Emergent networks in immune system shape space

The development of a computational model is reported which facilitates the study of emergent principles of human immune system effector T cell clonotype repertoire and its distribution and differentiation. In particular, the question of systemic self-organisation is addressed. The model represents an extension to earlier immune system shape space formalism, such that each activated effector T cell clonotype and respective immunogenic viral epitope is represented as a node in a two-dimensional network space, and edges between nodes models the affinity and clearance pressure applied to the antigen presenting cell bearing the target epitope. As the model is repeatedly exposed to infection by heterologous or mutating viruses, a distinct topology of the network shape space emerges which may offer a theoretical explanation of recent biological experimental results in the field of murine (mouse) cytotoxic T cell activation, apoptosis, crossreactivity, and memory - especially with respect to repeated reinfection. In the past, most discrete computational models of immune response to vira l infections have used separate real space or shape space formalisms. In this work, however, we have developed a model based on a combination of the two, with the objective of demonstrating how emergent behaviour and principles of self organisation may arise from a many-particle microscopic system. This is achieved by using a stochastic model of the lymphatic system as stimulus to a networ

A Coupled Mathematical Model of the Intracellular Replication of Dengue Virus and the Host Cell Immune Response to Infection

Dengue virus (DV) is a positive-strand RNA virus of the Flavivirus genus. It is one of the most prevalent mosquito-borne viruses, infecting globally 390 million individuals per year. The clinical spectrum of DV infection ranges from an asymptomatic course to severe complications such as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the latter because of severe plasma leakage. Given that the outcome of infection is likely determined by the kinetics of viral replication and the antiviral host cell immune response (HIR) it is of importance to understand the interaction between these two parameters. In this study, we use mathematical modeling to characterize and understand the complex interplay between intracellular DV replication and the host cells' defense mechanisms. We first measured viral RNA, viral protein, and virus particle production in Huh7 cells, which exhibit a notoriously weak intrinsic antiviral response. Based on these measurements, we developed a detailed intracellular DV replication model. We then measured replication in IFN competent A549 cells and used this data to couple the replication model with a model describing IFN activation and production of IFN stimulated genes (ISGs), as well as their interplay with DV replication. By comparing the cell line specific DV replication, we found that host factors involved in replication complex formation and virus particle production are crucial for replication efficiency. Regarding possible modes of action of the HIR, our model fits suggest that the HIR mainly affects DV RNA translation initiation, cytosolic DV RNA degradation, and naïve cell infection. We further analyzed the potential of direct acting antiviral drugs targeting different processes of the DV lifecycle in silico and found that targeting RNA synthesis and virus assembly and release are the most promising anti-DV drug targets

Addressing current challenges in cancer immunotherapy with mathematical and computational modeling

The goal of cancer immunotherapy is to boost a patient's immune response to a tumor. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumor microenvironment, immune-modulating effects of conventional treatments, and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modeling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumor classification, optimal treatment scheduling, and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modelers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumor-immune biology. We conclude the review with recommendations for modelers both with respect to methodology and biological direction that might help keep modelers at the forefront of cancer immunotherapy development.Comment: Accepted for publication in the Journal of the Royal Society Interfac

Functional genomics of a symbiotic community : shared traits in the olive fruit fly gut microbiota

The olive fruit fly Bactrocera oleae is a major pest of olives worldwide and houses a specialized gut microbiota dominated by the obligate symbiont “Candidatus Erwinia dacicola”. Ca. E. dacicola is thought to supplement dietary nitrogen to the host, with only indirect evidence for this hypothesis so far. Here, we sought to investigate the contribution of the symbiosis to insect fitness and explore the ecology of the insect gut. For this purpose, we examined the composition of bacterial communities associated with Cretan olive fruit fly populations, and inspected several genomes and one transcriptome assembly. We identified, and reconstructed the genome of, a novel component of the gut microbiota, Tatumella sp. TA1, which is stably associated with Mediterranean olive fruit fly populations. We also reconstructed a number of pathways related to nitrogen assimilation and interactions with the host. The results show that, despite variation in taxa composition of the gut microbial community, core functions related to the symbiosis are maintained. Functional redundancy between different microbial taxa was observed for genes involved in urea hydrolysis. The latter is encoded in the obligate symbiont genome by a conserved urease operon, likely acquired by horizontal gene transfer, based on phylogenetic evidence. A potential underlying mechanism is the action of mobile elements, especially abundant in the Ca. E. dacicola genome. This finding, along with the identification, in the studied genomes, of extracellular surface structure components that may mediate interactions within the gut community, suggest that ongoing and past genetic exchanges between microbes may have shaped the symbiosis

