Molecular Signatures of Tuberculosis-Diabetes Interaction: Metabolomics Study

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Type 2 diabetes mellitus (DM) is an acquired host factor that increases the risk for and severity of pulmonary tuberculosis (PTB). A report published in 2007 estimated that, in India, DM accounted for 14.8% (range 7.1% to 23.8%) of PTB and 20.2% (8.3% to 41.9%) of smear-positive PTB. Emerging data from India suggest that the spectrum of host metabolic disorders adversely effecting TB defense may include dyslipidemia and dysglycemia below the diagnostic cutoff for DM classification. The global burden of TB attributable to the full spectrum of host metabolic disorders may therefore be substantially greater than current estimates. The ~3 fold greater individual TB risk with DM is one tenth the risk impact of HIV but there are ~10 times more people living with DM than with HIV making the population-attributable risk similar for these two conditions. DM prevalence is rising at the fastest rate in countries with high TB burden including India. New knowledge is urgently needed to identify modifiable factors influencing TB risk and disease outcomes in people living with DM, and to inform the rational development of strategies to address this significant barrier to global TB control.

An understanding of the mechanistic basis for TB susceptibility in DM is emerging from animal models but there are major gaps in validation and translation to the DM-TB interaction in humans. Susceptibility of diabetic mice is attributable to impaired sentinel function of alveolar macrophages (9). The delayed innate immune response to infection leads to delayed adaptive T cell priming that is required to control Mycobacterium tuberculosis (MTB) replication. Once underway, the cell-mediated immunity in diabetic mice controls MTB replication but with a greater burden of immune pathology than occurs in nondiabetic mice with TB. Large, multi-site, systems biology investigations are needed to conclusively determine whether unique and generalizable metabolomic TB-DM signatures exist. Understanding the human TB-DM interaction at this mechanistic level will inform the rational of management strategies and drugs aimed at preventing and treating TB disease in this vulnerable population. In addition to differences in lipidomic or metabolomics profiles at baseline (TB diagnosis), it is likely that comorbid DM hampers the resolution of inflammation and sterilization of TB lesions in response to anti-TB treatment (ATT). Characterizing longitudinal “omic” profiles could reveal signature characteristics that may be used to identify patients most likely to benefit from extended ATT or host-directed therapies to accelerate microbiological cure, minimize the exacerbation of vascular and renal complications of DM, and limit pulmonary impairment after TB. 
A refined understanding of the systems immunology of the TB-DM interaction using test and validation sets can only be achieved by coordinated analysis of clinical data and samples from large cohorts at multiple sites. Population and site-specific differences in host and microbial factors are certain to influence the TB-DM interaction in ways that may be mechanistically informative and that may reveal a need for interventions tailored to geographic and/or individual patient characteristics. The dual TB-DM burden is already acute in India. The CTRIUMPH study associated with RePORT India is well positioned to develop a multi-site project investigating the TB-DM interaction.

The overall objective of this study is to identify metabolomic signatures unique to PTB patients with DM and to characterize its change in response to ATT. In doing so, we hope to generate strong preliminary data for a programmatic grant application seeking funding for a comprehensive systems biology investigation of the TB-DM interaction in India.

Specific Aims 

  1. Compare baseline metabolomic signatures between newly diagnosed drug-sensitive PTB patients with and without DM.
  2. Characterize and compare longitudinal change in metabolomic signatures in response to ATT between newly diagnosed drug-sensitive PTB patients with and without DM.

University of Massachusetts Medical School, Worcester, MA

Instituto Brasileiro para a Investigacao da Tuberculose, Salvador, Brazil