A Simple Cellular Automaton Model for Influenza A Viral Infections

Viral kinetics have been extensively studied in the past through the use of spatially homogeneous ordinary differential equations describing the time evolution of the diseased state. However, spatial characteristics such as localized populations of dead cells might adversely affect the spread of infection, similar to the manner in which a counter-fire can stop a forest fire from spreading. In order to investigate the influence of spatial heterogeneities on viral spread, a simple 2-D cellular automaton (CA) model of a viral infection has been developed. In this initial phase of the investigation, the CA model is validated against clinical immunological data for uncomplicated influenza A infections. Our results will be shown and discussed.Comment: LaTeX, 12 pages, 18 EPS figures, uses document class ReTeX4, and packages amsmath and SIunit

Modeling CD4+ T cells dynamics in HIV-infected patients receiving repeated cycles of exogenous Interleukin 7

Combination Antiretroviral Therapy (cART) succeeds to control viral replication in most HIV infected patients. This is normally followed by a reconstitution of the CD4$^+$ T cells pool; however, this does not happen for a substantial proportion of patients. For these patients, an immunotherapy based on injections of Interleukin 7 (IL-7) has been recently proposed as a co-adjutant treatment in the hope of obtaining long-term reconstitution of the T cells pool. Several questions arise as to the long-term efficiency of this treatment and the best protocol to apply. We develop a model based on a system of ordinary differential equations and a statistical model of variability and measurement. We can estimate key parameters of this model using the data from INSPIRE, INSPIRE 2 $\&$ INSPIRE 3 trials. In all three studies, cycles of three injections have been administered; in the last two studies, for the first time, repeated cycles of exogenous IL-7 have been administered. Our aim was to estimate the possible different effects of successive injections in a cycle, to estimate the effect of repeated cycles and to assess different protocols. The use of dynamical models together with our complex statistical approach allow us to analyze major biological questions. We found a strong effect of IL-7 injections on the proliferation rate; however, the effect of the third injection of the cycle appears to be much weaker than the first ones. Also, despite a slightly weaker effect of repeated cycles with respect to the initial one, our simulations show the ability of this treatment of maintaining adequate CD4$^+$ T cells count for years. We were also able to compare different protocols, showing that cycles of two injections should be sufficient in most cases. %Finally, we also explore the possibility of adaptive protocols

Mathematische Analyse des rezeptorvermittelten Immunzelltods bei angeborener antiviraler Immunität

Apoptosis is a series of complex biochemical processes of programmed cell death which occurs in multicellular organisms. This mechanism must be highly regulated and controlled; otherwise, harmful illness such as cancer and autoimmune diseases may occur. Apoptosis is a key mechanism during a typical viral immune response.In the course of an infection, this mechanism eliminates infected cells and by that,limits the resources for viral replication. Recently, regulation of the death recep-tor pathway by cFLIP, a key regulator of signaling complexes downstream of death receptors, was targeted experimentally to study the role of apoptosis in influenza A virus (IAV) infection. By increasing the expression level of cFLIP in transgenic mice, a higher accumulation of Natural Killer (NK) cells and a higher viral load in comparison to wild type(WT) mice were observed. However, the viral load was similar in both mice after 10 days. Infection and functional impairment of NK cells was assumed to be responsible for the observed results. In order to validate this hypothesis, a mathematical model was used to quantify the role of apoptosis medi-ated cell death in NK cells during the viral clearance. The model contains variables and parameters that represent population and interactions between healthy and in-fected epithelial cells, influenza A virions, healthy and infected NK cells. Several simplifications were made in order to better estimate the critical parameters of the model. Simulation results showed that infection of NK cells with a longer lifespan alone cannot explain the observed high viral load. However, by increasing the viral production of infected NK cells, the viral load data was fitted. The lack of caspase3, due to the over-expression of cFLIP, may contribute to higher viral production inNK cells. Furthermore, a shorter lifespan of healthy NK cells was predicted, which may be related to biological exhaustion due to higher infection level. The posteriors and the correlation analysis of the parameters showed that parameters associated with lifespan and the viral production of infected NK cells are linearly correlated.Die Apoptose ist ein komplexer biochemischer Prozess des programmierten Zelltod,die in mehrzelligen Organismen auftritt. Dieser Mechanismus muss eng kontrolliert werden, sonst können schädliche Krankheiten auftreten, so wie z.B. Krebs und Autoimmunerkrankungen. Während einer typischen viralen Immunantwort, werden infizierte Zellen durch Apoptose eliminiert, so dass die Ressourcen für die Virus-replikation begrenzt werden. cFLIP ist ein Inhibitor der Todesrezeptor-gesteuerten Apoptose. Die Regulation des extrinsischen Signalwegs durch cFLIP wurde erforscht um die Rolle der Apoptose während Influenza A Infektionen zu untersuchen. Hierfür wurden transgene Mäuse, die cFLIP in allen hämatopowerten Zellen exprimieren,mit dem Influenza A-Virus infiziert. Diese transgenen Mäuse haben mehr natürliche Killerzellen (NK) und höhere Viruslast aufgewiesen. Die Viruslast nach 10 Tagen waren ähnlich bei transgenen und Wildtyp (WT) Mäusen. Tafrishi argumentierte, dass die infizierten NK-Zellen und ihre Funktionsstörung verantwortlich für die Ergebnissen sind. Hierin wurde ein mathematisches Modell verwendet, um diese Hypothese zu validieren und die Rolle der Apoptose in NK Zellen durch Influenza A-Infektionen zu quantifizieren. Die Modellvariablen und Parameter darstellen die Population und Wechselwirkungen beidem Influenza A-Virus, gesunden und infizierten Epithelzellen und gesunden und infizierten NK-Zellen. Die Simulationsergebnissen demonstrieren, dass infizierte NK-Zellen, die eine längere Lebensdauer haben, nicht der Grund für die erhöhte Viruslast sind. Stattdessen ist eine höhere Virusproduktion von der infizierten NK-Zellen notwendig, um die Viruslast Daten anzupassen.Deshalb kann das Fehlen von Caspase 3, aufgrund der Überexpression von cFLIP,zu einer höheren Virusproduktion in den NK-Zellen beitragen. Darüber hinaus hat die Datenanpassung eine kürzere Lebensdauer der gesunden NK-Zellen vorhergesagt,aufgrund der biologischen Erschöpfung. Korrelationsanalysen der Parameter zeigten,dass die Lebensdauer und die Virusproduktion der infizierten NK-Zellen linear korreliert sind

