Proposed strategies to improve tuberculosis (TB) control include the targeting of interventions, such as active case finding in
specific high-risk groups; therefore, it is essential to identify and characterize the determinants of TB risk so that resources
and interventions can be directed at those most likely to develop and transmit TB. On this, epidemiological studies have
established an association between diabetes mellitus (DM) and active TB demonstrating that diabetic patients have an
approximately three times higher risk of developing active TB. Since DM is increasingly widespread, including in developing
countries where exposure to TB is more likely, it represents a serious threat to TB control. Further solidifying the problem,
recent studies on the association between DM and TB that have addressed the manifestations and outcomes of TB therapy,
indicate that diabetic patients present increased time to culture conversion or higher rates of treatment failure.
Several factors might underlie the increased susceptibility of DM patients to TB, such as genetic background and/or social
factors responsible for increased susceptibility to both diseases. However, noticeably, the increased risk for TB among DM
individuals was observed predominantly among subjects with baseline hemoglobin A1c (HbA1C) greater than 7% indicating an
underlying factor of incorrect control status of DM. Interestingly, studies evaluating the immune system in DM patients have
also pointed to a direct correlation between chronic hyperglycaemia and alteration in the immune system, where a chronic
low-grade inflammation, and activation of the innate immune system, are implicated in disease pathogenesis and potential
compromising of the immune response to pathogens. On this, two well-described features of the immune system, frequently
present in DM patients, may be of particular relevance in the increased susceptibility to TB, namely:
1)Altered eicosanoids metabolism: The correct production of eicosanoids, particularly leukotrienes (LT) and prostaglandins
(PG), is essential for the establishment of a protective innate immune response. Altered production of some of these molecules
(PGE2 and LTB4, Annex1) have been clearly shown to promote necrosis, instead of apoptosis, of infected macrophages and/or
neutrophils, and consequently delaying the establishment of a protective immune response against TB. Studies show that the
production of these molecules is altered in DM patients.
2)Deregulated production of cytokines: An excessive pro-inflammatory profile has been repetitively described in DM patients.
While the production of pro-inflammatory cytokines is essential to mount a protective immune response to TB it is also clear
that too much of these cytokines are deleterious and promote mycobacterial growth.
From this background the aims of this proposal are:
1)dissect how DM-induced alteration on the immune system interfere with the immune response to mycobacterial antigens;
2)how these alterations (cor)relate with susceptibility to develop active TB, speed of culture conversion and rates of treatment
failure.
We will sample adequate study groups (healthy individuals, individuals with DM only, individuals with TB only, and individuals
with both DM and TB). Socio-demographics and known risk factors associated with TB and DM will be documented at
enrollment. DM characterization will be done (type, medication and control). Blood tests will complement self-reported HIV
status. Latent TB will be evaluated by tuberculin skin test and IFN-gamma release assay. Glycemic and lipidic study will be
performed and body index mass will be recorded. We will investigate specific parameters of the immune response upon
mycobacterial antigens stimuli: the production of the eicosanoids LTB4 and PGE2 by neutrophils and macrophages; the
balance necrosis/apoptosis of these cells; and the profile of cytokines produced by peripheral leukocytes.
In the northern region of Portugal there are 23 TB outpatient centers that diagnose and treat around 1000 new TB patients per
year. All TB outpatient clinics have been contacted and 20 centers agreed already in participating. At those TB outpatient
centers, TB patients older than 18 years will be prospectively identified (diabetes status will be assessed at enrolment). TB
diagnosis will be based on isolation of Mycobacterium tuberculosis. Healthy individuals and diabetic patients for whom TB
status is thought to be negative will be randomly selected from the primary physician list in the health centers in the area of
the TB outpatient clinic.
This investigation will provide evidence to propose directed interventions towards diabetic patients in order to tackle TB
infection and eventually to treat TB infection. A better understanding of the mechanisms responsible for the worse outcome of
TB treatment in this group of patients will allow adequate clinical decisions to improve treatment outcome.