title: Temporal Expression of Peripheral Blood Leukocyte Biomarkers in a Macaca fascicularis Infection Model of Tuberculosis; Comparison with Human Datasets and Analysis with Parametric/Non-parametric Tools for Improved Diagnostic Biomarker Identification.
abstract: A temporal study of gene expression in peripheral blood leukocytes (PBLs) from a Mycobacterium tuberculosis primary, pulmonary challenge model Macaca fascicularis has been conducted. PBL samples were taken prior to challenge and at one, two, four and six weeks post-challenge and labelled, purified RNAs hybridised to Operon Human Genome AROS V4.0 slides. Data analyses revealed a large number of differentially regulated gene entities, which exhibited temporal profiles of expression across the time course study. Further data refinements identified groups of key markers showing group-specific expression patterns, with a substantial reprogramming event evident at the four to six week interval. Selected statistically-significant gene entities from this study and other immune and apoptotic markers were validated using qPCR, which confirmed many of the results obtained using microarray hybridisation. These showed evidence of a step-change in gene expression from an 'early' FOS-associated response, to a 'late' predominantly type I interferon-driven response, with coincident reduction of expression of other markers. Loss of T-cell-associate marker expression was observed in responsive animals, with concordant elevation of markers which may be associated with a myeloid suppressor cell phenotype e.g. CD163. The animals in the study were of different lineages and these Chinese and Mauritian cynomolgous macaque lines showed clear evidence of differing susceptibilities to Tuberculosis challenge. We determined a number of key differences in response profiles between the groups, particularly in expression of T-cell and apoptotic makers, amongst others. These have provided interesting insights into innate susceptibility related to different host `phenotypes. Using a combination of parametric and non-parametric artificial neural network analyses we have identified key genes and regulatory pathways which may be important in early and adaptive responses to TB. Using comparisons between data outputs of each analytical pipeline and comparisons with previously published Human TB datasets, we have delineated a subset of gene entities which may be of use for biomarker diagnostic test development.
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Sajid
authors.initials: S
authors.lastname: Javed
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Leanne
authors.initials: L
authors.lastname: Marsay
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Alice
authors.initials: A
authors.lastname: Wareham
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Kuiama S
authors.initials: KS
authors.lastname: Lewandowski
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Williams
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dennis
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Sally
authors.initials: S
authors.lastname: Sharpe
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Vipond
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Silman
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Public Health England, Infection Services, Health Protection Agency Porton, Porton Down, Salisbury, Wiltshire, United Kingdom.
authors.forename: Karen E
authors.identifier: 0000-0002-3059-9718
authors.initials: KE
authors.lastname: Kempsell
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D030541:Databases, Genetic; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D007962:Leukocytes / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D009169:Mycobacterium tuberculosis; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers