Systems biology in animal sciences

Systems biology is a rapidly expanding field of research and is applied in a number of biological disciplines. In animal sciences, omics approaches are increasingly used, yielding vast amounts of data, but systems biology approaches to extract understanding from these data of biological processes and animal traits are not yet frequently used. This paper aims to explain what systems biology is and which areas of animal sciences could benefit from systems biology approaches. Systems biology aims to understand whole biological systems working as a unit, rather than investigating their individual components. Therefore, systems biology can be considered a holistic approach, as opposed to reductionism. The recently developed ‘omics’ technologies enable biological sciences to characterize the molecular components of life with ever increasing speed, yielding vast amounts of data. However, biological functions do not follow from the simple addition of the properties of system components, but rather arise from the dynamic interactions of these components. Systems biology combines statistics, bioinformatics and mathematical modeling to integrate and analyze large amounts of data in order to extract a better understanding of the biology from these huge data sets and to predict the behavior of biological systems. A ‘system’ approach and mathematical modeling in biological sciences are not new in itself, as they were used in biochemistry, physiology and genetics long before the name systems biology was coined. However, the present combination of mass biological data and of computational and modeling tools is unprecedented and truly represents a major paradigm shift in biology. Significant advances have been made using systems biology approaches, especially in the field of bacterial and eukaryotic cells and in human medicine. Similarly, progress is being made with ‘system approaches’ in animal sciences, providing exciting opportunities to predict and modulate animal traits

Systems biology applied to vaccine and immunotherapy development

Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses

The current state of animal models and genomic approaches towards identifying and validating molecular determinants of Mycobacterium tuberculosis infection and tuberculosis disease

Animal models are important in understanding both the pathogenesis of and immunity to tuberculosis (TB). Unfortunately, we are beginning to understand that no animal model perfectly recapitulates the human TB syndrome, which encompasses numerous different stages. Furthermore, Mycobacterium tuberculosis infection is a very heterogeneous event at both the levels of pathogenesis and immunity. This review seeks to establish the current understanding of TB pathogenesis and immunity, as validated in the animal models of TB in active use today. We especially focus on the use of modern genomic approaches in these models to determine the mechanism and the role of specific molecular pathways. Animal models have significantly enhanced our understanding of TB. Incorporation of contemporary technologies such as single cell transcriptomics, high-parameter flow cytometric immune profiling, proteomics, proteomic flow cytometry and immunocytometry into the animal models in use will further enhance our understanding of TB and facilitate the development of treatment and vaccination strategies

MicroRNAs as a Biomarker in Tuberculosis

Tuberculosis caused by Mycobacterium tuberculosis remains a global health challenge. New biomarkers that support rapid and accurate TB diagnosis are urgently needed. MicroRNAs (miRNAs) are small non-coding RNAs that have recently come into prominence as promising biomarkers. This thesis explores the application of miRNAs as biomarkers in tuberculosis and explores their expression in macrophages. Using real-time quantitative reverse transcriptase polymerase chain reaction panels we investigated the expression of 175 miRNAs in a test set of 20 pulmonary TB patients and 20 healthy controls. 87 miRNAs were differentially regulated. Ten miRNAs were selected for validation in a larger cohort with newly diagnosed pulmonary TB sampled before the commencement of antibiotic therapy and then over the course of therapy. From the ten miRNAs selected, five were differentially regulated in newly diagnosed TB subjects. The capacity of M. tuberculosis to modulate miRNA expression in human macrophages was examined. Seven miRNAs were examined in human macrophages with and without M. tuberculosis infection. The expression of miRNA in M. tuberculosis infected macrophages largely mirrored the findings from the plasma with a few exceptions. Based on the findings from this work, miRNAs demonstrate great promise in their role as a potential biomarker for TB diagnostics