Virus Replication Strategies and the Critical CTL Numbers Required for the Control of Infection

Vaccines that elicit protective cytotoxic T lymphocytes (CTL) may improve on or augment those designed primarily to elicit antibody responses. However, we have little basis for estimating the numbers of CTL required for sterilising immunity at an infection site. To address this we begin with a theoretical estimate obtained from measurements of CTL surveillance rates and the growth rate of a virus. We show how this estimate needs to be modified to account for (i) the dynamics of CTL-infected cell conjugates, and (ii) features of the virus lifecycle in infected cells. We show that provided the inoculum size of the virus is low, the dynamics of CTL-infected cell conjugates can be ignored, but knowledge of virus life-histories is required for estimating critical thresholds of CTL densities. We show that accounting for virus replication strategies increases estimates of the minimum density of CTL required for immunity over those obtained with the canonical model of virus dynamics, and demonstrate that this modeling framework allows us to predict and compare the ability of CTL to control viruses with different life history strategies. As an example we predict that lytic viruses are more difficult to control than budding viruses when net reproduction rates and infected cell lifetimes are controlled for. Further, we use data from acute SIV infection in rhesus macaques to calculate a lower bound on the density of CTL that a vaccine must generate to control infection at the entry site. We propose that critical CTL densities can be better estimated either using quantitative models incorporating virus life histories or with in vivo assays using virus-infected cells rather than peptide-pulsed targets

Dynamics of Naive and Memory CD4 T-cells in Chronically Infected HIV Patients Post-Injection of Down-Modulated CCR5 Memory CD4-Cells

HIV/AIDS, a sexually transmitted diseases continues to affect the lives of millions of individuals worldwide. This retrovirus targets CD4 T-cell populations, the main driver of the immune system by using the chemokine co-receptor 5 (CCR5). Despite the success of the highly active antiretroviral therapy in reconstituting the immune system, HIV infected individuals still suffer from low CD4 T-cell counts. Recently, researchers were able to highlight the success of immunotherapy in restoring the CD4 T-cell count. To further, investigate such importance, our collaborators at case Western University injected CCR5-down-modulated memory CD4 T-cells into 9 chronically infected HIV patients. Using a linear transitions from the naive to the effector memory state, a non linear ordinary differential equation model was used to model the experiment. Various data fitting techniques in Matlab Stan and Monolix software were used to estimate the model parameters (proliferation, death, transition and birth rates) before and after the initiation of the treatment to study the change of the cell dynamics. Our fittings have indicated an increase in the memory stem and na\"{\i}ve cell lifespan post-clinical trial. Using sensitivity analysis, we showed that the na\"{\i}ve cell birth rate from the thymus lambda, the memory stem cell proliferation rate p_ST and the central memory cell death rate d_C played an important role in restoring the CD4 T-cell count. A stochastic model for the CD4 T-cells population was developed to examine if fluctuations from the stochastic simulation were able to capture the experimental data measurements. The findings of this study indicates the importance of looking further into how modified CD4 T-cells are able to restore the T-cell counts which thereby decrease the HIV virus pool and help HIV patients to maintain a low level of the virus and most importantly a high level of T-cell count

Inheritance, differential expression, and candidate gene analyses for Avr2 in Phytophthora sojae

