Date Published: July 4, 2013
Publisher: Public Library of Science
Author(s): Anna K. Coussens, Robert J. Wilkinson, Vladyslav Nikolayevskyy, Paul T. Elkington, Yasmeen Hanifa, Kamrul Islam, Peter M. Timms, Graham H. Bothamley, Alleyna P. Claxton, Geoffrey E. Packe, Mathina Darmalingam, Robert N. Davidson, Heather J. Milburn, Lucy V. Baker, Richard D. Barker, Francis A. Drobniewski, Charles A. Mein, Leena Bhaw-Rosun, Rosamond A. Nuamah, Christopher J. Griffiths, Adrian R. Martineau, Thomas R. Hawn.
Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin.
Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), emerged as a pathogen in Africa and has co-evolved with humans following migration to Europe and Asia some 70,000 years ago . Distinct phylogenetic lineages of MTB consistently associate with human populations of different genetic ancestry in a variety of settings – and elicit differing immune responses from antigen-presenting cells of healthy donors in vitro–. Antimycobacterial immune responses might therefore be expected to vary between TB patients of different ethnic origin; however, studies investigating this question have not been conducted. Demonstration of significant ethnic variation in inflammatory responses at presentation and after initiation of treatment would have implications for the development of immunodiagnostics and for the identification of surrogate endpoints for trials of antituberculous drugs.
Clinically significant ethnic differences in immune responses to Plasmodium falciparum and human immunodeficiency virus have previously been described , , but to our knowledge, this study is the first to address the question of whether inflammatory responses vary between TB patients of different ethnic origin. We report that inflammatory profiles vary significantly between TB patients of African and Eurasian ancestry having similar clinical and demographic characteristics, and that these differences associate primarily with ethnic variation in host rather than bacillary genotype. We also show that ethnic differences in inflammatory profiles observed at presentation persist after completion of intensive-phase therapy, and that immunological correlates of speed of sputum bacillary clearance differ markedly between patients of African vs. Eurasian ancestry. These findings have important implications for the design of studies investigating immunological biomarkers of response to antituberculous therapy.