• An Adaptive Control Scheme for Interleukin-2 Therapy.

      Khailaie, Sahamoddin; Montaseri, Ghazal; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Elsevier (Cell Press), 2020-10-12)
      Regulatory T cells (Treg) are suppressor cells that control self-reactive and excessive effector conventional T helper cell (Tconv) responses. Breakdown of the balance between Tregs and Tconvs is a hallmark of autoimmune and inflammatory diseases. Interleukin-2 (IL-2) is a growth factor for both populations and subtle leverage to restore the healthy immune balance in IL-2 therapy. By using a mechanistic mathematical model, we introduced an adaptive control strategy to design the minimal therapeutic IL-2 dosage required to increase and stabilize Treg population and restrict inflammatory response. This adaptive protocol allows for dose adjustments based on the feedback of the immune kinetics of the patient. Our simulation results showed that a minimal Treg population was required to restrict the transient side effect of IL-2 injections on the effector Tconv response. In silico results suggested that a combination of IL-2 and adoptive Treg transfer therapies can limit this side effect.
    • Agent-Based Modeling of T Cell Receptor Cooperativity.

      Siokis, Anastasios; Robert, Philippe A; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (MDPI, 2020-09-04)
      Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR-pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon.
    • Analysis of Practical Identifiability of a Viral Infection Model.

      Nguyen, Van Kinh; Klawonn, Frank; Mikolajczyk, Rafael; Hernandez-Vargas, Esteban Abelardo; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
      Mathematical modelling approaches have granted a significant contribution to life sciences and beyond to understand experimental results. However, incomplete and inadequate assessments in parameter estimation practices hamper the parameter reliability, and consequently the insights that ultimately could arise from a mathematical model. To keep the diligent works in modelling biological systems from being mistrusted, potential sources of error must be acknowledged. Employing a popular mathematical model in viral infection research, existing means and practices in parameter estimation are exemplified. Numerical results show that poor experimental data is a main source that can lead to erroneous parameter estimates despite the use of innovative parameter estimation algorithms. Arbitrary choices of initial conditions as well as data asynchrony distort the parameter estimates but are often overlooked in modelling studies. This work stresses the existence of several sources of error buried in reports of modelling biological systems, voicing the need for assessing the sources of error, consolidating efforts in solving the immediate difficulties, and possibly reconsidering the use of mathematical modelling to quantify experimental data.
    • Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm?

      Marschall, Andrea L J; Dübel, Stefan; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2016)
      Challenges posed by complex diseases such as cancer, chronic viral infections, neurodegenerative disorders and many others have forced researchers to think beyond classic small molecule drugs, exploring new therapeutic strategies such as therapy with RNAi, CRISPR/Cas9 or antibody therapies as single or as combination therapies with existing drugs. While classic antibody therapies based on parenteral application can only reach extracellular targets, intracellular application of antibodies could provide specific advantages but is so far little recognized in translational research. Intrabodies allow high specificity and targeting of splice variants or post translational modifications. At the same time off target effects can be minimized by thorough biochemical characterization. Knockdown of cellular proteins by intrabodies has been reported for a significant number of disease-relevant targets, including ErbB-2, EGFR, VEGFR-2, Metalloproteinase MMP2 and MMP9, β-amyloid protein, α-synuclein, HIV gp120, HCV core and many others. This review outlines the recent advances in ER intrabody technology and their potential use in therapy.
    • Assessment of effective mitigation and prediction of the spread of SARS-CoV-2 in Germany using demographic information and spatial resolution.

      Kühn, Martin J; Abele, Daniel; Mitra, Tanmay; Koslow, Wadim; Abedi, Majid; Rack, Kathrin; Siggel, Martin; Khailaie, Sahamoddin; Klitz, Margrit; Binder, Sebastian; et al. (Elsevier, 2021-06-30)
      on-pharmaceutical interventions (NPIs) are important to mitigate the spread of infectious diseases as long as no vaccination or outstanding medical treatments are available. We assess the effectiveness of the sets of non-pharmaceutical interventions that were in place during the course of the Coronavirus disease 2019 (Covid-19) pandemic in Germany. Our results are based on hybrid models, combining SIR-type models on local scales with spatial resolution. In order to account for the age-dependence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we include realistic prepandemic and recently recorded contact patterns between age groups. The implementation of non-pharmaceutical interventions will occur on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. In order to account for spatial heterogeneity, we use a graph approach and we include high-quality information on commuting activities combined with traveling information from social networks. The remaining uncertainty will be accounted for by a large number of randomized simulation runs. Based on the derived factors for the effectiveness of different non-pharmaceutical interventions over the past months, we provide different forecast scenarios for the upcoming time.
    • 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.
    • Attaching and effacing pathogens: the effector ABC of immune subversion.

      Riebisch, Anna Katharina; Mühlen, Sabrina; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Future Medicine Ltd., 2020-07-27)
      The innate immune response resembles an essential barrier to bacterial infection. Many bacterial pathogens have, therefore, evolved mechanisms to evade from or subvert the host immune response in order to colonize, survive and multiply. The attaching and effacing pathogens enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Escherichia albertii and Citrobacter rodentium are Gram-negative extracellular gastrointestinal pathogens. They use a type III secretion system to inject effector proteins into the host cell to manipulate a variety of cellular processes. Over the last decade, considerable progress was made in identifying and characterizing the effector proteins of attaching and effacing pathogens that are involved in the inhibition of innate immune signaling pathways, in determining their host cell targets and elucidating the mechanisms they employ. Their functions will be reviewed here.
    • B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2.

      Reimer, Dorothea; Meyer-Hermann, Michael; Rakhymzhan, Asylkhan; Steinmetz, Tobit; Tripal, Philipp; Thomas, Jana; Boettcher, Martin; Mougiakakos, Dimitrios; Schulz, Sebastian R; Urbanczyk, Sophia; et al. (Elsevier (CellPress), 2020-08-11)
      Plasma cells secreting affinity-matured antibodies develop in germinal centers (GCs), where B cells migrate persistently and directionally over defined periods of time. How modes of GC B cell migration influence plasma cell development remained unclear. Through genetic deletion of the F-actin bundling protein Swiprosin-1/EF-hand domain family member 2 (EFhd2) and by two-photon microscopy, we show that EFhd2 restrains B cell speed in GCs and hapten-specific plasma cell output. Modeling the GC reaction reveals that increasing GC B cell speed promotes plasma cell generation. Lack of EFhd2 also reduces contacts of GC B cells with follicular dendritic cells in vivo. Computational modeling uncovers that both GC output and antibody affinity depend quantitatively on contacts of GC B cells with follicular dendritic cells when B cells migrate more persistently. Collectively, our data explain how GC B cells integrate speed and persistence of cell migration with B cell receptor affinity.
    • Batch Cultivation Model for Biopolymer Production

      Torres-Cerna, C. E.; Alanis, A. Y.; Poblete-Castro, I.; Hernandez-Vargas, E. A.; BRICS, Braunschweiger Zentrum für Systembiology, Rbenring 56, 38106 Braunschweig, Germany. (2017-04-15)
    • The biology and mathematical modelling of glioma invasion: a review.

      Alfonso, J C L; Talkenberger, K; Seifert, M; Klink, B; Hawkins-Daarud, A; Swanson, K R; Hatzikirou, H; Deutsch, A; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany. (2017-11)
      Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion.
    • Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions.

      Hatzikirou, H; Alfonso, J C L; Mühle, S; Stern, C; Weiss, S; Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38124 Braunschweig, Germany. (2015-11-06)
      Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
    • Case Numbers Beyond Contact Tracing Capacity Are Endangering the Containment of COVID-19.

      Linden, Matthias; Dehning, Jonas; Mohr, Sebastian B; Mohring, Jan; Meyer-Hermann, Michael; Pigeot, Iris; Schöbel, Anita; Priesemann, Viola; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
      [No abstract available]
    • 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.
    • Commentary: "Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?".

      Robert, Philippe A; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2015)
    • Computational Study to Determine When to Initiate and Alternate Therapy in HIV Infection.

      Haering, Matthias; Hördt, Andreas; Müller, A; Hernandez-Vargas, Esteban Abelardo (2014)
      HIV is a widespread viral infection without cure. Drug treatment has transformed HIV disease into a treatable long-term infection. However, the appearance of mutations within the viral genome reduces the susceptibility of HIV to drugs. Therefore, a key goal is to extend the time until patients exhibit resistance to all existing drugs. Current HIV treatment guidelines seem poorly supported as practitioners have not achieved a consensus on the optimal time to initiate and to switch antiretroviral treatments. We contribute to this discussion with predictions derived from a mathematical model of HIV dynamics. Our results indicate that early therapy initiation (within 2 years postinfection) is critical to delay AIDS progression. For patients who have not received any therapy during the first 3 years postinfection, switch in response to virological failure may outperform proactive switching strategies. In case that proactive switching is opted, the switching time between therapies should not be larger than 100 days. Further clinical trials are needed to either confirm or falsify these predictions.
    • 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
    • [The contribution of epidemiological models to the description of the outbreak of the COVID-19 pandemic].

      Priesemann, Viola; Meyer-Hermann, Michael; Pigeot, Iris; Schöbel, Anita; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Springer, 2021-07-30)
      After the global outbreak of the COVID-19 pandemic, an infection dynamic of immense extent developed. Since then, numerous measures have been taken to bring the infection under control. This was very successful in the spring of 2020, while the number of infections rose sharply the following autumn. To predict the occurrence of infections, epidemiological models are used. These are in principle a very valuable tool in pandemic management. However, they still partly need to be based on assumptions regarding the transmission routes and possible drivers of the infection dynamics. Despite numerous individual approaches, systematic epidemiological data are still lacking with which, for example, the effectiveness of individual measures could be quantified. Such information generated in studies is needed to enable reliable predictions regarding the further course of the pandemic. Thereby, the complexity of the models could develop hand in hand with the complexity of the available data. In this article, after delineating two basic classes of models, the contribution of epidemiological models to the assessment of various central aspects of the pandemic, such as the reproduction rate, the number of unreported cases, infection fatality rate, and the consideration of regionality, is shown. Subsequently, the use of the models to quantify the impact of measures and the effects of the "test-trace-isolate" strategy is described. In the concluding discussion, the limitations of such modelling approaches are juxtaposed with their advantages.
    • Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells.

      Pae, Juhee; Ersching, Jonatan; Castro, Tiago B R; Schips, Marta; Mesin, Luka; Allon, Samuel J; Ordovas-Montanes, Jose; Mlynarczyk, Coraline; Melnick, Ari; Efeyan, Alejo; et al. (Rockefeller University Press, 2021-04-01)
      During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by "inertia." We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
    • Das gemeinsame Interesse von Gesundheit und Wirtschaft: Eine Szenarienrechnung zur Eindämmung der Corona Pandemie

      Dorn, Florian; et al.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (ifo Institut, 2020-05-12)
      [No Abstract available]
    • Deceleration of fusion-fission cycles improves mitochondrial quality control during aging.

      Figge, Marc Thilo; Reichert, Andreas S; Meyer-Hermann, Michael; Osiewacz, Heinz D; Applied Systems Biology, Leibniz-Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute and Friedrich Schiller University, Jena, Germany. (2012-06)
      Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span.