Phytophthora sojae is an oomycete responsible for seed, root and stem rot of soybean plants. Managing this disease relies on growing soybean cultivars with race-specific resistance (Rps) genes that deliver complete host immunity in the presence of corresponding pathogen avirulence (Avr) effector proteins. The aims of this study were to characterize virulence towards Rps2 among different P. sojae strains, track the inheritance of this trait, and attempt to identify an Avr2 gene. Fifteen P. sojae strains were tested for virulence towards Rps2 and crosses were performed between selected virulent and avirulent strains to follow the inheritance of virulence. Although parental strains were consistent in their virulence phenotype, many progeny were unstable. Of two candidate genes for Avr2 tested, neither showed co-segregation with the Rps2-virulence trait. Overall, results indicate that virulence towards Rps2 is inherited in a non-Mendelian fashion; the factors responsible could include epistasis, gene conversion, or other epigenetic phenomena

Implementation of functional safety in a robotic manufacturing cell using iec 61508 standard and siemens technology

The past 50 years have seen a staggering amount of change in the technology and the business of process automation. The programmable logic controller (PLC) based control and monitoring system is a proven technology used to not only control processes but also to perform safety functions for processes in many industrial applications. There are many opportunities for improvements in any process or manufacturing system. One of the opportunities is achieving accurate safety function for measurement and process control to prevent human injury or death. The programmable electronic systems (PES) such as PLC systems are increasingly being used to perform safety functions as an integral part of the process or plant control system. A Robotic Manufacturing Cell is an example of a PES system and is used as an experimental setup for this work. The IEC 61508 standard defines various phases involved in the overall safety lifecycle for the PES system. This thesis study concentrates on such phases that include safety analysis methods, selection of an appropriate safety control system, implementation of safety as per the standard and safety validation. In this study four test cases are selected to perform safety analysis and implementation. It is verified how the conventional safety analysis method (FMEA) can be used to estimate the risk associated with each test case. As recommended by IEC 61508, a Risk-Graph method is used to calculate the Safety Integrity Level (SIL) requirement for each test case. A number of factors are required to be considered for selecting the appropriate safety control system architecture. After studying these factors and the safety analysis results, the Siemens safety PLC-based control system with SIL 3 configuration is selected for this application. IEC 61508 also recommends implementation of independent control systems for normal operation and safety. This study demonstrates how two independent PLC based control systems, one for normal operations and other for safety-related functions, are implemented to offer the most effective solution for this application. This is achieved by using PLCs from two different manufacturers, a non-safety PLC for normal operations and a Siemens safety PLC for safety-related functions. This study focuses on Machine Safety, and it can be used as a guideline for implementation of functional safety in real-life manufacturing environment

SMC-based immunity against extrachromosomal DNA elements.

SMC and SMC-like complexes promote chromosome folding and genome maintenance in all domains of life. Recently, they were also recognized as factors in cellular immunity against foreign DNA. In bacteria and archaea, Wadjet and Lamassu are anti-plasmid/phage defence systems, while Smc5/6 and Rad50 complexes play a role in anti-viral immunity in humans. This raises an intriguing paradox - how can the same, or closely related, complexes on one hand secure the integrity and maintenance of chromosomal DNA, while on the other recognize and restrict extrachromosomal DNA? In this minireview, we will briefly describe the latest understanding of each of these complexes in immunity including speculations on how principles of SMC(-like) function may explain how the systems recognize linear or circular forms of invading DNA

Genetics of Coxiella burnetii: on the path of specialization

Coxiella burnetii is an extremely infectious, zoonotic agent that causes Q fever in humans. With the exception of New Zealand, the bacterium is distributed worldwide. Coxiella is classified as a select agent based on its past and potential use as a bioweapon and its threat to public health. Despite decades of research, we know relatively little regarding Coxiella?s molecular pathogenesis, and a vaccine is not widely available. This article briefly reviews the unusual genetics of C. burnetii; a pathogen that retains telltale genetic mementos collected over the course of its evolutionary path from a free-living bacterium to an obligate intracellular parasite of eukaryotic host cell phagosomes. Understanding why these genetic elements are maintained may help us better understand the biology of this fascinating pathogen