Meta-analysis of host response networks identifies a common core in tuberculosis

Tuberculosis remains a major global health challenge worldwide, causing more than a million deaths annually. To determine newer methods for detecting and combating the disease, it is necessary to characterise global host responses to infection. Several high throughput omics studies have provided a rich resource including a list of several genes differentially regulated in tuberculosis. An integrated analysis of these studies is necessary to identify a unified response to the infection. Such data integration is met with several challenges owing to platform dependency, patient heterogeneity, and variability in the extent of infection, resulting in little overlap among different datasets. Network-based approaches offer newer alternatives to integrate and compare diverse data. In this study, we describe a meta-analysis of host’s whole blood transcriptomic profiles that were integrated into a genome-scale protein–protein interaction network to generate response networks in active tuberculosis, and monitor their behaviour over treatment. We report the emergence of a highly active common core in disease, showing partial reversals upon treatment. The core comprises 380 genes in which STAT1, phospholipid scramblase 1 (PLSCR1), C1QB, OAS1, GBP2 and PSMB9 are prominent hubs. This network captures the interplay between several biological processes including pro-inflammatory responses, apoptosis, complement signalling, cytoskeletal rearrangement, and enhanced cytokine and chemokine signalling. The common core is specific to tuberculosis, and was validated on an independent dataset from an Indian cohort. A network-based approach thus enables the identification of common regulators that characterise the molecular response to infection, providing a platform-independent foundation to leverage maximum insights from available clinical data

Increased Levels of BAFF and APRIL Related to Human Active Pulmonary Tuberculosis

BACKGROUND: Despite great efforts to improve diagnosis and treatment, tuberculosis (TB) remains a major health problem worldwide, especially in developing countries. Lack of concrete immune markers is still the obstacle to properly evaluate active TB. Therefore, identification of more validated biomarkers and phenotypic signatures is imperative. In particular, T cell-related biomarkers are more significant. METHODOLOGY: To understand the nature of CD4(+) T cell-derived signatures involved in infection and disease development, we examined and analyzed whole genome expression profiles of purified CD4(+) T cells from healthy individuals (HD), two distinct populations with latent infection (with low or high IFN-γ levels, LTB(L)/LTB(H)) and untreated TB patients. Following, we validated the expression profiles of genes in the peripheral CD4(+) T cells from each group and examined secretion levels of distinct cytokines in serum and pleural effusion. PRINCIPAL FINDINGS: Our bio-informatic analyses indicate that the two latent populations and clinical TB patients possess distinct CD4(+) T cell gene expression profiles. Furthermore, The mRNA and protein expression levels of B cell activating factor (BAFF), which belongs to the TNF family, and a proliferation-inducing ligand (APRIL) were markedly up-regulated at the disease stage. In particular, the dramatic enhancement of BAFF and APRIL in the pleural effusion of patients with tuberculosis pleurisy suggests that these proteins may present disease status. In addition, we found that the BAFF/APRIL system was closely related to the Th1 immune response. Our study delineates previously unreported roles of BAFF and APRIL in the development of tuberculosis, and these findings have implications for the diagnosis of the disease. Our study also identifies a number of transcriptional signatures in CD4(+) T cells that have the potential to be utilized as diagnostic and prognostic tools to combat the tuberculosis epidemic

The how and why of lncRNA function: An innate immune perspective.

Next-generation sequencing has provided a more complete picture of the composition of the human transcriptome indicating that much of the "blueprint" is a vastness of poorly understood non-protein-coding transcripts. This includes a newly identified class of genes called long noncoding RNAs (lncRNAs). The lack of sequence conservation for lncRNAs across species meant that their biological importance was initially met with some skepticism. LncRNAs mediate their functions through interactions with proteins, RNA, DNA, or a combination of these. Their functions can often be dictated by their localization, sequence, and/or secondary structure. Here we provide a review of the approaches typically adopted to study the complexity of these genes with an emphasis on recent discoveries within the innate immune field. Finally, we discuss the challenges, as well as the emergence of new technologies that will continue to move this field forward and provide greater insight into the biological importance of this class of genes. This article is part of a Special Issue entitled: ncRNA in control of gene expression edited by Kotb Abdelmohsen

Multi-omics technologies applied to tuberculosis drug discovery

Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound. Secondly, in a discovery chemistry approach, to identify the mode of action of lead compounds derived from high-throughput screens, progressing from compound to target. The advantage of multi-omics methodologies in both of these settings is that omics approaches are unsupervised and unbiased to a priori hypotheses, making omics useful tools to confirm drug action, reveal new insights into compound activity, and discover new avenues for inquiry. This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery