Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment.
BACKGROUND
Currently, there are no tools to accurately predict tuberculosis relapse. This study aimed to determine whether patients who experience tuberculosis relapse have different immune responses to mycobacteria in vitro than patients who remain cured for 2 years.


METHODS
Patients with an initial episode of pulmonary tuberculosis were recruited in South Africa. Diluted blood, collected at diagnosis and after 2 and 4 weeks of treatment, was cultured with live Mycobacterium tuberculosis for 6 days, and cellular RNA was frozen. Gene expression in samples from 10 patients who subsequently experienced relapse, confirmed by strain genotyping, was compared to that in samples from patients who remained cured, using microarrays.


RESULTS
At diagnosis, expression of 668 genes was significantly different in samples from patients who experienced relapse, compared with expression in patients who remained successfully cured; these differences persisted for at least 4 weeks. Gene ontology and biological pathways analyses revealed significant upregulation of genes involved in cytotoxic cell-mediated killing. Results were confirmed by real-time quantitative reverse-transcription polymerase chain reaction analysis in a wider patient cohort.


CONCLUSIONS
These data show that patients who will subsequently experience relapse exhibit altered immune responses, including excessively robust cytolytic responses to M. tuberculosis in vitro, at the time of diagnosis, compared with patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited in drug development.
TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Jacqueline M
JM
Cliff
TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Jang-Eun
JE
Cho
TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Ji-Sook
JS
Lee
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences/MRC Centre for Molecular and Cellular Biology/DST NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
Katharina
K
Ronacher
TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Elizabeth C
EC
King
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences/MRC Centre for Molecular and Cellular Biology/DST NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
Paul
P
van Helden
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences/MRC Centre for Molecular and Cellular Biology/DST NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.
Gerhard
G
Walzl
TB Centre and Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Hazel M
HM
Dockrell
D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000276:immunology; D015415:Biomarkers; D001773:Blood Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009163:Mycobacterium bovis; D009169:Mycobacterium tuberculosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D055815:Young Adult
D000995:Antitubercular Agents; D001500:BCG Vaccine; D015415:Biomarkers; D012333:RNA, Messenger
blood; drug development; microarray; patient; transcriptomics