Novel travel time aware metapopulation models and multi-layer waning immunity for late-phase epidemic and endemic scenarios.

In the realm of infectious disease control, accurate modeling of the transmission dynamics is pivotal. As human mobility and commuting patterns are key components of communicable disease spread, we introduce a novel travel time aware metapopulation model. Our model aims to enhance estimations of disease transmission.

Soluble ACE2 correlates with severe COVID-19 and can impair antibody responses.

Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 μg/mL total sACE2 in moderate and severe patients.

Germinal centers are permissive to subdominant antibody responses.

Introduction: A protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens.

Suppressive might of a few: T follicular regulatory cells impede auto-reactivity despite being outnumbered in the germinal centres.

The selection of high-affinity B cells and the production of high-affinity antibodies are mediated by T follicular helper cells (Tfhs) within germinal centres (GCs). Therein, somatic hypermutation and selection enhance B cell affinity but risk the emergence of self-reactive B cell clones. Despite being outnumbered compared to their helper counterpart, the ablation of T follicular regulatory cells (Tfrs) results in enhanced dissemination of self-reactive antibody-secreting cells (ASCs).

Spatial dysregulation of T follicular helper cells impairs vaccine responses in aging.

The magnitude and quality of the germinal center (GC) response decline with age, resulting in poor vaccine-induced immunity in older individuals. A functional GC requires the co-ordination of multiple cell types across time and space, in particular across its two functionally distinct compartments: the light and dark zones. In aged mice, there is CXCR4-mediated mislocalization of T follicular helper (T) cells to the dark zone and a compressed network of follicular dendritic cells (FDCs) in the light zone.

Amount of antigen, T follicular helper cells and affinity of founder cells shape the diversity of germinal center B cells: A computational study.

A variety of B cell clones seed the germinal centers, where a selection stringency expands the fitter clones to generate higher affinity antibodies. However, recent experiments suggest that germinal centers often retain a diverse set of B cell clones with a range of affinities and concurrently carry out affinity maturation. Amid a tendency to flourish germinal centers with fitter clones, how several B cell clones with differing affinities can be concurrently selected remains poorly understood.

Apoptotic cell fragments locally activate tingible body macrophages in the germinal center.

Germinal centers (GCs) that form within lymphoid follicles during antibody responses are sites of massive cell death. Tingible body macrophages (TBMs) are tasked with apoptotic cell clearance to prevent secondary necrosis and autoimmune activation by intracellular self antigens. We show by multiple redundant and complementary methods that TBMs derive from a lymph node-resident, CD169-lineage, CSF1R-blockade-resistant precursor that is prepositioned in the follicle.

Tingible body macrophages arise from lymph node-resident precursors and uptake B cells by dendrites.

Antibody affinity maturation depends on the formation of germinal centers (GCs) in lymph nodes. This process generates a massive number of apoptotic B cells, which are removed by a specialized subset of phagocytes, known as tingible body macrophages (TBMs). Although defects in these cells are associated with pathological conditions, the identity of their precursors and the dynamics of dying GC B cell disposal remained unknown.

mutation yields supercompetitive B cells primed for malignant transformation.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation.

predicted therapy against chronic infection leads to bacterial clearance .

can lead to chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronic infection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies for clearance. A therapeutic protocol with heat-killed (HKSA) was quantified and tested .

Antibody Mediated Intercommunication of Germinal Centers.

Antibody diversification and selection of B cells occur in dynamic structures called germinal centers (GCs). Passively administered soluble antibodies regulate the GC response by masking the antigen displayed on follicular dendritic cells (FDCs). This suggests that GCs might intercommunicate via naturally produced soluble antibodies, but the role of such GC-GC interactions is unknown.

Investigating the Mechanism of Germinal Center Shutdown.

Germinal centers (GCs) are transient structures where affinity maturation of B cells gives rise to high affinity plasma and memory cells. The mechanism of GC shutdown is unclear, despite being an important phenomenon maintaining immune homeostasis. In this study, we used a mathematical model to identify mechanisms that can independently promote contraction of GCs leading to shutdown.

Reprogramming of Amino Acid Metabolism Differs between Community-Acquired Pneumonia and Infection-Associated Exacerbation of Chronic Obstructive Pulmonary Disease.

Amino acids and their metabolites are key regulators of immune responses, and plasma levels may change profoundly during acute disease states. Using targeted metabolomics, we evaluated concentration changes in plasma amino acids and related metabolites in community-acquired pneumonia (CAP, = 29; compared against healthy controls, = 33) from presentation to hospital through convalescence. We further aimed to identify biomarkers for acute CAP vs.

Testing and isolation to prevent overloaded healthcare facilities and reduce death rates in the SARS-CoV-2 pandemic in Italy.

Background: During the first wave of COVID-19, hospital and intensive care unit beds got overwhelmed in Italy leading to an increased death burden. Based on data from Italian regions, we disentangled the impact of various factors contributing to the bottleneck situation of healthcare facilities, not well addressed in classical SEIR-like models. A particular emphasis was set on the undetected fraction (dark figure), on the dynamically changing hospital capacity, and on different testing, contact tracing, quarantine strategies.

The transition between acute and chronic infections in light of energy control: a mathematical model of energy flow in response to infection.

Background: Different parts of an organism like the gut, endocrine, nervous and immune systems constantly exchange information. Understanding the pathogenesis of various systemic chronic diseases increasingly relies on understanding how these subsystems orchestrate their activities.

Methods: We started from the working hypothesis that energy is a fundamental quantity that governs activity levels of all subsystems and that interactions between subsystems control the distribution of energy according to acute needs.

From affinity selection to kinetic selection in Germinal Centre modelling.

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC.

Improving personalized tumor growth predictions using a Bayesian combination of mechanistic modeling and machine learning.

Background: In clinical practice, a plethora of medical examinations are conducted to assess the state of a patient's pathology producing a variety of clinical data. However, investigation of these data faces two major challenges. Firstly, we lack the knowledge of the mechanisms involved in regulating these data variables, and secondly, data collection is sparse in time since it relies on patient's clinical presentation.

Appropriate relaxation of non-pharmaceutical interventions minimizes the risk of a resurgence in SARS-CoV-2 infections in spite of the Delta variant.

We analyze the relaxation of non-pharmaceutical interventions (NPIs) under an increasing number of vaccinations in Germany. For the spread of SARS-CoV-2 we employ a SIR-type model that accounts for age-dependence and includes realistic contact patterns between age groups. The implementation of NPIs occurs on changed contact patterns, improved isolation, or reduced infectiousness when, e.

Regional opening strategies with commuter testing and containment of new SARS-CoV-2 variants in Germany.

Background: Despite the vaccination process in Germany, a large share of the population is still susceptible to SARS-CoV-2. In addition, we face the spread of novel variants. Until we overcome the pandemic, reasonable mitigation and opening strategies are crucial to balance public health and economic interests.

Systemic Lactate Acts as a Metabolic Buffer in Humans and Prevents Nutrient Overflow in the Postprandial Phase.

On an organismal level, metabolism needs to react in a well-orchestrated manner to metabolic challenges such as nutrient uptake. Key metabolic hubs in human blood are pyruvate and lactate, both of which are constantly interconverted by very fast exchange fluxes. The quantitative contribution of different food sources to these metabolite pools remains unclear.

The common interests of health protection and the economy: evidence from scenario calculations of COVID-19 containment policies.

We develop a novel approach integrating epidemiological and economic models that allows data-based simulations during a pandemic. We examine the economically optimal opening strategy that can be reconciled with the containment of a pandemic. The empirical evidence is based on data from Germany during the SARS-CoV-2 pandemic.

Competition for refueling rather than cyclic reentry initiation evident in germinal centers.

Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation and proliferation in dark zones (DZs) and selection in light zones (LZs). GC B cells exit cell cycle a number of hours before entering LZs; therefore, continued participation in responses requires that they subsequently reenter cell cycle and move back to DZs, a process known as cyclic reentry. Affinity enhancements are thought to arise by B cells having to compete to initiate cyclic reentry each time they enter LZs, with T cell help being a major determinant; however, direct proof is lacking.

Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

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.