Bloom, CI; (2012) The Study of Blood Transcriptional Signatures to Improve Medical Management and Understanding of Active Pulmonary Tuberculosis and Similar Respiratory Diseases Including Sarcoidosis. Doctoral thesis , University College of London.

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Abstract

Tuberculosis is the leading cause of death from curable infectious diseases. New approaches for prevention, diagnosis, and treatment are urgently needed. Understanding the underlying immunopathogenesis is vital to achieve this. Transcriptional profiling of peripheral blood has been successfully applied to inflammatory and infectious diseases to improve understanding of disease mechanisms. Berry et al. 2010, recently revealed distinct transcriptional signatures of pulmonary tuberculosis, leading to new knowledge on tuberculosis pathogenesis. Transcriptional profiling also differentiated active TB from other infections and inflammatory diseases. This present study compared whole blood transcriptional profiles of pulmonary tuberculosis to the similar respiratory diseases sarcoidosis, community acquired pneumonia and primary lung cancer. Methods Microarray technology and data mining strategies were used to examine whole blood genome-wide transcriptional profiles from patients and controls, before and after treatment. Results Transcriptional profiles of tuberculosis and sarcoidosis were comparable to each other but disparate from pneumonia and lung cancer profiles. The dominant genes in the tuberculosis and sarcoidosis profiles were the over-abundance of interferon-inducible genes, the genes showed a higher expression in the tuberculosis patients. The dominant genes in the pneumonia and cancer profiles were the over-abundance of inflammation genes, and under-abundance of protein translation genes in the pneumonia profiles. 144-transcripts were able to distinguish the tuberculosis patients from all other samples with good sensitivity and specificity. The transcriptional profiles from the tuberculosis, pneumonia and sarcoidosis patients significantly changed after receiving successful treatment. The tuberculosis profiles significantly changed by two weeks after treatment initiation, earlier than any validated biomarker of treatment response. Conclusions This study has provided new insight into the parallels and differences of the molecular signatures of these similar respiratory diseases. The findings may have also revealed prospective pragmatic biomarkers for disease diagnosis and treatment monitoring which are being further investigated.

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