Mathematische Modellierung der Steuerung der Immunantwort in viralen und bakteriellen Krankheiten

The role of the first days of an infection is crucial for the immune protection from many bacterial and viral diseases. Already in the first hours after infection, molecules with antiviral and antibacterial properties are secreted, and the recruitment of the first immune cells to the infection site starts. Although these early immune responses often determine the disease severity and can prevent the establishment of an infection, their dynamics and the interplay between different components of immunity are often poorly understood. In this study, dynamic mathematical modelling approaches were explored in order to elucidate quantitative relationships between different parts of the host immmunity and the pathogen. To this end, models for a bacterial disease and a viral disease were developed. Lyme disease is a widespread tick-borne infection caused by Borrelia burgdorferi and can lead to severe symptoms in humans. It induces strong and effective immune responses in mammals, but it still yields a remarkably high infectivity. Mathematical models for bacterial movement during dissemination of the bacteria, phagocytosis and molecular adaptation of the bacteria were investigated in order to gain insight into escape from the host immunity by Borrelia burgdorferi. The model has been analysed with respect to these questions in basic science; however, it provides the basis for evaluation with respect to options in prevention and therapy of Lyme disease. As an example of a viral disease, a dynamic quantitative model describing the dynamics of cytokines as the major component in immune signalling and their interplay during influenza infections was developed. Due to difficulties in parts of the modelling process, the existing methodology was extended by a novel method for the estimation of model parameters and the method was validated. The cytokine model is useful not only in modelling viral infections, but as a modelling framework for a variety of different problems, since cytokines are involved in the immune response to all infectious diseases and in autoimmune diseases.Die ersten Tage einer Infektion spielen eine entscheidende Rolle für den Schutz durch das Immunsystem vor diversen bakteriellen und viralen Erkrankungen. Bereits in den ersten Stunden nach einer Infektion werden Moleküle mit antiviralen und antibakteriellen Eigenschaften abgegeben und erste Immunzellen werden an den Infektionsherd rekrutiert. Obwohl diese frühe Immunantwort oft entscheidend für die Schwere einer Erkrankung ist und sogar eine Erkrankung ganz verhindern kann, ist ihre Dynamik und das Wechselspiel zwischen verschiedenen Bestandteilen des Immunsystems oft nicht im Detail verstanden. In dieser Studie wurden mathematische Modellierungsansätze untersucht, um quantitative Zusammenhänge zwischen verschiedenen Teilen der Wirtsimmunität und dem Pathogen zu verstehen. Dazu wurden Modelle für eine bakterielle und eine virale Erkrankung entwickelt. Lyme Borreliose ist eine weitverbreitete, von Zecken übertragene Krankheit, die von Borrelia burgdorferi ausgelöst wird und schwere Symptome im Menschen verursacht. Sie führt zu einer ausgeprägten und effektiven Immunantwort in Säugetieren, aber ist dennoch sehr ansteckend. Um die Immunevasion besser zu verstehen, wurden mathematische Modelle für bakerielle Fortbewegung während der Ausbreitung der Bakterien, für Phagozytose und molekulare Anpassungen der Bakterien untersucht. Das Modell wurde in Bezug auf Fragestellungen aus der Grundlagenforschung untersucht; es stellt aber eine Basis dar, auf der eine Untersuchung in Bezug auf Fragen der Therapie und Prävention von Lyme Borreliose möglich ist. Als Beispiel für eine virale Erkrankung wurde ein quantitatives Modell entwickelt, dass die Dynamik von Zytokinen, einem wichtigen Bestandteil in Immunsignalwegen, und ihre Interaktionen in Influenzainfektionen beschreibt. Aufgrund von Problemstellungen in Teilen des Modellierungsprozesses konnte die bestehende Methodik durch eine neue Methode zur Abschätzung von Modellparametern erweitert und die Methode validiert werden. Das entwickelte Zytokinmodell ist nicht nur für die Modellierung viraler Erkrankungen hilfreich, sondern überdies als Modellierungskonzept für eine Reihe verschiedener Probleme, da Zytokine Bestandteil der Immunreaktion in allen Infektionskrankheiten und auch in Autoimmunerkrankungen sind

Population Dynamics of Borrelia burgdorferi in Lyme Disease

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

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Measuring the Neutrino Cross Section Using 8 years of Upgoing Muon Neutrinos Observed with IceCube

The IceCube Neutrino Observatory detects neutrinos at energies orders of magnitude higher than those available to current accelerators. Above 40 TeV, neutrinos traveling through the Earth will be absorbed as they interact via charged current interactions with nuclei, creating a deficit of Earth-crossing neutrinos detected at IceCube. The previous published results showed the cross section to be consistent with Standard Model predictions for 1 year of IceCube data. We present a new analysis that uses 8 years of IceCube data to fit the ν$_{μ}$ absorption in the Earth, with statistics an order of magnitude better than previous analyses, and with an improved treatment of systematic uncertainties. It will measure the cross section in three energy bins that span the range 1 TeV to 100 PeV. We will present Monte Carlo studies that demonstrate its sensitivity