Haematalogical investigations in children

The haematology laboratory is able to perform a number of tests to help establish the cause of illness in children. The full blood count (FBC, also known as a complete blood count, CBC) is one of the most basic blood tests performed on children attending hospital or a primary care clinic. All doctors should therefore have an understanding of how the test is performed, possible pitfalls, be able to interpret results and know when more specialised testing or advice is required. Other haematological investigations in routine use include coagulation screens, blood film examination, reticulocyte counts and methods for estimation of iron stores and detection of abnormal haemoglobins. This section will focus on these basic tests and simple algorithms for the subsequent investigation and differential diagnosis of the commonest haemato-logical abnormalities encountered in general paediatric practice. The reader is referred to Chapter 15 for an account of the clinical presentation and management of primary haematological disorders in children

Modeling microevolution in a changing environment: The evolving quasispecies and the Diluted Champion Process

Several pathogens use evolvability as a survival strategy against acquired immunity of the host. Despite their high variability in time, some of them exhibit quite low variability within the population at any given time, a somehow paradoxical behavior often called the evolving quasispecies. In this paper we introduce a simplified model of an evolving viral population in which the effects of the acquired immunity of the host are represented by the decrease of the fitness of the corresponding viral strains, depending on the frequency of the strain in the viral population. The model exhibits evolving quasispecies behavior in a certain range of its parameters, ans suggests how punctuated evolution can be induced by a simple feedback mechanism.Comment: 15 pages, 12 figures. Figures redrawn, some additional clarifications in the text. To appear in Journal of Statistical Mechanics: Theory and Experimen

Mathematical models for immunology:current state of the art and future research directions

The advances in genetics and biochemistry that have taken place over the last 10 years led to significant advances in experimental and clinical immunology. In turn, this has led to the development of new mathematical models to investigate qualitatively and quantitatively various open questions in immunology. In this study we present a review of some research areas in mathematical immunology that evolved over the last 10 years. To this end, we take a step-by-step approach in discussing a range of models derived to study the dynamics of both the innate and immune responses at the molecular, cellular and tissue scales. To emphasise the use of mathematics in modelling in this area, we also review some of the mathematical tools used to investigate these models. Finally, we discuss some future trends in both experimental immunology and mathematical immunology for the upcoming years

Characterization of potential biomarkers of reactogenicity of licensed antiviral vaccines: randomized controlled clinical trials conducted by the BIOVACSAFE consortium

Funding text The authors are grateful for the vital contributions of the participating study volunteers, clinicians, nurses, and laboratory technicians at the Surrey study site. The work by Roberto Leone, laboratory technician at Humanitas Clinical and Research Center, is gratefully acknowledged. Finally, they thank Ellen Oe (GSK) for scientific writing assistance. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115308, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. The contribution of the European Commission to the Advanced Immunization Technologies (ADITEC) project (grant agreement n° 280873) is also gratefully acknowledged. Publisher Copyright: © 2019, The Author(s).Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.Peer reviewe

The SUMO Ligase Protein Inhibitor of Activated STAT 1 (PIAS1) is a constituent PML-NB protein that contributes to the intrinsic antiviral immune response to herpes simplex virus 1 (HSV-1)

Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukaemia (PML)-nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signalling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase Protein Inhibitor of Activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well characterized PML-NB proteins. In contrast to Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation