In 2017, a RePORT International internal small grant program funded a cross-consortium (India, Brazil, and South Africa) project to study the important interaction between TB and Type 2 diabetes mellitus (DM). Type 2 DM is an acquired host factor that increases the risk for and severity of pulmonary tuberculosis.  Results from the Effects of Diabetes on Tuberculosis (EDOTS) study show that 54% of newly diagnosed adult TB patients in Chennai are diabetic and only 25% are normoglycemic. Emerging data from Brazil and India suggest that the spectrum of host metabolic disorders adversely affecting TB defense may include dyslipidemia and dysglycemia below the diagnostic cutoff for DM classification. We conclude that the global burden of TB attributable to the full spectrum of host metabolic disorders is substantially greater than current estimates.  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. 

 

Rationale

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 particular geographic and/or individual patient characteristics. The dual TB/DM burden is already acute in India and Brazil. The number of people living with DM in sub-Saharan Africa (35.4 million in 2015) is expected to reach 72.1 million in 2040. That is a greater proportionate increase than is predicted for any other region in the world, which raises the specter of complex and potentially devastating interaction of TB, DM, and HIV. The cohort research units associated with RePORT India, RePORT Brazil, and RePORT South Africa are well positioned to develop a multisite project investigating the TB-DM interaction.

Based on the stated magnitude of the problem and the investigators' plans for study, NIH/NIAID/DAIDS has provided funding to RePORT International investigators to work across three different RePORT consortia to analyze data and specimens collected in the context of RePORT studies to lay the foundation for a competitive NIH multiproject (PO1) proposal to investigate the interactions between these major communicable and noncommunicable diseases. The primary focus is on TB outcomes, but DM and HIV outcomes will be intertwined and add value to the program. The project received funding in 2016.  

 

Specific Aims

These aims reflect the goals of a comprehensive project spanning the three participating countries. Initial funding from DAIDS will be used to generate preliminary data for each of the aims to support a future PO1 proposal.   

Aim 1.   To define the spectrum of dysglycemia in TB patients from South Africa, Brazil, and India.

Aim 2.   To determine whether TB/DM comorbidity is associated with a qualitatively or quantitatively distinct baseline transcriptomic, proteomic, metabolomic, and/or lipidomic profiles compared to TB and/or DM alone.  

Aim 3.   To determine whether TB/DM comorbidity is associated with a qualitative or quantitative difference in the resolution of perturbed transcriptomic, proteomic, metabolomic, and/or lipidomic profiles during and after antimicrobial chemotherapy.

 

Investigators

RePORT Brazil: Bruno Andrade (FIOCRUZ); Timothy Sterling (Vanderbilt)

RePORT India: Padmapriya Darsini (NIRT); Amita Gupta (JHMI); Hardy Kornfeld (UMMS); Vidya Mave (BJMC); Vijay Viswanathan (MV Diabetes Research Center)

RePORT South Africa: Neil Martinson (PHRU); Jonathan Golub (JHMI)

RePORT International Coordinating Center (RICC): Carol Hamilton (FHI 360)