time of drug administration. Our in silico results revealed that the treatment with adaptive control-based drug scheduling is able to either increase the drug virological efficacy or reduce the drug dose while keeping the same virological efficacy. Thus, adaptive adjustment of the drug dose would reduce not only the potential side effects but also the amount of stored oseltamivir required for the prevention of outbreaks.
    • IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.

      Prajeeth, Chittappen K; Dittrich-Breiholz, Oliver; Talbot, Steven R; Robert, Philippe A; Huehn, Jochen; Stangel, Martin; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (2018-01-01)
      Autoreactive T cells that infiltrate into the central nervous system (CNS) are believed to have a significant role in mediating the pathology of neuroinflammatory diseases like multiple sclerosis. Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes. Our previous work demonstrated that effectors secreted by Th1 and Th17 cells have different capacities to influence the phenotype and function of glial cells. We have shown that Th1-derived effectors altered the phenotype and function of both microglia and astrocytes whereas Th17-derived effectors induced direct effects only on astrocytes but not on microglia. Here we investigated if effector molecules associated with IFN-γ producing Th1 cells induced different gene expression profiles in microglia and astrocytes. We performed a microarray analysis of RNA isolated from microglia and astrocytes treated with medium and Th-derived culture supernatants and compared the gene expression data. By using the criteria of 2-fold change and a false discovery rate of 0.01 (corrected
    • Computer Simulation of Multi-Color Brainbow Staining and Clonal Evolution of B Cells in Germinal Centers.

      Meyer-Hermann, Michael; Binder, Sebastian C; Mesin, Luka; Victora, Gabriel D; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (2018-01-01)
      Clonal evolution of B cells in germinal centers (GCs) is central to affinity maturation of antibodies in response to pathogens. Permanent or tamoxifen-induced multi-color recombination of B cells based on the brainbow allele allows monitoring the degree of color dominance in the course of the GC reaction. Here, we use computer simulations of GC reactions in order to replicate the evolution of color dominance
    • Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34 Cells.

      Theobald, Sebastian J; Khailaie, Sahamoddin; Meyer-Hermann, Michael; Volk, Valery; Olbrich, Henning; Danisch, Simon; Gerasch, Laura; Schneider, Andreas; Sinzger, Christian; Schaudien, Dirk; et al. (Frontiers, 2018-01-01)
      uman cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.
    • Cellular automaton models for time-correlated random walks: derivation and analysis.

      Nava-Sedeño, J M; Hatzikirou, H; Klages, R; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-12-05)
      Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is "data-driven". Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous diffusion for the dynamics of interacting cell populations, like confluent cell monolayers and cell clustering.
    • A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.

      Zhao, Gang; Wirth, Dagmar; Schmitz, Ingo; Meyer-Hermann, Michael; Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106, Germany. (2017-11-08)
      Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field.