Uncontrolled diabetes, immune dysregulation and tuberculosis

点击翻译按钮获取中文摘要

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.