Abstract
The majority of Mycobacterium tuberculosis (Mtb) infections remain asymptomatic with only up to 10% progressing to clinical tuberculosis. However, the constituents of the effective “protective immunity” against tuberculosis responsible for containing most infections remain unknown. Evaluating gene transcriptional profiles in tuberculosis clinical cohorts is one approach to understanding the spectrum of tuberculosis progression. It is clear that apoptosis plays a role in the control of tuberculosis but the utility of apoptosis-related genes as surrogate markers of protection against tuberculosis has not been well investigated. To characterize potential surrogate markers that could discriminate different phases of the clinical tuberculosis spectrum, we investigated gene expression of several TNF-alpha dependent apoptotic genes (TNFR1, TNFR2, FLICE, FLIPs) by real-time RT-PCR of peripheral blood cells from cohorts of individuals with active tuberculosis or potential exposure to tuberculosis.Newly diagnosed tuberculosis patients (n = 23), their close household contacts (n = 80), and community controls (n = 46) were tested at intervals over a period of up to two years. Latent infection or previous Mtb contact was assessed by ELISPOT and TST and complete blood counts were performed during the follow up.Results showed significant upregulation of FLIPs expression by infected individuals regardless of clinical status at entry to the study. A higher percentage of lymphocytes was found in the infected household contacts that remained healthy. In contrast, in individuals with active TB, a significant upregulation of TNFR2 expression, a significantly higher percentage of monocytes and a significantly decreased lymphocyte count were seen, compared to subjects that remained healthy. Moreover, the household contacts who subsequently developed signs of TB also had a significantly high number of monocytes.These data suggest tuberculosis may be associated with decreased T-cell survival (perhaps due to apoptosis) while inhibition of apoptosis in monocytes could lead to a relative increase in these cells: a situation predicted to favour Mtb.
Highlights
It has been estimated that a third of the world population is infected with bacteria from the Mycobacterium tuberculosis complex (MTC)
A full set of results was available for 149 (23 IC, 80 household contacts (HC), 46 community controls (CC)) of the 163 subjects who agreed to participate in the study
Changes in the expression of TNF-associated apoptotic genes seemed to be associated with changes in the distribution of immune cells in the peripheral blood of various clinical groups defined on the basis of TB status
Summary
It has been estimated that a third of the world population is infected with bacteria from the Mycobacterium tuberculosis complex (MTC). These bacteria are the causal agents of tuberculosis (TB), a major cause of morbidity and mortality worldwide. Current diagnostic tests for tuberculosis can detect previous exposure to members of the MTC. These tests cannot distinguish between previous infection and active disease, and this greatly hampers TB control programs. As the protective immune response to TB in humans has not been clearly defined, it is difficult to identify the infected individuals likely to develop active disease and requiring treatment. The identification of risk factors for the development of active TB, and the monitoring of treatment success or of the protection provided by vaccines would all be vital steps towards containment of the TB epidemic [2], [3]
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