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

Sajid Javed, Leanne Marsay, Alice Wareham, Kuiama S. Lewandowski, Ann Williams, Michael Dennis, Sally Sharpe, Richard Vipond, Nigel Silman, Graham Ball, Karen E. Kempsell

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8 Citations (Scopus)

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.

Original languageEnglish
Article numbere0154320
JournalPLoS ONE
Volume11
Issue number5
DOIs
Publication statusPublished - 1 May 2016

Bibliographical note

Funding Information:
This study was funded by the Department of Health (DH) and Public Health England (PHE). The views expressed in this publication are those of the authors and not necessarily those of the PHE or the DH. We acknowledge Joanne Underwood for assistance with data analysis and compiling the manuscript and the Biological Investigations Group at PHE for conducting the animal procedures.

Publisher Copyright:
© 2016 Javed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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