• 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.
    • Modeling the three stages in HIV infection.

      Hernandez-Vargas, Esteban A; Middleton, Richard H; SIMM, Helmholtz Zentrum für Infektionsforschung, Inhoffenstraße 7, D-38124 Braunschweig, Germany. (2013-03-07)
      A typical HIV infection response consists of three stages: an initial acute infection, a long asymptomatic period and a final increase in viral load with simultaneous collapse in healthy CD4+T cell counts. The majority of existing mathematical models give a good representation of either the first two stages or the last stage of the infection. Using macrophages as a long-term active reservoir, a deterministic model is proposed to explain the three stages of the infection including the progression to AIDS. Simulation results illustrate how chronic infected macrophages can explain the progression to AIDS provoking viral explosion. Further simulation studies suggest that the proposed model retains its key properties even under moderately large parameter variations. This model provides important insights on how macrophages might play a crucial role in the long term behavior of HIV infection.
    • Modelling collective cell motion: are on- and off-lattice models equivalent?

      Nava-Sedeño, Josué Manik; Voß-Böhme, Anja; Hatzikirou, Haralampos; Deutsch, Andreas; Peruani, Fernando (2020-07-27)
    • The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas.

      Jain, Harsh Vardhan; Müller, A (2011-02-01)
      Resistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x(L), whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x(L) that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-x(L) for survival. Numerical simulations predict the existence of a threshold of Bcl-x(L) below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists.
    • Molecular mechanism of Ena/VASP-mediated actin-filament elongation.

      Breitsprecher, Dennis; Kiesewetter, Antje K; Linkner, Joern; Vinzenz, Marlene; Stradal, Theresia E B; Small, John Victor; Curth, Ute; Dickinson, Richard B; Faix, Jan (2011-02-02)
      Ena/VASP proteins are implicated in a variety of fundamental cellular processes including axon guidance and cell migration. In vitro, they enhance elongation of actin filaments, but at rates differing in nearly an order of magnitude according to species, raising questions about the molecular determinants of rate control. Chimeras from fast and slow elongating VASP proteins were generated and their ability to promote actin polymerization and to bind G-actin was assessed. By in vitro TIRF microscopy as well as thermodynamic and kinetic analyses, we show that the velocity of VASP-mediated filament elongation depends on G-actin recruitment by the WASP homology 2 motif. Comparison of the experimentally observed elongation rates with a quantitative mathematical model moreover revealed that Ena/VASP-mediated filament elongation displays a saturation dependence on the actin monomer concentration, implying that Ena/VASP proteins, independent of species, are fully saturated with actin in vivo and generally act as potent filament elongators. Moreover, our data showed that spontaneous addition of monomers does not occur during processive VASP-mediated filament elongation on surfaces, suggesting that most filament formation in cells is actively controlled.
    • A molecular theory of germinal center B cell selection and division.

      Meyer-Hermann, Michael; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Cell Press, 2021-08-24)
      The selection of B cells (BCs) in germinal centers (GCs) is pivotal to the generation of high-affinity antibodies and memory BCs, but it lacks global understanding. Based on the idea of a single Tfh-cell signal that controls BC selection and division, experiments appear contradictory. Here, we use the current knowledge on the molecular pathways of GC BCs to develop a theory of GC BC selection and division based on the dynamics of molecular factors. This theory explains the seemingly contradictory experiments by the separation of signals for BC fate decision from signals controlling the number of BC divisions. Three model variants are proposed and experiments are predicted that allow one to distinguish those. Understanding information processing in molecular BC states is critical for targeted immune interventions, and the proposed theory implies that selection and division can be controlled independently in GC reactions.
    • Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization.

      Volk, Valery; Reppas, Andreas I; Robert, Philippe A; Spineli, Loukia M; Sundarasetty, Bala Sai; Theobald, Sebastian J; Schneider, Andreas; Gerasch, Laura; Deves Roth, Candida; Klöss, Stephan; et al. (2017)
      Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses in vivo. Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8+ T cell responses in NOD.Cg-Rag1 tm1Mom -Il2rγ tm1Wj humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8+ memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses in vivo. A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation.
    • Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help.

      Merino Tejero, Elena; Lashgari, Danial; García-Valiente, Rodrigo; Gao, Xuefeng; Crauste, Fabien; Robert, Philippe A; Meyer-Hermann, Michael; Martínez, María Rodríguez; van Ham, S Marieke; Guikema, Jeroen E J; et al. (Frontiers, 2021-02-05)
      Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.
    • Naive- and Memory-like CD21 B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders.

      Freudenhammer, Mirjam; Voll, Reinhard E; Binder, Sebastian C; Keller, Baerbel; Warnatz, Klaus (2020-09-09)
      An expansion of CD21low B cells has been described in a variety of diseases associated with persistent immune stimulation as in chronic infection, immunodeficiency, or autoimmunity. Different developmental stages of CD21low B cells have been highlighted in specific diseases; however, a systematic comparison of distribution, phenotype, and signaling capacity of these populations has not yet been performed to delineate the pivotal character of this unusual B cell population. Screening of more than 200 patients with autoimmune disease demonstrated that the prevalence of patients with expanded CD21low B cells varies between diseases. The expansion was frequent in patients with systemic lupus erythematosus, in which it correlated to relative B cell lymphopenia and duration of disease. Different proportions of distinct developmental stages of CD21low B cells co-occur in nearly all patients with autoimmune disease. Although in most patients, naive-like and CD27- switched memory B cells were the most prominent CD21low subpopulations, there was no detectable association of the pattern with the underlying disease. Despite their distinct developmental stage, all CD21low B cells share a common core phenotype including the increased expression of inhibitory receptors, associated with an elevated constitutive phosphorylation of proximal signaling molecules downstream of the BCR but impaired Ca2+ mobilization and NF-κB activation after BCR stimulation. Further, this was accompanied by impaired upregulation of CD69, although CD86 upregulation was preserved. Beyond maturation-associated differences, the common core characteristics of all CD21low B cell populations suggests either a common ancestry or a shared sustained imprint by the environment they originated in.
    • Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

      Formaglio, Pauline; Alabdullah, Mohamad; Siokis, Anastasios; Handschuh, Juliane; Sauerland, Ina; Fu, Yan; Krone, Anna; Gintschel, Patricia; Stettin, Juliane; Heyde, Sandrina; et al. (Cell Press, 2021-10-15)
      Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
    • Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling.

