UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON
Grant: $225,000 - National Institutes of Health - Jul. 30, 2009
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Award Description: DESCRIPTION (provided by applicant): The growing pandemic of type 2 diabetes (DM) is being increasingly recognized as a threat to tuberculosis (TB) control. Epidemiological studies consistently show DM patients are more susceptible to TB, but the underlying mechanism is unclear. We recently showed that patients with DM and TB have hyperexpression of type 1 cytokines after stimulating white blood cells with a Mycobacterium tuberculosis extract. Despite mounting this apparently protective response, TB patients with DM take longer to clear M. tuberculosis during the course of treatment than non-DM patients. The higher IFN- ? levels (and higher bacterial burden) seen in mice with established M. tuberculosis infection and chronic diabetes is thought to be the consequence of a delayed innate response. These observations led us to hypothesize that inefficient bacterial containment in humans with DM is due to dysfunctional immunity that involves either an inability to mount a timely response, and/or a less effective response resulting from a specific immune defect. To explore these possibilities we propose a prospective case-control study examining whether newly-diagnosed TB patients with poorly- controlled DM (TB-DMp) differ in the recall response to a mycobacterial antigen from those with no DM and euglycemia (TB-noDM). Whole blood from participants will be incubated with M. tuberculosis whole cell lysate, and their stimulated plasma and white blood cells will be harvested at five time points during the first 24h of this recall response. We will evaluate the dynamics of cytokine and chemokine secretion (Aim 1) and the differential mRNA expression of an extended panel of immune system components (Aim 2) in the context of three stages: i) monocyte activation and differentiation into antigen presenting cells (innate response), ii) activation of memory T lymphocytes that may express cytokines associated with protection or exacerbation of TB (adaptive response), and iii) expression of effectors by macrophages or cytotoxic T lymphocytes that ultimately kill MTB (effector response). Alterations in the timing and/or type of recall response in TB-DMp patients will be established by longitudinal analysis using generalized estimating equations. The final model will take into account possible confounders and effect modifiers. These results will further provide a list of candidate molecules with altered expression in TB-DMp patients and the basis for selection of optimal time points to study each stage of response in future studies. The long-term goal is to understand the mechanisms explaining the association between TB and DM, to develop new recommendations for improved management and prevention of TB in DM patients. Our ability to propose studies on diseases that affects millions of patients worldwide rests on our access to a population of TB patients where 36% present DM, and our state-of-the art laboratory which is close to the TB clinics. PUBLIC HEALTH RELEVANCE: As the type 2 DM pandemic accelerates, there is a growing body of literature reporting increased susceptibility of these patients to pulmonary TB. In this project we will explore whether poor diabetes control compromises the immune response to mycobacteria. This is the first step towards understanding the biological basis of the association between these two diseases, and therefore designing strategies to manage these patients more efficiently.
Project Description: Aim 1. Compare the kinetics of T1 immunity in response to mycobacterial antigens in patients with TB and DM (TB-DM) versus TB without DM (TB-noDM). Aim 2. Determine whether monocytes from TB-DM patients have a compromised response to IFN-?, leading to failure in macrophage activation events associated with MTB killing. We are finalizing the preparation of the recombinant antigens to be used in the stimulation assays for Aims 1 and 2. Both ESAT-6 and CFP-10 have been isolated and we show it is antigenic for PPD+ individuals or for TB patients. Furthermore, the lower titer of the response to PPD-negative individuals shows that background levels are low, suggesting successful endotoxin removal (see Figure). Our next step will be to prepare the antigens for field use. We will titrate the ideal concentration after antigens are lyophilized into individual tubes that will be ready to begin stimulation at the field.
Jobs Summary: Field Coordinator @ 55% (Sept. 16, 2009 thru current) Job duties include assisting Dr. Restrepo by coordinating the activities at all sites, including the collection and transportation of specimens from the study sites to the Brownsville laboratories, keeping up with the IRB approval for both study sites, order reagents and supplies, coordinate specimen transportation between the Brownsville laboratory, translate documents (including IRBs) between English to Spanish. This individual will also enter the data for the Mexican site and manage the database. Phlebotomist @ 60% (Sept. 16, 2009 thru current) Job duties include contacting participants in Texas, inviting them to participate, carry out interview, collect blood and set up the whole blood assay, measure blood glucose on and coordinate with the field coordinator for the transportation of specimens to Brownsville. Graduate Student @ 50% (Sept. 16, 2009 thru current) This individual will be doing her thesis work under the direct supervision of Dr. Blanca Restrepo. This was defined once funding for Dr. Restrepo’s R21 was awarded with ARRA funds As of Oct. 1, the following will also be in place: 50% Graduate Student This individual will be able to continue her thesis work under the direct supervision of Dr. Blanca Restrepo. This was defined once funding for Dr. Restrepo’s R21 was awarded with ARRA funds. Without this funding, this job would not have been possible. 25% Lab Technician. This individual's job duties include conducting and coordinating the experiments on the specimens collected, preparing antigens for stimulation, ensuring batch quality control, writing and versing the Standard Operating Procedures for specimen collection and handling, ensuring quality control in specimen processing at the field sites, performing ELISA and Panomics assays, phosphoylation, cell separation, HbA1c testing, entering these data into the database, and conducting the sputum cultures. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
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