PIs: Damien Chaussabel and Anne O'Garra (The National Institute for Medical Research, London, UK)
Funding Organization: The Dana Foundation
Project Start: January 1, 2007
Project End: December 31, 2009
Abstract:
Tuberculosis (TB) is a major and increasing cause of morbidity and mortality worldwide caused by infection with the pathogen Mycobacterium tuberculosis (MTb). The diagnosis of pulmonary TB (PTB) is difficult, can take weeks or may require invasive procedures. Some individuals showing reactivity to MTb antigens, suggesting infection, but without evidence of active disease, are termed latent TB.
We cannot yet predict those that will develop active disease. Although deficiencies of individual components of the immune response have been shown to reduce protection against MTb, the contribution of these in individuals without such deficiencies has not been quantified, and it remains unknown why some infected individuals develop TB disease while the majority remains healthy, albeit with latent disease.
Blood constitutes an accessible source of clinically relevant information and a comprehensive molecular phenotype of blood cells can be obtained by generating microarray gene expression profiles. We postulate that whole blood from patients with TB will carry transcriptional signatures and provide a new perspective on mechanisms of immunopathogenesis and constitute a source of clinically relevant diagnostic and prognostic markers.
We also aim to identify factors in the global host response to MTb determining latency and active disease, how these factors are modified in active PTB by chemotherapy, and to identify biomarkers for the diagnosis of TB and monitoring of disease progression/response to treatment. This study will be conducted by a multidisciplinary team composed of clinicians and immunologists from St. Mary's Hospital and NIMR, London, together with immunologists and bioinformaticians at BIIR, Dallas.
Methodology: Three cohorts of patients will be recruited: (i) Potentially active PTB based on clinical diagnosis, subsequently confirmed MTb culture positive; (ii) latent TB; (iii) healthy volunteer controls. We will establish transcriptional signatures of patients with PTB and latent TB in comparison to healthy donors. Parallel immune phenotyping and immune reactivity studies will also be performed, that will support the interpretation of the microarray data and provide insight into mechanisms of disease pathogenesis.
Longitudinal samples from patients with confirmed active PTB will be analyzed. These patients will receive antibiotic therapy for six months, and their signature will then be compared to the baseline obtained from patients with latent TB, allowing comparison of the chemotherapy cured TB with latent TB.
We have now generated preliminary data from samples collected at St Mary's and shipped to BIIR for microarray analysis, showing the feasibility of the study. Most strikingly, a potent increase in expression of interferon (IFN) inducible genes was observed in a PTB patient. This potent increase in IFN inducible genes clearly demonstrates an expected detectable immune response to MTb infection and the feasibility of obtaining a meaningful transcriptional signature.
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