      Fava, E; Dehghany, J; Ouwendijk, J; Müller, A; Niederlein, A; Verkade, P; Meyer-Hermann, M; Solimena, M; Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany. (2012-04)
      Knowledge of number, size and content of insulin secretory granules is pivotal for understanding the physiology of pancreatic beta cells. Here we re-evaluated key structural features of rat beta cells, including insulin granule size, number and distribution as well as cell size.
    • Observers for biological systems

      Alanis, Alma Y.; Hernandez-Gonzalez, Miguel; Hernandez-Vargas, Esteban Abelardo; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2014-11)
    • 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.
    • 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
    • Optimal therapy scheduling for a simplified HIV infection model

      Hernandez-Vargas, Esteban Abelardo; Colaneri, Patrizio; Middleton, Richard H.; Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. (2014-07-09)
    • Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection.

      Boianelli, Alessandro; Sharma-Chawla, Niharika; Bruder, Dunja; Hernandez-Vargas, Esteban Abelardo; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2016)
      Influenza pandemics and seasonal outbreaks have shown the potential of Influenza A virus (IAV) to enhance susceptibility to a secondary infection with the bacterial pathogen Streptococcus pneumoniae (Sp). The high morbidity and mortality rate revealed the poor efficacy of antiviral drugs and vaccines to fight IAV infections. Currently, the most effective treatment for IAV is by antiviral neuraminidase inhibitors. Among them, the most frequently stockpiled is Oseltamivir which reduces viral release and transmission. However, effectiveness of Oseltamivir is compromised by the emergence of resistant IAV strains and secondary bacterial infections. To date, little attention has been given to evaluate how Oseltamivir treatment strategies alter Influenza viral infection in presence of Sp coinfection and a resistant IAV strain emergence. In this paper we investigate the efficacy of current approved Oseltamivir treatment regimens using a computational approach. Our numerical results suggest that the curative regimen (75 mg) may yield 47% of antiviral efficacy and 9% of antibacterial efficacy. An increment in dose to 150 mg (pandemic regimen) may increase the antiviral efficacy to 49% and the antibacterial efficacy to 16%. The choice to decrease the intake frequency to once per day is not recommended due to a significant reduction in both antiviral and antibacterial efficacy. We also observe that the treatment duration of 10 days may not provide a clear improvement on the antiviral and antibacterial efficacy compared to 5 days. All together, our in silico study reveals the success and pitfalls of Oseltamivir treatment strategies within IAV-Sp coinfection and calls for testing the validity in clinical trials.
    • PD-1 Blockade Aggravates Epstein-Barr Virus Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4 T Cell Dysregulations.

      Volk, Valery; Theobald, Sebastian J; Danisch, Simon; Khailaie, Sahamoddin; Kalbarczyk, Maja; Schneider, Andreas; Bialek-Waldmann, Julia; Krönke, Nicole; Deng, Yun; Eiz-Vesper, Britta; et al. (Frontiers, 2021-01-12)
      Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.
    • Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth.

      Nakagawa, Rinako; Toboso-Navasa, Amparo; Schips, Marta; Young, George; Bhaw-Rosun, Leena; Llorian-Sopena, Miriam; Chakravarty, Probir; Sesay, Abdul Karim; Kassiotis, George; Meyer-Hermann, Michael; et al. (National Academy of Sciences, 2021-01-12)
      Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.
    • 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.
    • Population Dynamics of Borrelia burgdorferi in Lyme Disease.

      Binder, Sebastian C; Telschow, Arndt; Meyer-Hermann, Michael; Department of Systems Immunology, Helmholtz Centre for Infection Research Braunschweig, Germany. (2012)
      Many chronic inflammatory diseases are known to be caused by persistent bacterial or viral infections. A well-studied example is the tick-borne infection by the gram-negative spirochaetes of the genus Borrelia in humans and other mammals, causing severe symptoms of chronic inflammation and subsequent tissue damage (Lyme Disease), particularly in large joints and the central nervous system, but also in the heart and other tissues of untreated patients. Although killed efficiently by human phagocytic cells in vitro, Borrelia exhibits a remarkably high infectivity in mice and men. In experimentally infected mice, the first immune response almost clears the infection. However, approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase. We developed a mathematical model describing the bacterial growth and the immune response against Borrelia burgdorferi in the C3H mouse strain that has been established as an experimental model for Lyme disease. The peculiar dynamics of the infection exclude two possible mechanistic explanations for the regrowth of the almost cleared bacteria. Neither the hypothesis of bacterial dissemination to different tissues nor a limitation of phagocytic capacity were compatible with experiment. The mathematical model predicts that Borrelia recovers from the strong initial immune response by the regrowth of an immune-resistant sub-population of the bacteria. The chronic phase appears as an equilibration of bacterial growth and adaptive immunity. This result has major implications for the development of the chronic phase of Borrelia infections as well as on potential protective clinical interventions.